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Summary

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Summary

EL AVANCE EN EL TRATAMIENTO DE LA EPOC BASADO EN SÓLIDAS RAÍCES

El tratamiento con evidencia desde el inicio1

Mejora en eficacia: función pulmonar, calidad de vida y disnea vs. tiotropio1,2

En dispositivo RESPIMAT®3

1. Fergusson GT, Flezar M, Korn S et al. Efficacy of tiotropium+olodaterol in patients with chronic obstructive disease by initial disease severity and treatment intensity: a post hoc analysis. Adv Ther. 2015 Jun;32(6):523-36. 2. Buhl R, et al. Tiotropium plus olodaterol fixed-dose combination vs monocomponents in COPD (GOLD 2-4). Eur Respir J 201; 45: 969-979. 3. Ficha técnica Spiolto Respimat. Disponible en: http://www.aemps.gob.es/cima/dochtml/ft/79967/FichaTecnica_79967.html.

WWW.AVANCESENRESPIRATORIO.COM

Summary

1. NOMBRE DEL MEDICAMENTO Spiolto Respimat 2,5 microgramos/2,5 microgramos, solución para inhalación. 2. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA La dosis liberada es de 2,5 microgramos de tiotropio (como bromuro monohidrato) y 2,5 microgramos de olodaterol (como hidrocloruro) por pulsación. La dosis liberada es la dosis disponible para el paciente después de pasar por la boquilla. Para consultar la lista completa de excipientes, ver sección 6.1. 3. FORMA FARMACÉUTICA Solución para inhalación. Solución para inhalación transparente, incolora. 4. DATOS CLÍNICOS 4.1 Indicaciones terapéuticas Spiolto Respimat está indicado como tratamiento broncodi-latador de mantenimiento para aliviar los síntomas en pacientes adultos con enfermedad pulmonar obstructiva crónica (EPOC). 4.2 Posología y forma de administración Posología Este medicamento es únicamente para uso por vía inhalatoria. El cartucho sólo puede introducirse y utilizarse con el inhalador Respimat. Una dosis son dos pulsa-ciones del inhalador Respimat. Adultos La dosis recomendada es de 5 microgramos de tiotropio y 5 microgramos de olodaterol administrados en dos pulsaciones mediante el inhalador Respimat una vez al día y a la misma hora. No debe superarse la dosis recomendada. Población de edad avanzada Los pacientes de edad avanzada pueden utilizar Spiolto Respimat a la dosis recomendada. Insuficiencia hepática e insuficiencia renal Spiolto Respimat contiene tiotropio que se excreta predominantemente por vía renal y olodaterol que se metaboliza predominantemente en el hígado. Insuficiencia hepática Los pacientes con insuficiencia hepática leve o moderada pueden utilizar Spiolto Res-pimat a la dosis recomendada. No se dispone de datos sobre el uso de olodaterol en pacientes con insuficiencia hepática grave. Insuficiencia renal Los pacientes con insufi-ciencia renal pueden utilizar Spiolto Respimat a la dosis recomendada. En pacientes con insuficiencia moderada a grave (aclaramiento de creatinina ≤ 50 ml/min) ver 4.4 y 5.2. Spiolto Respimat contiene olodaterol. La experiencia con el uso de olodaterol en pacientes con insuficiencia renal grave es limitada. Población pediátrica No existe una reco-mendación de uso específica para Spiolto Respimat en la población pediátrica (menores de 18 años). Forma de administración Para asegurar la correcta administración del medicamento, el paciente debe ser instruido por un médico u otros profesionales sanitarios sobre cómo usar el inhalador. INSTRUCCIONES DE USO Y MANIPULACIÓN PARA EL PACIENTE 1) Introducción del cartucho Antes de la primera utilización debe seguir los pasos del 1 al 6: 1 Con la tapa verde claro (A) cerrada, presionar el cierre de seguridad (E) mientras se retira la base transparente (G). 2 Sacar el cartucho (H) de la caja. Empujar el extremo estrecho del cartucho dentro del inhalador hasta que haga clic. El cartucho debe empujarse firmemente contra una superficie firme para asegurar que se ha introducido completamente (2b). El cartucho no estará a ras del inhala-dor, verá la anilla plateada del extremo inferior del cartucho. No sacar el cartucho una vez se ha introducido en el inhalador. 3 Colocar nuevamente la base transparente (G). No volver a retirar la base transparente. 2) Preparación del inhalador Spiolto Respimat para la primera utilización 4 Sujetar el inhalador Spiolto Respimat en posición vertical, con la tapa verde claro (A) cerrada. Girar la base (G) en la dirección de las flechas rojas de la etiqueta hasta que haga clic (media vuelta). 5 Abrir completamente la tapa verde claro (A). 6 Dirigir el inhalador Spiolto Respimat hacia el suelo. Presionar el botón de liberación de dosis (D). Cerrar la tapa verde claro (A). Repetir los pasos 4, 5 y 6 hasta observar una nube. Después, repetir los pasos 4, 5 y 6 tres veces más para asegurar que el inhalador está listo para ser utilizado. Ahora su inhalador Spiolto Respimat está listo para ser utilizado. Estos pasos no afectan al número de dosis disponibles. Después de la preparación, su inhalador Spiolto Respimat podrá liberar 60 pulsaciones (30 dosis). Utilización diaria de su inhalador Spiolto Respimat Necesitará usar este inhalador SÓLO UNA VEZ AL DÍA. Cada vez que lo use, inhale DOS PULSACIONES. I Sujetar el inhalador Spiolto Respimat en posición vertical, con la tapa verde claro (A) cerrada, para evitar la liberación accidental de dosis. Girar la base (G) en la dirección de las flechas rojas de la etiqueta hasta que haga clic (media vuelta). II Abrir completamente la tapa verde claro (A). Espirar lenta y profundamente, luego cerrar los labios alrededor del final de la boquilla sin cubrir las válvulas de aire (C). Dirigir el inhalador Spiolto Respimat hacia la parte posterior de la garganta. Presionar el botón de liberación de dosis (D) mientras inspira lenta y profundamente a través de la boca y continuar inspirando lentamente tanto tiempo como pueda. Mantener la respiración du-rante 10 segundos o hasta que le sea posible. III Repetir los pasos I y II para completar la dosis. Necesitará usar este inhalador sólo UNA VEZ AL DÍA. Cierre la tapa verde claro hasta que vuelva a utilizar su inhalador Spiolto Respimat. Si no ha utilizado el inhalador Spiolto Respimat durante más de 7 días, libere una pulsación hacia el suelo. Si no ha utilizado el inhalador Spiolto Respimat durante más de 21 días, repita los pasos del 4 al 6 hasta que observe una nube. Entonces repita los pasos del 4 al 6 tres veces más. Cuándo cambiar el inhalador Spiolto Respimat El inhalador Spiolto Respimat contiene 60 pulsaciones (30 dosis). El indicador de dosis marca, aproximada-mente, cuánta medicación queda. Cuando el indicador alcance la zona roja de la escala, aproximadamente queda medicación para 7 días (14 pulsaciones). En este momento necesita una nueva receta médica de Spiolto Respimat. Una vez el indicador de dosis ha alcanzado el final de la zona roja (es decir, se han utilizado las 30 dosis), el inhalador Spiolto Respimat está vacío y se bloquea automáticamente. En este punto la base ya no puede girarse más. Como máximo, tres meses después de haber sido utilizado, el in-halador Spiolto Respimat debe desecharse aunque no haya sido utilizado todo el medicamento. Cómo mantener el inhalador Limpiar la boquilla incluyendo la parte metá-lica que se encuentra dentro de la misma, sólo con un trapo húmedo o un pañuelo, al menos una vez a la semana. Cualquier pequeña decoloración de la boquilla no afecta al funcionamiento del inhalador Spiolto Respimat. Si es necesario, limpiar con un trapo húmedo la parte exterior del inhalador Spiolto Respimat. 4.3 Contraindicaciones Hiper-sensibilidad a tiotropio u olodaterol o a alguno de los excipientes incluidos en la sección 6.1. Antecedentes de hipersensibilidad a atropina o sus derivados, p. ej. ipratropio u oxitropio. 4.4 Advertencias y precauciones especiales de empleo Asma Spiolto Respimat no debe ser utilizado para asma. La eficacia y seguridad de Spiolto Respimat en asma no han sido estudiadas. No para uso agudo Spiolto Respimat no está in-dicado en el tratamiento de episodios agudos de broncoespasmo, es decir, como tratamiento de rescate. Broncoespasmo paradójico Al igual que con otros fármacos administrados por vía inhalatoria, Spiolto Respimat puede causar broncoespasmos paradójicos que pueden ser potencialmente mortales. En caso de producirse un broncoespasmo paradójico, se debe interrumpir el tratamiento con Spiolto Respimat de inmediato y sustituir por un tratamiento alternativo. Efectos anticolinérgicos rela-cionados con tiotropio Glaucoma de ángulo estrecho, hiperplasia prostática u obstrucción del cuello de la vejiga Dada la actividad anticolinérgica de tiotropio, Spiolto Respimat debe utilizarse con precaución en pacientes con glaucoma de ángulo estrecho, hiperplasia prostática u obstrucción del cuello de la vejiga. Síntomas oculares Debe advertirse a los pacientes que eviten la introducción del spray en los ojos. Se les debe indicar que ello puede provocar o empeorar un glaucoma de ángulo estrecho, dolor o molestia ocular, visión borrosa transitoria, halos visuales o imágenes coloreadas, junto con enrojecimiento ocular por congestión de la conjuntiva y edema de la córnea. Si aparece cualquier combinación de estos síntomas oculares, los pacientes deben interrumpir el uso de Spiolto Respimat y consultar inmediatamente un especialista. Caries dental La sequedad de boca, observada con el tratamiento anticolinérgico, a largo plazo puede asociarse con caries dental. Pacientes con insuficiencia renal En pacientes con insuficiencia renal de moderada a grave (aclaramiento de creatinina ≤ 50 ml/min), Spiolto Respimat sólo debe utilizarse si el beneficio esperado supera el riesgo potencial, ya que la concentración plasmática de tiotropio aumenta cuando la función renal está disminuida. No existe experiencia a largo plazo en pacientes con insuficiencia renal grave. Efectos cardiovasculares Se excluyeron de los ensayos clínicos los pacientes con historia de infarto de miocardio durante el año an-terior, arritmia cardíaca inestable o potencialmente mortal, hospitalizados debido a insuficiencia cardíaca durante al año anterior o con diagnóstico de taquicardia paroxística (> 100 latidos por minuto). Por lo tanto, la experiencia en estos grupos de pacientes es limitada. Spiolto Respimat debe utilizarse con precaución en estos grupos de pacientes. Como con otros agonistas beta2-adrenérgicos, olodaterol puede producir un efecto cardiovascular clínicamente significativo en algunos pacientes medido por aumentos de la frecuencia del pulso, de la presión arterial y/u otros síntomas. En caso de producirse estos efectos, puede ser necesario interrumpir el tratamiento. Además, se ha notificado que los agonistas beta-adrenérgicos producen cambios en el electrocardiograma (ECG), como aplanamiento de la onda T y depresión del segmento ST, aunque se desconoce la relevancia clínica de estas observaciones. Los agonistas beta2-adrenérgicos de acción prolongada deben administrarse con precaución en pacientes con enfermedades cardiovasculares, particularmente enfermedad coronaria isquémica, descompensación cardíaca grave, arritmias cardíacas, cardiomiopatía hipertrófica obstructiva, hipertensión y aneurisma; en pacientes con trastornos convulsivos o tirotoxicosis; en pacientes con prolongación del intervalo QT o sospecha de prolongación del intervalo QT (p.ej. QT> 0,44 s) y en pacientes especialmente sensibles a los efectos de las aminas simpaticomiméticas. Hipopotasemia Los agonistas beta2-adrenérgicos pueden producir hipopotasemia significativa en algunos pacientes, lo cual puede aumentar el riesgo de que se produzcan efectos adversos cardiovasculares. El descenso de los niveles de potasio en sangre suele ser transitorio y no requiere suplementos. En pacientes con EPOC grave, la hipopotasemia se puede ver potenciada por la hipoxia y por el tratamiento concomitante (ver sección 4.5), lo que puede aumentar la susceptibilidad a las arritmias cardíacas. Hiper-glucemia La inhalación de dosis elevadas de agonistas beta2-adrenérgicos puede producir aumentos de la glucosa en sangre. Anestesia Se requiere precaución en el caso de intervención quirúrgica planificada con anestésicos de hidrocarburos haloge-nados debido al aumento de la susceptibilidad a los efectos cardíacos adversos de los agonistas beta broncodilatadores. Spiolto Respimat no debe utilizarse en combinación con otras medicaciones que contengan agonistas beta2-adrenérgicos de acción prolongada. A los pacientes que hayan estado tomando agonistas beta2-adrenérgicos de acción corta por vía inhalatoria de forma regular (p.ej. cuatro veces al día) se les debe indicar que sólo deben usarlos para el alivio de los síntomas respiratorios

