Uso de treprostinil sistémico en una paciente con hipertensión pulmonar grave, sin respuesta a la máxima terapia disponible / Use of treprostinil in a patient with a severe pulmonary arterial hypertension no responding to the maximal therapy available

En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.

In high risk Pulmonary Arterial Hypertension (PAH) patients with functional class (FC) IV, specific therapy must be combined and must include systemic prostacyclin (PGI2), meanwhile they are enlisted for double lung transplant (DLT). In Chilean Public Health System, nebulized Iloprost is the only PGI2 available to combine with Sildenafil and either Ambrisentan or Bosentan as endothelin receptor antagonist. This association is not enough for severe cases with right ventricular (RV) dysfunction. The first case from the National Institute of Thorax as a referral center is presented now in a 24 years-old lady treated with treprostinil. She has severe PAH with DLT indication. Treprostinil is a PGI2 analog, for subcutaneous use in a dose from 1 to 40 ng/kg/min. She was extremely sick, with FC IV, she walked < 300 m at 6 min walking test (6 MWT), presented pericardial effusion and severe RV dysfunction, with TAPSE (echocardiography index for RV dysfunction)=13 cm/s, ProBNP > 2,500 pg/ml. Six months after being at intensive care unit with triple therapy (Sildenafil, ambrisentan and nebulized Iloprost) plus oxygen, diuretics and milrinone, she was finally discharged after receiving a 3 weeks treprostinil course. She came back to work two months later and her condition was more stable: FC III, she walked > 440 m at 6MWT, with a significant improvement in RV function with TAPSE = 19. Although ProBNP decreased to 1,491pg/ml, it was still high, pointing out the progressive nature of her disease. However, she met a better clinical condition which allows her to reach a much better quality of life from a personal, familial and social point of view.

Análogos de prostaglandinas I2 (epoprostenol y treprostinil) para el tratamiento de la hipertensión pulmonar refractaria secundaria a displasia broncopulmonar en un lactante / Prostaglandin 12 analogs (epoprostenol and treprostinil) as a treatment for refractory bronchopulmonary dysplasia-induced pulmonary hypertension in an infant

La hipertensión pulmonar es una complicación frecuente de la displasia broncopulmonar. A pesar de su alta incidencia, existen pocos tratamientos disponibles. El epoprostenol y el treprostinil son análogos de las prostaglandinas I2, que activan la adenilato ciclasa e incrementan el adenosín monofosfato cíclico en las células de la musculatura lisa de la arteria pulmonar y pueden resultar eficaces en el tratamiento de estos pacientes. Se presenta el caso de un prematuro de extremado bajo peso con hipertensión pulmonar secundaria a displasia broncopulmonar grave, no respondedora a óxido nítrico inhalado y sildenafilo, que fue tratado con análogos de prostaglandinas I2. En nuestro paciente, este tratamiento evidenció mejoría clínica y ecocardiográfica significativa tras varias semanas de tratamiento.

Pulmonary hypertension is a common complication of bronchopulmonary dysplasia, with a high mortality rate. Despite the high incidence of pulmonary hypertension, there are few available treatments. Epoprostenol and treprostinil are prostaglandin I2 analogs that activate adenylate cyclase and increase cyclic adenosine monophosphate in the pulmonary arterial smooth muscle cells. Therefore, they may be an effective treatment for these patients. We report the use of prostaglandin I2 analogs in an extremely low birth weight preterm baby with severe bronchopulmonary dysplasia associated with pulmonary hypertension non-responding to inhaled nitric oxide and sildenafil. In our patient this treatment resulted in remarkable clinical and echocardiographic improvement, evident after a few weeks of treatment.

Tratamiento específico de la hipertensión arterial pulmonar. Experiencia de la policlínica de hipertensión pulmonardel Hospital Maciel, período 2009-2011 / Specific treatment of pulmonary arterial hypertension. Experience of the pulmonary hypertension clinic at the polyclinic Hospital Maciel, period 2009-2011