Ficha técnica Inhalador Spiolto Respimat y cartucho Spiolto Respimat

Tapa (A)

Boquilla (B)

Válvulas de aire (C)

Botón de liberación de dosis (D)

Cierre de seguridad (E)

Base transparente (G)

Elemento perforador (I)

Indicador de dosis (F)

Cartucho (H)

lleno

vacío

cierre de seguridad

válvula de aire

1

5 6

2a 2b 3 4

I II III

Summary

agudos. Spiolto Respimat no debe usarse con una frecuencia superior a una vez al día. Hipersensibilidad Como con todos los medicamentos, pueden producirse reacciones de hipersensibilidad inmediata después de la administración de Spiolto Respimat. 4.5 Interacción con otros medicamentos y otras formas de interacción Aunque no se han realizado estudios formales de interacción entre fármacos in vivo con Spiolto Respimat y otros medicamentos, Spiolto Respimat inhalado se ha usado de manera simultánea con otros medicamentos para la EPOC, incluyendo broncodilatadores simpaticomiméticos de acción corta y corticosteroides inhalados sin evidencia clínica de interacciones entre fármacos. Agentes anticolinérgicos La administración conjunta de bromuro de tiotropio, un componente de Spiolto Respimat, con otros medicamentos anticolinérgicos no se ha estudiado por lo tanto no se recomienda. Agentes adrenérgicos La administración simultánea de otros agentes adrenérgicos (administrados solos o como parte de una terapia combinada) puede incrementar las reacciones adversas de Spiolto Respimat. Derivados de la xantina, esteroides o diuréticos La administración simultánea de derivados de la xantina, esteroides o diuré-ticos no ahorradores de potasio pueden incrementar los efectos hipopotasémicos de los agonistas adrenérgicos (ver sección 4.4). Betabloqueantes Los bloqueantes beta-adrenérgicos pueden atenuar o antagonizar el efecto de olodaterol. Se podría considerar la administración de betabloqueantes cardioselectivos, aunque éstos deben ser administrados con precaución. Inhibidores de la MAO y antidepresivos tricíclicos, fármacos prolongadores del intervalo QTc Los inhibidores de la monoaminooxi-dasa o los antidepresivos tricíclicos u otros fármacos que causan una prolongación del intervalo QTc pueden potenciar el efecto de Spiolto Respimat en el sistema cardiovascular. Interacciones farmacocinéticas entre fármacos No se ha observado un efecto relevante en la exposición sistémica a olodaterol en los estudios de interacciones entre fármacos con administración conjunta de fluconazol, utilizado como modelo de inhibición del CYP2C9. La administración conjunta de ketoconazol como in-hibidor potente de la gp-P y del CYP3A4 aumentó la exposición sistémica a olodaterol un 70%, aproximadamente. No es necesario un ajuste de dosis de Spiolto Respimat. Las investigaciones in vitro han mostrado que olodaterol no inhibe las enzimas CYP o los transportadores de fármacos a las concentraciones plasmáticas alcanzadas en la práctica clínica. 4.6 Fertilidad, embarazo y lactancia Embarazo Tiotropio Hay datos muy limitados relativos al uso de Spiolto Respimat en mujeres embarazadas. Los estudios en animales no sugieren efectos perjudiciales directos ni indirectos en términos de toxicidad para la reproducción a niveles de exposición clínicamente relevante. Olodaterol No hay datos clínicos disponibles sobre el uso de olodaterol du-rante el embarazo. Los datos no clínicos con olodaterol revelaron efectos típicos de otros agonistas beta2-adrenérgicos a dosis mayores a las terapéuticas. Como medida de precaución, es preferible evitar el uso de Spiolto Respimat durante el embara-zo. Como otros agonistas beta2-adrenérgicos, olodaterol, un componente de Spiolto Respimat, puede inhibir el parto debido a un efecto relajante sobre el músculo liso uterino. Lactancia No hay datos clínicos disponibles de mujeres lactantes expuestas a tiotropio y/o olodaterol. En estudios en animales con tiotropio y olodaterol, se han detectado las sustancias y/o sus metabolitos en la leche de ratas lactantes pero se desconoce si tiotropio y/o olodaterol se excretan en la leche materna. Se debe de-cidir si es necesario interrumpir la lactancia o interrumpir el tratamiento con Spiolto Respimat tras considerar el beneficio de la lactancia para el niño y el beneficio del tratamiento con Spiolto Respimat para la madre. Fertilidad No hay datos clínicos disponibles sobre el efecto en la fertilidad de tiotropio y olodaterol o la combinación de ambos componentes. Los estudios preclínicos realizados con los componentes individuales tiotropio y olodaterol no mostraron efectos adversos sobre la fertilidad. 4.7 Efectos sobre la capacidad para conducir y utilizar máquinas No se han realizado estudios de los efectos sobre la capacidad de conducir y utilizar máquinas. De todos modos, se debe informar a los pacientes de que se han notificado mareos y visión borrosa con el uso de Spiolto Respimat. Por ello, se recomienda tener precaución al conducir un coche o utilizar máquinas. Si los pacientes experimentan dichos síntomas, deben evitar realizar tareas potencialmente peligrosas como conducir o utilizar máquinas. 4.8 Reacciones adversas a. Resumen del perfil de seguridad Muchas de las reacciones adversas listadas pueden asignarse a las propiedades anticolinérgicas de bromuro de tiotropio o a las propiedades ß2-adrenérgicas de olodaterol, los componentes de Spiolto Respimat. b. Resumen tabulado de reacciones adversas Las frecuencias asignadas a las reacciones adversas listadas a continuación se basan en porcentajes de tasas de incidencia bruta de reacciones adversas al fármaco (es decir, acontecimientos atribuidos a Spiolto Respimat) observadas en el grupo de tiotropio 5 microgramos/olodaterol 5 microgramos (1.302 pacientes), recopiladas de 5 ensayos clínicos activos o controlados con placebo, con grupos paralelos, en pacien-tes con EPOC, con periodos de tratamiento en un rango de 4 a 52 semanas. Las reacciones adversas notificadas en todos los ensayos clínicos con Spiolto Respimat se muestran a continuación siguiendo la clasificación por órganos y sistemas. También se incluyen todas las reacciones adversas previamente notificadas con uno de los componentes individuales. La frecuencia se define según la siguiente convención: Muy frecuentes (≥1/10); frecuentes (≥1/100 a <1/10); poco frecuentes (≥1/1.000 a <1/100); raras (≥1/10.000 a <1/1.000); muy raras (<1/10.000); frecuencia no conocida (no puede estimarse a partir de los datos disponibles). Clasificación por órganos y sistemas Infecciones e infestaciones Reacción adversa Nasofaringitis Rara Clasificación por órganos y sistemas Trastornos del metabolismo y de la nutrición Reacción adversa Deshidratación No conocida Clasificación por órganos y sistemas Trastornos del sistema nervioso Reacción adversa Mareos Poco frecuente Reacción adver-sa Insomnio Poco frecuente Reacción adversa Cefalea Poco frecuente Clasificación por órganos y sistemas Trastornos oculares Reacción adversa Visión borrosa Rara Reacción adversa Glaucoma No conocida Reacción adversa Aumento de la presión intraocular No conocida Clasificación por órganos y sistemas Trastornos cardíacos Reacción adversa Fibrilación auricular Poco frecuente Reacción adversa Palpitaciones Poco frecuente Reacción adversa Taquicardia Poco frecuente Reac-ción adversa Taquicardia supraventricular Rara Clasificación por órganos y sistemas Trastornos vasculares Reacción adversa Hipertensión Poco frecuente Clasificación por órganos y sistemas Trastornos respiratorios, torácicos y mediastínicos Reacción adversa Tos Poco frecuente Reacción adversa Disfonía Rara Reacción adversa Epistaxis Rara Reacción adversa Laringitis Rara Reacción adversa Faringitis Rara Reacción adversa Broncoespasmo No conocida Reacción adversa Sinusitis No conocida Clasificación por órganos y sistemas Trastornos gastrointestinales Reacción adversa Sequedad de boca Frecuente Reacción adversa Estreñimiento Poco frecuente Reacción adversa Gingivitis Rara Reacción adversa Náuseas Rara Reacción adversa Candidiasis orofaríngea Rara Reacción adversa Obstrucción intestinal, incluyendo íleo paralítico No conocida Reacción adversa Caries dental No conocida Reacción adversa Disfagia No conocida Reacción adversa Reflujo gastroe-sofágico No conocida Reacción adversa Glositis No conocida Reacción adversa Estomatitis No conocida Clasificación por órganos y sistemas Trastornos de la piel y del tejido subcutáneo, trastornos del sistema inmunológico Reacción adversa Angioedema Rara Reacción adversa Urticaria Rara Reacción adversa Hipersensibilidad Rara Reacción adversa Prurito Rara Reacción adversa Reacción anafiláctica No conocida Reacción adversa Erupción No conocida Reacción adversa Piel seca No conocida Reacción adversa Infección de la piel/úlcera en la piel No conocida Clasificación por órganos y sistemas Trastornos musculoesqueléticos y del tejido conjuntivo Reacción adversa Dolor de espalda1 Rara Reacción adversa Artralgia Rara Reacción adversa Tumefacción en articulación No conocida Clasificación por órganos y sistemas Trastornos renales y urinarios Reacción adversa Retención urinaria Rara Reacción adversa Disuria Rara Reacción adversa Infección del tracto urina-rio No conocida .1 reacciones adversas notificadas con Spiolto Respimat pero no con los componentes individuales. c. Descripción de reacciones adversas seleccionadas Spiolto Respimat combina propiedades anticolinérgicas y β-adrenérgicas debido a sus componentes tiotropio y olodaterol. Perfil de reacciones adversas anticolinérgicas En los ensayos clínicos a largo plazo de 52 semanas de duración con Spiolto Respimat, la reacción adversa anticolinérgica observada más frecuentemente fue la se-quedad de boca que ocurrió en aproximadamente el 1,7% de los pacientes tratados con Spiolto Respimat y en 2,7% y 1% en los brazos de tiotropio 5 microgramos y olodaterol 5 microgramos, respectivamente. La sequedad de boca provocó el abando-no en 1 de 1.029 pacientes tratados con Spiolto Respimat (0,1%). Reacciones adversas graves relacionadas con efectos anticolinérgicos incluyen glaucoma, estreñimiento, obstrucción intestinal incluyendo íleo paralítico y retención urinaria. Perfil de reacciones adversas β-adrenérgicas En los ensayos clínicos a largo plazo de 52 semanas de duración con Spiolto Respimat, las reacciones adversas β-adrenérgicas observadas más frecuentemente fueron palpitaciones, taquicardia e hipertensión. Oloda-terol, un componente de Spiolto Respimat forma parte del grupo farmacoterapéutico de los agonistas beta2-adrenérgicos de acción prolongada. Por ello, debe considerarse la aparición de otros efectos adversos no listados arriba, relacionados con la familia de los agonistas beta-adrenérgicos tales como arritmia, isquemia miocárdica, angina de pecho, hipotensión, temblores, nerviosismo, espasmos musculares, fatiga, malestar, hipopotasemia, hiperglucemia y acidosis metabólica. d. Otras poblacio-nes especiales Puede ocurrir un aumento en el efecto anticolinérgico con el aumento de la edad. Notificación de sospechas de reacciones adversas Es importante notificar las sospechas de reacciones adversas al medicamento tras su autorización. Ello permite una supervisión continuada de la relación beneficio/riesgo del medicamento. Se invita a los profesionales sanitarios a notificar las sospechas de reacciones adversas a través del Sistema Español de Farmacovigilancia de Medicamentos de Uso Humano: www.notificaRAM.es 4.9 Sobredosis Hay información limitada sobre la sobredosis con Spiolto Respimat. Spiolto Respimat se ha estudiado a dosis de hasta 5 microgramos/10 microgramos (tiotropio/olodaterol) en pacientes con EPOC y a dosis de hasta 10 microgramos/40 microgramos (tiotropio/olodaterol) en sujetos sanos; no se observaron efectos clínicamente relevantes. Una sobredosis podría provocar efectos antimuscarínicos exagerados de tiotropio y/o efectos β2agonistas exa-gerados de olodaterol. Síntomas Sobredosis de tiotropio anticolinérgico Dosis elevadas de tiotropio pueden provocar la aparición de signos y síntomas anticolinérgicos. No obstante, después de la administración de una dosis única inhalada de hasta 340 microgramos de bromuro de tiotropio en voluntarios sanos, no hubo reacciones adversas anticolinérgicas sistémicas. Adicionalmente, no se observaron reacciones adversas relevantes más allá de sequedad de boca/garganta y sequedad de la mucosa nasal, tras la administración durante 14 días de una dosis de hasta 40 microgramos de tiotropio solución para inhalación en voluntarios sanos con la excepción de una reducción pronunciada en el flujo salival a partir del séptimo día. Sobredosis de oloda-terol β-agonista Una sobredosis de olodaterol probablemente provoque efectos exagerados típicos de los agonistas beta2-adrenérgicos, p.ej. isquemia miocárdica, hipertensión o hipotensión, taquicardia, arritmias, palpitaciones, mareo, nerviosismo, insomnio, ansiedad, cefalea, temblor, boca seca, espasmos musculares, náuseas, fatiga, malestar, hipopotasemia, hiperglucemia y acidosis metabólica. Tratamiento en caso de sobredosis El tratamiento con Spiolto Respimat debe ser interrumpido. Aplicar tratamiento de apoyo y sintomático. En casos graves se requiere hospitalización. Se puede considerar el uso de betabloqueantes cardioselectivos, pero sólo bajo vigilancia extrema ya que el uso de betabloqueantes adrenérgicos puede provocar broncoespasmo. 6. Datos farmacéuticos 6.1 Lista de excipientes Cloruro de benzalconio; Edetato disódico; Agua purificada; Ácido clorhídrico 1M (para ajustar el pH). 6.2 Incompatibilidades No procede. 6.3 Periodo de validez 3 años. Periodo de validez en uso: 3 meses. 6.4 Precauciones especiales de conservación No congelar. 6.5 Naturaleza y contenido del envase Tipo de envase y material en contacto con el medicamento: Solución contenida en un cartucho de polietileno/polipropileno con un tapón de polipropileno con un anillo de sellado de silicona integrado. El cartucho está incluido en un cilindro de aluminio. Cada cartucho contiene 4 ml de solución para inhalación. Tamaños de los envases y dispositivos disponibles: Envase indivi-dual: 1 inhalador Respimat y 1 cartucho que proporciona 60 pulsaciones (30 dosis). Envase doble: 2 envases individuales, cada uno contiene 1 inhalador Respimat y 1 cartucho que proporciona 60 pulsaciones (30 dosis). Envase triple: 3 envases individua-les, cada uno contiene 1 inhalador Respimat y 1 cartucho que proporciona 60 pulsaciones (30 dosis). Envase de ocho: 8 envases individuales, cada uno contiene 1 inhalador Respimat y 1 cartucho que proporciona 60 pulsaciones (30 dosis). Puede que solamente estén comercializados algunos tamaños de los envases. 6.6 Precauciones especiales de eliminación y otras manipulaciones La eliminación del medicamento no utilizado y de los materiales que hayan estado en contacto con él se realiza-rá de acuerdo con la normativa local. 7. Titular de la autorización de comercialización Boehringer Ingelheim International GmbH. Binger Strasse 173, D-55216 Ingelheim am Rhein. Alemania. 8. Número(s) de autorización de comercialización 79.967 9. fecha de la primera autorización/renovación de la autorización Junio 2015. 10. Fecha de la revisión del texto Mayo 2015. 11. Presentación y PVP Envase con un inhalador Respimat y un cartucho que contiene 60 pulsaciones (30 dosis). PVP IVA 81,49 € 12. Condiciones de prescripción y dispensación Con receta médica. Reembolsable por el Sistema Nacional de Salud. Medicamento de aportación reducida.