Introducción:la hipertensión pulmonar (HP) es una condición hemodinámica definida por un aumento de la presiónarterial pulmonar media (PmAP) 25 mmHg en reposo estimada mediante el cateterismo cardíaco derecho (CCD). Secomunica la experiencia adquirida en el diagnóstico, seguimiento y tratamiento de la hipertensión arterial pulmonar(HAP) y de la HP tromboembólica crónica (HPTEC) de la policlínica de HP del Hospital Maciel. Métodos: se analiza una cohorte de 15 pacientes (2009-2011). Se estimaron la clase funcional (CF), la prueba de caminata de 6 minutos (P6M), la excursión sistólica del plano del anillo tricuspídeo (ESPAT) y la velocidad sistólica pico(Sm). La severidad hemodinámica fue estimada por CCD. Se definió respuesta vasorreactiva aguda (RVA) positiva porel descenso de la PmAP 10 mmHg, alcanzando un valor absoluto 40 mmHg sin cambios o aumento del índice cardíaco (IC). Los datos se expresaron como media ± DS. Se empleó el test de t student pareado para comparar el efecto deltratamiento específico y el test de Kruskal-Wallis para comparaciones entre los grupos, con una p<0,05.Resultados:la edad promedio fue de 43 ± 12 años, 12 (80%) mujeres. Diez (67%) del grupo 1 y 5 (33%) del grupo 4. El20% se presentó en CF I-II y 80% en CF III-IV. El tiempo de seguimiento fue de 19 ± 11 meses. La ESPAT y la Sm basales fueron de 17 ± 7 mm y 11 ± 2 cm/s, respectivamente. La PmAP fue de 54 ± 15 mmHg, la presión auricular derecha 11± 6 mmHg, IC 2,1 ± 0,7 l/min/m2, resistencia vascular pulmonar 1.087 ± 625 dinas.s.cm-5, capacitancia pulmonar 1,3 ±0,6 ml/mmHg. Un paciente presentó RVA positiva. Se empleó sildenafil (100%), bosentan (50%) e iloprost (43%); en71% el tratamiento fue combinado. No se registró hepatotoxicidad por bosentan durante el período de seguimiento. Unpaciente murió por rechazo a recibir tratamiento específico. Los 14 pacientes restantes presentaron una mejoría de laCF (3,0 ± 0,8 versus 2,1 ± 0,8, p<0,05), así como de la P6M ...

Pulmonary arterial hypertension in children: a medical update.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.

Hipertensión pulmonar idiopática en pediatría: caso clínico y revisión de la literatura / Idiopathic pulmonary hypertension in pediatric age: a case report and review

Idiopathic pulmonary hypertension is a rare disease in the pediatric age. Symptoms are subtle in first stages delaying diagnosis and resulting in worst outcomes. Therefore pediatricians should be aware of the initial symptoms. We report the case of a 13 years oíd girl, who started with progressive dyspnea 9 months before diagnosis. She was admitted to our hospital because of productive cough, fever and shortness of breath. Chest X ray showed enlargement of right ventricle and pulmonary artery. Echocardiography was suggestive of pulmonary hypertension and the diagnosis was confirmed by cardiac catheterization. Work up far secondary causes of pulmonary hypertension was negative and pulmonary hypertension was considered idiopathic. Treatment with oxygen, diuretics, L-arginine, sildenafil, iloprost and acenocumarol was started with good clinical response.

La hipertensión pulmonar idiopática es de rara ocurrencia en la edad pediátrica siendo los síntomas iniciales muy sutiles e inespecíficos, lo que retarda el diagnóstico empeorando el pronóstico. Se presenta el caso de una niña 13 años, quien comienza con disnea progresiva 9 meses antes del diagnóstico. Ingresa por cuadro de tos húmeda, fiebre y dificultad respiratoria de 3 días de evolución. La radiografía de tórax muestra ventrículo derecho aumentado de tamaño y tronco de la arteria pulmonar prominente sospechándose una probable cardiopatía. Se realiza ecocardiografía que demuestra hipertensión pulmonar, la cual es corroborada por el sondeo cardíaco. Todos los exámenes de laboratorio fueron negativos para causas secundarias, estableciéndose el diagnóstico de hipertensión pulmonar idiopática. Se inicia manejo con oxígeno, diuréticos, L-arginina, sildenafil, iloprost nebulizado y acenocumarol, con lo cual la paciente evoluciona favorablemente.

Treatment of pulmonary arterial hypertension

OBJETIVO: Estabelecer uma revisão acerca do manejo diagnóstico e terapêutico da hipertensão pulmonar na população pediátrica, com ênfase nos aspectos farmacológicos. FONTES DOS DADOS: Busca eletrônica de publicações nas bases de dados MEDLINE/PubMed, LILACS e Cochrane Collaboration. Estabeleceu-se uma estratégia de busca priorizando a identificação de ensaios clínicos (controlados ou não controlados), revisões sistemáticas e diretrizes publicados nos últimos 10 anos. SíNTESE DOS DADOS: Muitos avanços têm sido incorporados ao conhecimento da hipertensão pulmonar nos últimos anos. Aspectos relativos a diferenças nos mecanismos fisiopatológicos da doença entre as diferentes faixas etárias têm modificado o tratamento e o prognóstico dos pacientes. Uma ação combinada de propriedades vasodilatadoras mais seletivas e ação antiproliferativa e o emprego de novas drogas representam princípios fundamentais das novas propostas terapêuticas. Para considerar benefícios associados à utilização dessas novas terapêuticas, é fundamental que cada paciente tenha a sua doença adequadamente diagnosticada, classificado o grau de comprometimento da doença e a sua capacidade de reatividade vascular estabelecida, o que é mais difícil na população pediátrica. CONCLUSÃO: Até o momento, não existe um tratamento que possa ser considerado ideal para o manejo da hipertensão pulmonar. Considerando a possibilidade do emprego de novas drogas, a maioria dos estudos existentes foi conduzida em populações adultas. Poucos dados são disponíveis para crianças, sendo a maioria ensaios clínicos não controlados e séries de casos. Considerando diferenças já estabelecidas entre os mecanismos da doença e aspectos prognósticos entre as diferentes faixas etárias, é difícil afirmar que tais drogas possam ser incorporadas, com as mesmas indicações e os mesmos resultados, ao tratamento da hipertensão pulmonar infantil.