REVISTA ESPAÑOLA DE PATOLOGÍA TORÁCICA

Summary

98

Managing EditorAntonio Álvarez Kindelán (Córdoba)

Associate EditorRut Ayerbe García. (Huelva)

Drafting CommitteeBernardino Alcázar Navarrete (Granada)Virginia Almadana Pacheco (Sevilla)Ricardo Arrabal Sánchez (Málaga)Candelaria Caballero Eraso (Sevilla)José Calvo Bonachera (Almería)Adolfo Domenech del Río (Málaga)Dionisio Espinosa Jiménez (Cádiz)Nuria Feu Collado (Córdoba)German García de Vinuesa Calvo (Mérida)Bernabé Jurado Gámez (Córdoba)Paula Moreno Casado (Cordoba)Alicia Padilla Galo (Marbella)Gerardo Pérez Chica (Jaén)

Editorial BoardInmaculada Alfageme Michavila (Sevilla)María del Sol Arenas de Larriva (Córdoba) Manuel Arenas Gordillo (Sevilla)Emilia Barrot Cortes (Sevilla)Ana Isabel Blanco Orozco (Sevilla)Alberto Beiztegui Sillero (Sevilla)Carmen Carmona Bernal (Sevilla)Luis Fdo. Cassini Gómez de Cádiz (Granada)M.ª del Pilar Cejudo Ramos (Sevilla)Manuel Cepero Valdés (La Habana-Cuba)

Pilar Cordero Montero (Badajoz)Jaime Corral Peñafiel (Cáceres)Francisco Javier Cosano Povedano (Córdoba)Antonio Cueto Ladrón de Guevara (Granada)Daniel del Castillo Otero (Jerez de la Frontera, Cádiz)José Luis de la Cruz Ríos (Málaga)Carlos Disdier Vicente (Cáceres)Teresa Elías Hernández (Sevilla)Victor M. Encinas Tobajas (Sevilla)Luis Manuel Entrenas Costa (Córdoba)Javier Fernández de Córdoba Gamero (Huelva) José Fernández Guerra (Málaga)Enrique García Martínez (Granada)Rafael García Montesinos (Málaga)Cayo J. García Polo (Cádiz)Marcos García Rueda (Málaga)Arturo Gómez González (México)Lourdes Gómez Izquierdo (Sevilla)Jesús Grávalos Guzmán (Huelva)Jacinto Hernández Borge (Badajoz)Fernando Hernández Utrera (Huelva)Pilar Íñigo Naranjo (Badajoz)Luis Jara Palomares (Sevilla) Rafael Jiménez Merchán (Sevilla)Rafael Lama Martínez (Córdoba)Antonio León Jiménez (Cádiz)José Luis López-Campos Bodineau (Sevilla)Francisco Marín Sánchez (Málaga)Francisca Lourdes Márquez Pérez (Badajoz)Antonio Martín Ucar (Reino Unido)Juan Fernando Masa Jiménez (Cáceres)

Juan Fco. Medina Gallardo (Sevilla)Teodoro Montemayor Rubio (Sevilla)Antonio Pereira Vega (Huelva)Antonio M. Pérez Fernández (Badajoz)Francisco Ortega Ruiz (Sevilla)Remedios Otero Candelera (Sevilla)Andrés Palomar Lever (México)Elvira Pérez Escolano (Jerez de la Frontera)Esther Quintana Gallego (Sevilla)Florencio Quero Valenzuela (Granada)Juan Antonio Riesco Miranda (Cáceres)Ignacio Rodríguez Blanco (Badajoz)Francisco Rodríguez Panadero (Sevilla)José A. Rodríguez Portal (Sevilla)Mª Auxiliadora Romero Falcón (Sevilla)Ana Dolores Romero Ortiz (Granada)Pedro José Romero Palacios (Granada) Beatriz Romero Romero (Sevilla)Fernando Romero Valero (Cádiz)José Antonio Ruiz Navarrete (Viena)Ángel Salvatierra Velázquez (Córdoba)Mª Ángeles Sánchez Armengol (Sevilla)Julio Sánchez de Cos Escuín (Cáceres)Francisco Santos Luna (Córdoba)Dolores Sebastián Gil (Málaga) Agustín Sojo González (Cáceres)J. Gregorio Soto Campos (Jerez de la Frontera)José M. Vaquero Barrios (Córdoba)Rosa Vázquez Oliva (Huelva)Rosario Ysamat Marfá (Córdoba)

Published by Asociación de Neumología y Cirugía Torácica del Sur

Drafting and Administration

Southern Pulmonology and Thoracic Surgery Association

Technical SecretariatC/ Virgen de la Cinta, 21Edificio Presidente B-2, 11º C. 41011 SevillaTel.: 954 28 27 37 – Fax: 954 27 60 80e-mail: neumosur@neumosur. nethttp://www.neumosur.net© Copyright 2017 Southern Pulmonology and Thoracic Surgery Association All rights reserved

Layout design: Neumosur

The Spanish Journal of Thoracic Disease (Revista Española de Patología Torácica) is the Official Journal of the Southern Pulmonology and Thoracic Surgery Association.Included in the Spanish Medical Index (Índice Médico Español).Nationally distributed quarterly publication, with four issues per year.Forum which includes articles on basic science, medical illness and thoracic surgery.The Spanish Journal of Thoracic Disease is exclusively distributed among medical professionals.Articles undergo a critical review by two editors before being accepted for the publication.The Southern Pulmonology and Thoracic Surgery Association does not necessarily share the opinions expressed in this journal.

Key title: Rev Esp Patol Torac

Legal deposit. S. 872-2009ISSN: 1889-7347

Neumosur Board of Directors

ChairAurelio Arnedillo Muñoz

Vice-chairJuan Fco. Medina Gallardo

General SecretaryEduardo Márquez Martín

TreasurerJesús Fdo. Sánchez Gómez

Thoracic Surgery MemberFlorencio Quero Valenzuela

Western Andalusia MemberEva Vázquez Gandullo

Eastern Andalusia MemberMercedes Martín Romero

Extremadura MemberJuan José Garrido Romero

Young Doctors MemberMarta Entrenas Castillo

Institutional and Professional RelationsFrancisco Casas Maldonado

Editor-in-ChiefAurelio Arnedillo Muñoz (Cádiz)

Assistant EditorCarmen Calero Acuña (Sevilla)

http://www.neumosur.net

99


Summary

OriginalsAnti-fibrotic treatment in idiopathic pulmonary fibrosis; Our real-life experienceF. Díaz Chantar, J. Martín Juan, L. Gómez Izquierdo, S. Navarro Herrero, M.P. Serrano Gotarredona, J.A. Rodríguez Portal ............................................................................................................... 102 The influence of comorbidities in the mortality of patients with stable COPDA. Arnedillo Muñoz, J.L. López Campos, F. Casas Maldonado, P. Cordero Montero, I. Alfageme Michavila .................................................................................................................................................. 109

The usefulness of transcutaneous monitoring of CO2 during a sleep study in the Sleep Disorder UnitM. Sánchez Bommatty, M. Merino Sánchez, A. León Jiménez, M.P. Foncubierta Fernández, F. Fernández Pérez .............................................................................................................................. 117

Algorithm to eliminate inhaled corticoids in COPDF. M. Páez Codeso, A. Dorado Galindo, D. Jiménez Fernández, M. Arroyo Varela, M. García Rueda, J. L. de la Cruz Ríos .......................................................................................................................... 125

Special articleAlgorithm for the Withdrawal of Inhaled Corticosteroids in COPDA. Arnedillo Muñoz, F. Carboneros de la Fuente, F. Casas Maldonado, J.D. García Jiménez, R. Gimeno Galván, A. Hidalgo Molina, C. Merinas López, E. Molina Ortiz, G. Pérez Chica, M.A. Sánchez Quiroga, J.G. Soto Campos, A. Valido Morales, E. Vázquez Gandullo .............................................................................................................................. 136

ImageLung tumor, thrombotic microangiopathy; an infrequent presentation in breast cancerE. Moya Sánchez, N. Romera Romera, E. Ruiz Carazo ............................................................................................................................................................................................................................................. 141

Residents’ presentationNon-Surgical Procedures for Lung Cancer StagingM.H. Reyes Cotes, J.M. Sánchez Nieto ........................................................................................................................................................................................................................................................................... 143

Volume 29. Issue 2. June 2017Table of Contents,


Summary

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OriginalesTratamiento antifibrótico en la fibrosis pulmonar idiopática. Nuestra experiencia en la vida realF. Díaz Chantar, J. Martín Juan, L. Gómez Izquierdo, S. Navarro Herrero, M.P. Serrano Gotarredona, J.A. Rodríguez Portal ............................................................................................................... 102 Influencia de las comorbilidades en la mortalidad de pacientes con EPOC establesA. Arnedillo Muñoz, J.L. López Campos, F. Casas Maldonado, P. Cordero Montero, I. Alfageme Michavila ................................................................................................................................................. 109