OBJECTIVE: To perform a review of the diagnostic and therapeutic management of pulmonary hypertension in the pediatric population, with emphasis on pharmacological factors. SOURCES: Electronic search of publications on the MEDLINE/PubMed, LILACS and Cochrane Collaboration databases. The search strategy adopted gave priority to the identification of clinical trials (controlled or uncontrolled), systematic reviews and directives published during the last 10 years. SUMMARY OF THE FINDINGS: Many advances have been incorporated into our understanding of pulmonary hypertension during recent years. Issues related to differences in the pathophysiological mechanism of the disease between different age groups have altered both the treatment and prognosis of patients. The combined effect of more selective vasodilatory properties and antiproliferative action and the employment of new drugs are the basic principles of new treatment proposals. In order to be able to gauge the benefits associated with the use of these new therapies, it is of fundamental importance that all patients have their disease correctly diagnosed, the degree of functional compromise classified and their vascular reactivity capacity established, which is more difficult with pediatric patients. CONCLUSIONS: To date there is no treatment that can be considered ideal for the management of pulmonary hypertension. With reference to the possibility of employing new drugs, the majority of studies that have been published were undertaken with adult populations. Few data are available on children, and the majority of studies are uncontrolled trials or case series. Taking into account differences that have already been established between different age groups in terms of disease mechanisms and prognostic aspects, it is difficult to claim that these drugs can be incorporated into the treatment of childhood pulmonary hypertension with the same indications and results.

Actualización en el diagnóstico y terapéutica en hipertensión pulmonar arterial / Update in the diagnosis and therapy for pulmonary arterial hypertension

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.

Hipertensión pulmonar / Pulmonary hypertension

Pulmonary Hypertension is a term to describe the increase in the pulmonary arteries pressure. The primary pulmonary hypertension is an illness characterized by sustained elevation in the pulmonary arteries pressures; is a rare disease associated with a poor long-term prognosis. The development of new diagnostic tests and an appropriate classification of the pulmonary hypertension have improved the identification and treatment of the secondary causes resulting in an increased survival. Recent findings suggest a multifactorial etiology, including genetics mutations and environmental factors. The novel vasodilators drugs like prostacyclin have changed the natural history of pulmonary hypertension; consequently, the surgical strategies are currently indicated only in the case of failure of medical treatment. Despite of these advances, new investigations will be necessary to find the cure of the pulmonary hypertension.

Tratamiento con óxido nítrico inhalado en pacientes con hipertensión pulmonar / Treatment with inhaled nitric oxide in patients with pulmonary hypertension

Objetivo.Comparar la respuesta hemodinámica de óxido nítrico inhalado versus la respuesta a prostaciclina intravenosa.Metodología.Luego que el comité de investigación aprobó el estudio, 64 pacientes (rango de edad:9 meses a 38 años),con hipertensión pulmonrar(HP), fueron estudiados en el laboratorio de cateterismo cardíaco.Las presiones de la arteria pulmonar y presiones arteriales fueron tomadas directamente. El consumo de oxígeno fue medido (Waters MRM-2), y el gasto cardíaco fue calculado usando la ecuación de Fick.Siguiendo la línea base de las medidas hemodinámicas, los pacientes recibieron en el mismo orden,prostaciclina IV y el otro óxido nítrico inhalado de 20 a 80 p.p.m.Las mediciones fueron repetidas,la máxima respuesta fue tomada y el uso de droga se detuvo.Se tomaron de nuevo las mediciones de línea base antes que la segunda droga fuera administrada, y las mediciones se repitieron.Una disminución en la PAPm>20/100 fue considerada como una respuesta clínica. Los datos fueron analizados utilizando la prueba t, considerándose significativo una p<0.05. Resultados. Cincuenta pacientes cursaron con HP idiopática, 20 eran del sexo masculino, diez y seis pacientes tuvieron respuesta clínica al óxido nítrico inhalado y cuatro respondieron sólo a la prostaciclina. Conclusiones.Oxido nítrico inhalado y prostaciclina IV son efectivos en identificar los pacientes con HP con vasoreactividad pulmonar. El óxido nítrico inhalado no tiene efecto significativo en la presión arterial sistémica, mientras que la prostaciclina produce una disminución en la presión arterial media, así como aumento en el índice cardíaco.La respuesta negativa a un vasodilatador no implica respuesta negativa al otro.

Púrpura trombótica trombocitopénica: diagnóstico y tratamiento de dos casos / Thrombotic and thrombocytopenic purpura: diagnosis and management of two cases

Se presentan dos casos de púrpura trombótica trombocitopénica internados en nuestro servicio en quienes se instituyó un tratamiento combinado con infusiones de plasma, antiagregantes plaquetarios y corticoides, obteniéndose éxito en uno de ellos y fracaso en el otro. Se revisa la bibliografía mundial y se comentan las características clínicas y las modalidades terapéuticas utilizadas en la actualidad.