Utilidad de la monitorización transcutánea de CO2 durante el registro polisomnográfico en una unidad de sueñoM. Sánchez Bommatty, M. Merino Sánchez, A. León Jiménez, M.P. Foncubierta Fernández, F. Fernández Pérez ............................................................................................................................. 117

Análisis descriptivo de 10 años de broncoscopia terapéutica intervencionistaF. M. Páez Codeso, A. Dorado Galindo, D. Jiménez Fernández, M. Arroyo Varela, M. García Rueda, J. L. de la Cruz Ríos .......................................................................................................................... 125

Artículo especialAlgoritmo de retirada de corticoides Inhalados en la EPOCA. Arnedillo Muñoz, F. Carboneros de la Fuente, F. Casas Maldonado, J.D. García Jiménez, R. Gimeno Galván, A. Hidalgo Molina, C. Merinas López, E. Molina Ortiz, G. Pérez Chica, M.A. Sánchez Quiroga, J.G. Soto Campos, A. Valido Morales, E. Vázquez Gandullo .............................................................................................................................. 136

ImagenMicroangiopatía trombótica tumoral pulmonar, una forma infrecuente de presentación de cáncer de mamaE. Moya Sánchez, N. Romera Romera, E. Ruiz Carazo ............................................................................................................................................................................................................................................. 141

Ponencia de residentesProcedimientos de estadificación no quirúrgicos en el cáncer de pulmónM.H. Reyes Cotes, J.M. Sánchez Nieto ........................................................................................................................................................................................................................................................................... 143

Volumen 29. Número 2. Junio, 2017SUMARIO


Summary

101

ANTIFIBROTIC THERAPY FOR IDIOPATHIC PULMONARY FIBROSIS: OUR REAL-LIFE ExPERIENCE

Díaz Chantar F., et al. The results for 27 patients diagnosed with idio-pathic pulmonary fibrosis are presented following ATS/ERS 2011 criteria, 8 of whom received pirfenidome treatment and 19 of whom received treatment with nintedanib. Both treatments were well tolerated with side effects such as digestive symptoms and mild photosensitivity. Rev Esp Patol Torac 2017; 29 (2): 102-106

INFLUENCE OF COMORBIDITIES IN STABLE COPD PA-TIENT MORTALITY

Arnedillo Muñoz A., et al. Prospective study on mortality associated with comorbidities among stable COPD patients.A high prevalence of comorbi-dities has been observed.The number of comorbidities and the existence of anxiolytic treatment were associated with higher mortality.Mortality was hig-her among those COPD patients with 2 or more comorbidities. Rev Esp Patol Torac 2017; 29 (2): 109-116

THE PRACTICALITY OF TRANSCUTANEOUS CO2 MONI-TORING DURING POLYSOMNOGRAM RECORDING IN A SLEEP UNIT

Sánchez Bommatty M., et al. The practicality of transcutaneous CO2 mon-itoring in baseline sleepstudies and CPAP and BIPAP titration in patients with SAHS and OHS. Hypoventilation is detected in many patients, without mon-itoring intolerance or side effects.We believe that it can be useful for a variety of sleep-related breathing disorders. Rev Esp Patol Torac 2017; 29 (2): 117-124

ANáLISIS DESCRIPTIvO DE 10 AñOS DE BRONCOSCOPIA TERAPéUTICA INTERVENCIONISTA

Páez Codeso F. M., et al. We have completed a review of our case histories as it has been 10 years since interventional bronchoscopy was implemented in our center.This paper describes the characteristics of patients who have un-dergone said treatment, the type of lesion, survival and intervention technique used.The discussion analyzes our cases, taking advantage of a brief bibliogra-phical review. Rev Esp Patol Torac 2017; 29 (2): 125-133

Volume 29. Issue 2. June 2017

SUMMARIES OF THE ARTICLES

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Summary

Rev Esp Patol Torac 2017; 29 (2) 102-106

ORIGINALS

Antifibrotic therApy for idiopAthic pulmonAry fibroSiS: our reAl-life experience

F. Díaz Chantar1, J. Martín Juan1, L. Gómez Izquierdo2, S. Navarro Herrero3, M.P. Serrano Gotarredona3, J.A. Rodríguez Portal1, 4.1Unidad Médico-Quirúrgica de Enfermedades Respiratorias. Servicio de Neumología HHUU Virgen del Rocío. Sevilla. 2Unidad de Gestión de Anatomía Patológica. HHUU Virgen del Rocío. Sevilla. 3Unidad de Gestión de Radiología. HHUU Virgen del Rocío. Sevilla. 4CIBERES, Instituto Carlos III

AbstractIdiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneu-monias, It is a fibrosing, chronic and progressive pneumonia, limited to the lung,cause unk-nown, with malicious prognosis, without curative treatment in this moment. Is characterized for a radiological and histological pattern of Usual Interstitial Pneumonia (UIP).Especially affectsover 50 years old. Its evolution is unpredictable at the time of diagnosis conditioning a progressive decrease in lung function.Currently, there are antifibrotic treatments that have proven effective in Progression of the disease and, therefore, improving the prognosis1. Regarding the use of these treatments in real life, outside the clinical trials.objetive: We present the results of the follow-up of 27 patients diagnosed withidiopathic pulmonary fibrosis, according to ATS / ERS 2011 criteria2, 8 of them being treated with pir-fenidone and 19 on treatment with nintedanib. Both treatments have been well tolerated, its adverse events have been digestive symptons and photosensibility.

Key words: Idiopathic pulmonary fibrosis, pirfenidona, nintedanib, antifibrotics

Received: June 21, 2016. Accepted: February 12, 2017.

Fátima Díaz [email protected]

trAtAmiento AntifibrÓtico en lA fibroSiS pulmonAr idiopÁ-ticA. nueStrA experienciA en lA VidA reAl

resumenLa fibrosis pulmonar idiopática (FPI) es la forma más común de las neumonías intersticiales idiopáticas. Es una neumonía fibrosante, crónica y progresiva, limitada al pulmón, de causa desconocida, con mal pronóstico y, hasta el momento, sin tratamiento curativo. Se caracteriza por un patrón radiológico e histológico de Neumonía Intersticial Usual (NIU).Afecta sobre todo a adultos mayores de 50 años. Su evolución es impredecible en el momento del diagnós-tico, condicionando una disminución progresiva de la función pulmonar.Actualmente, existen tratamientos antifibróticos que han demostrado eficacia en frenar la progresión de la enfermedad y, por tanto, mejorando el pronóstico1. Existe poca información con respecto al uso de estos tratamientos en la vida real, fuera del ámbito de los ensayos clínicos.Presentamos los resultados del seguimiento de 27 pacientes diagnosticados de fibrosis pul-monar idiopática, según los criterios de la ATS/ERS 20112, 8 de ellos en tratamiento con pirfenidona y 19 en tratamiento con nintedanib. Ambos tratamientos han sido bien tolerados, siendo sus efectos adversos más comunes los síntomas digestivos y la fotosensibilidad, de carácter leve.

palabras clave: Fibrosis pulmonar idiopática, pirfenidona, nintedanib, antifibróticos.

mailto:fdchantar%40gmail.com?subject=Revista%20Neumosur

103 Rev Esp Patol Torac 2017; 29 (2) 102-106

F. Díaz Chantar et al. Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis: Our Real-life Experience

Summary

introduction Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia. It is a chronic and progressive pneumonia which leads to fibrosis. Limited to the lungs with an unknown origin and poor prognosis, until now there has been no curative treatment. The average survival rate is estimated to be between 3 and 5 years from the onset of symptoms3. There are currently antifibrotic therapies available which can slow down the progression of the disease. Both pirfenidome and nintedanib have prov-en to be effective in decreasing the rate of deterioration in lung function, measured in terms of forced vital capacity (FVC); they manage to slow the progression of the disease and, in the case of pirfenidome, data shows an increased survival rate4. In general, the treatments are well tolerated according to data from clinical trials and they produce few side effects, those that do appear being easy to manage. As of now, there is little information about the response to these treatments outside of clinical studies. Both treatments are approved for mild-moderate IPF when FVC is greater than 50%5.

obJectiVeS The objective of the present study is to provide a descriptive and retro-spective analysis of the clinical and functional characteristics, as well as the response to antifibrotic therapy and the tolerance in real life through a cohort of patients diagnosed with idiopathic pulmonary fibrosis who have been pre-scribed treatment with antifibrotic drugs.

methodS A descriptive, observational study has been carried out on a retrospective cohort comprised of 27 patients diagnosed with IPF, according to ATS/ERS 2011 criteria2, included from October 2014 to November 2015. Pirfenidome (Esbriet®) treatment was administered to 8 of the 27 patients in said cohort in the form of 267 mg tablets. Treatment began with 3 tablets per day (1 tablet every 8 hours), and the dosage was increased weekly according to tolerance, until reaching a normal dosage of 9 tablets per day (3 tablets every 8 hours, corresponding to a total dosage of 2,403 mg). The remaining 19 patients re-ceived a 150 mg dosage of nintedanib (Ofev®) every 12 hours.

Data was collected regarding: age, gender, anthropometric data (weight, size, body mass index); lung function tests at the start and end of the mon-itoring period (FVC, diffusion, distance covered during the 6-minute walk test); tobacco use (pack-year); method of diagnosis (high resolution comput-erized tomography [HRCT], lung biopsy, multidisciplinary session); type of antifibrotic treatment prescribed; length of treatment; side effects and clinical progress. The chi-square test was used for the statistical analysis of the qualitative variables and the student’s t-test was used for quantitative variables using 0.05 as the value for statistical significance. Data was analyzed with the SPSS 13 software package.

reSultS Data for 27 patients was analyzed (Table 1), of which 19 received treatment with nintedanib at an average dosage of 300 mg for an average of 6.3 ± 3.9 months (1-12 month range) and 8 received treatment with pirfenidome at an average dosage of 2,403 mg for an average of 10 ± 3.9 months (3-14 month range). Average patient age was 70 ±10 (53-81 years old) for pirfenidome and 68 ± 2.1 (54-79) for nintedanib. There were more men than women in both groups, with a proportion of 3:1. With regard to functional tests, moderate limitation was shown, with a FVC of 68 ± 4% for the pirfenidome group and 71 ± 3.9% for those receiving nin-tedanib. The group undergoing treatment with pirfenidome had significantly higher DLCO values at the beginning of treatment, 43 ± 14 with a range of 43-61% versus 32 ± 8 with a range of 23-52% in the nintedanib group (p <0.01). This difference continued until the end of the evaluation period. The-re were no differences in meters walked during the walk test between groups. Lung function remained stable, with drops in both FVC and DLCO of less than 5% during the monitoring period. All patients underwent HRCT for diagnosis and, in the cases where HRCT did not show a definitive NIU pattern, a biopsy was done via video-assisted thoracoscopic surgery: in 3 cases within the pirfenidome group and 5 in the nintedanib group. A higher incidence of emphysema was seen in the ninte-danib group: 36.8% versus 11% in the pirfenidome group (p <0.01). For all cases not requiring a biopsy, a diagnosis was made through a multidisciplinary



Summary

evaluation by the pulmonologist, radiologist and pathologist. Both drugs were well tolerated, with both groups showing primarily diges-tive side effects in addition to mild photosensitivity in the case of pirfenido-me treatment. However, these side effects caused very few patients to stop treatment (Table 2). During the monitoring period, 2 patients in the pirfenidome group and 3 in the nintedanib group passed away, all of which were due to disease progres-sion. One of the 19 patients from the nintedanib group received a successful transplant.

table 1. demographic and functional data

PIRFENIDOME (n= 8)

ASCEND NINTEDANIB(n= 19)

INPUL-SIS-1

AGE (years) 70 ± 10 (53-81) 68.4 ± 6.7 68 ± 2.1 (54-79) 66.9 ± 8,4MALE/FEMALE (%) 75/25 79/21 89/11 81/19

TOBACCO (pack-year) 37 ± 12

Initial FVC (%) 68 ± 4 (47-76) 67.8 ± 11.2 71 ± 3.9 (49-104) 79.5 ± 17Final FVC (%) 60 ± 3 (45-10) 68 ± 4 (46-100)Initial DLCO (%) 43 ± 14 (43-61) 43.7 ± 10.5 32 ± 8 (23-52) 47.8 ± 12.3Final DLCO (%) 41 ± 1.5 (40-57) 30 ± 3 (20-52)6-minute walk test (meters) 422 ± 54 415 ± 98.5 458 ± 23

Initial/final saturation 95 ± 1/84 ± 3 93 ± 0.65/82 ± 1.28

HRCT emphysema 1 (11%) 32% 7 (37%) 39%BIOPSY 2 (22%) 30.9% 5 (26%) 19.4%

table 2. Side effects

PIRFENIDOME (n= 8)

ASCEND (n 278)

NINTEDANIB (n 19)

INPULSIS (n 329)

None 5 (55%) 9 (47%)Epigastralgia 2 (22%) 17.6% 2 (22%) 3.3%Photosensitivity 1 (11%) 28.1% -- --↑Transaminases 1 (11%) ≠ 3% 1 (5%) 4.9%Diarrhea -- 22.3% 5 (26%) 63.2%Weight loss -- 12.6% 2 (22%) --Exitus 2 (22%) 3.5% 3 (18%) 5.5%Withdrawal 1 (11%) 19.8% 2 (22%) 23.7%

≠. In one case a single patient experienced more than one side effect.

Figure 1: nintedanib functional progression in % throughout the monitoring period.



Summary

diScuSSion The data presented shows that the new antifibrotic therapies are well toler-ated, have few side effects which can easily be managed in most cases and do not usually require patients to withdraw from treatment. IPF is a chronic and progressive disease with a poor short-term prognosis for which there had been no effective treatment until now3. In 2014, 3 studies were published which analyzed the efficacy of different IPF treatments. The PANTHER study6 showed that N-acetyl cysteine was not more effective than the placebo in terms of drop in FVC. The ASCEND study7 reflected that pir-fenidome was effective in slowing the drop in FVC, with differences from the placebo group in disease progression and, jointly analyzed with patients from the CAPACITY program8, IPF treatment was shown to increase survival for the first time. The INPULSIS study with nintedanib5 showed an improvement in the drop in FVC with respect to the placebo group and this drug was then proven to decrease the number of exacerbations9. There is little information about the effects and tolerance for new drugs in real life, outside the area of clinical trials, especially for drugs recently being marketed. Our patients’ characteristics were very similar to those included in the clinical trials and, in general, the drugs have been well tolerated. Although

it must be pointed out that the data presented was taken over a short period, the side effects were those anticipated, especially digestive problems in both cases, and the incidence has been even better than that reflected in the clinical trials. Drug treatment only needed to be stopped in 3 out of 27 cases due to intolerance. There was a slight increase in transaminases in only one case, which was resolved without requiring any further treatment and did not re-quire the drug dosage to be reduced. Both treatments require periodical checks for liver function. In the case that liver enzymes increase 2-fold, the dosage needs to be reduced over 15 days and, if the patient stabilizes, the initial dosage can be resumed. Treatment must only definitively be suspended in cases of a more than 5-fold increase in enzymes10. This has not been necessary within our cohort. The incidence of diarrhea, the most frequent side effect of nintedanib, was 26%, lower than the 63% reported in the clinical trials and which has not required stopping drug treatment. To manage the side effect, dietary measures should be taken and it may require oral administration of loperamide 2 mg. In the case of pir-fenidome treatment, photosensitivity has been very mild, occurring in a single case and it did not require stopping drug treatment. Avoiding sun exposure and the use of sunscreen year-round is recommended, which considerably reduces the incidence of this problem11. There have been some differences in the functional tests between treatment groups. In the nintedanib group, the DLCO was significantly lower, which can explain the higher number of patients with emphysema in this group (37%). The presence of emphysema in the upper lobes is frequent among IPF pa-tients, especially those who have smoked and this may lead to a greater decline in DLCO12 and a higher incidence of pulmonary hypertension13. The rate of emphysema in the clinical trials was 39% in the INPULSIS study and 32% in the ASCEND study. The rate of patients with emphysema within our cohort is very similar, 37%. This fact is not believed to have had any influence on drug tolerance. There were no differences between groups at either the start or end of evaluation for FVC and meters covered during the walk test. This study has some limitations. A retrospective descriptive analysis of the tolerance for antifibrotic therapies in real life has been done. There are a great-er number of patients being treated with nintedanib than with pirfenidome. As our objective was not to evaluate the efficacy of these drugs, which has already been contrasted in randomized clinical trials, we do not have informa-tion about the clinical and functional progression (FVC, dyspnea, 6-minute

Figure 2: pirfenidome functional progression in % throughout the monitoring period.



Summary

walk test) before and after the start of treatment. It is a small cohort, 27 pa-tients studied over a short period, and this may be why there have not been withdrawals due to lack of efficacy, but we believe this reflects the true activity of our consults. Although work is beginning to appear regarding real-life ef-fects14, there is little information available in the area of antifibrotic therapy for IPF. In summary, both pirfenidome and nintedanib are recommended medi-cines for the treatment of IPF15. They have shown to be effective in slowing the progression of IPF, are well tolerated and have mild short-term side ef-fects which can easily be managed.

biblioGrAphy1. Hunninghake GM. A new hope for idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:

2142-21432. Ganesh Raghu, Harold R et al. Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines

for Diagnosis and Management Am J RespirCrit Care Med. 2011; 183: 788–824.3. American Thoracic Society, European Respiratory Society. American Thoracic Society/

European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165: 277–304.

4. King TE Jr, Bradford WZ, Castro-Bernardini S et al. A phase 3 trial of pirfenidone in pa-tients with idiopathic pulmonary fibrosis. ASCEND. N Engl J Med 2014; 370: 2083-92.

5. Richeldi L, du Bois RM, Raghu G et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. INPULSIS-1 e INPULSIS-2. N Engl J Med 2014; 370: 2071-82.

6. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King Jr TE, Raghu G. Randomized trial of acetylcysteine in idiopathic pul-monary fibrosis. N Engl J Med. 2014; 370: 2093–101.

7. King Jr TE, Bradford WZ, Castro-Bernardini S et al. A phase 3 trial of pirfenidone in pa-tients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370: 2083–92.

8. Noble PW, Albera C, Bradford WZ et al. Pirfenidone in patients with idiopathic pulmonary fibrosis CAPACITY): Two randomised trials. Lancet. 2011; 377: 1760–9.

9. Richeldi L, Cottin V, Du Bois R et al. Nitedanib in patients with idiopathic pulmonary fibrosis: combined evidence from de TOMORROW and IMPULSIS trials. Respiratory Medicine 2016: 113; 74-79.

10. Jiang C, Huang H, Liu J, Wang Y, Lu Z, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: A meta-analysis of randomized controlled trials. PLoS One. 2012; 7: e47024.

11. Costabel U, Bendstrup E, Cottin V et al. Pirfenidone in idiopathic pulmonary fibrosis: ex-pert panel discussion on the management of drug-related adverse events. AdvTher. 2014; 31 (4): 375-91.

12. Ryerson CJ, Hartman T, Elicker BM et al. Clinical features and outcomes in combined

pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis. Chest 2013; 144 (1): 234–240.

13. F. Martínez, S. Safrin, D. Weycker et al.The clinical course of patients with idiopathic pul-monary fibrosis Ann Intern Med 2005:142; 963–967.

14. Hughes G, Toellner H, Morris H et al. Real World Experiences: pirfenidone and Ninteda-nib are effective and well tolerated treatments for Idiophatic Pulmonary Fibrosis. 2016. J. Clin Med 2016; 5 (9): 78.

15. Raghu G, Rochberg B, Zhang Y et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis: An Update of the 2011 Clinical Practice Guideline. Am J RespirCritCareMed 2015: 192, 2, pp e3–e19.

Summary

Summary

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Summary

ORIGINALS


InfluencIa de laS comorbIlIdadeS en la mortalIdad de pa-cIenteS con epoc eStableS

resumenobjetivo: Estudiar la relación entre las comorbilidades y la mortalidad por cualquier causa en pacientes con EPOC en fase estable, en nuestro ámbito geográfico.material y métodos: Estudio observacional prospectivo longitudinal multicéntrico de una co-horte de pacientes con EPOC en situación estable. Se recogieron datos demográficos, funcionales respiratorios, índice de comorbilidad de Charlson y escala hospitalaria de ansiedad y depresión. Los pacientes fueron seguidos durante 3 años. En el caso de fallecimiento se indagó para deter-minar la causa de la muerte.resultados: Se estudiaron 138 pacientes con una edad media de 66,3 ± 10,3 años y FEV1 medio de 51,3 ± 16,9%. El índice de Charlson medio fue de 4,66 ± 1,57. Presentaban depresión el 17,2% y ansiedad el 12,7%. Fallecieron 13 (9,5%) pacientes, 5 de cáncer de pulmón, 5 por agudización de la EPOC, 1 por carcinoma de colon, otro por infarto agudo de miocardio (IAM) y otro por insu-ficiencia cardiaca congestiva (ICC). En el análisis multivariado el número de comorbilidades (HR 1,926; IC 95%: 1,384 - 2,680) y la existencia de tratamiento ansiolítico (HR 4,072; IC 95%: 1,106 - 14,987) se asociaron a mayor mortalidad. El análisis mediante curvas de supervivencia de Kaplan-Meier, mostró que los pacientes con 2 o más comorbilidades, además de la EPOC, presentaban mayor mortalidad que los que tenían una o ninguna (35,52 ± 0,2 vs 33 ± 1,3 meses, p = 0,039).conclusiones: La prevalencia de comorbilidades en pacientes con EPOC estable fue elevada. La mortalidad de estos pacientes se relacionó con el número de comorbilidades y el tratamiento ansiolítico. La mortalidad fue superior en aquellos pacientes con 2 o más comorbilidades.

palabras clave: EPOC, comorbilidades, mortalidad, índice de Charlson.

Received: December 3, 2015. Accepted: February 13, 2017.

Aurelio Arnedillo Muñ[email protected]

A. Arnedillo Muñoz1, J.L. López Campos2, F. Casas maldonado3, P. Cordero Montero4, I. Alfageme Michavila5.1Unidad de Neumología y Alergia. Hospital U. Puerta del Mar (Cádiz). 2Unidad Médico-Quirúrgica de Enfermedades Respiratorias. Instituto de Biomedicina de Sevilla (IBiS). Hospital U. Virgen del Rocío (Sevilla). CIBER de Enfermedades Respiratorias (CIBERES) 3Servicio de Neumología. Hospital U. San Cecilio (Granada). 4Servicio de Neumología. Hospital Infanta Cristina (Badajoz). 5Servicio de Neumología. Hospital U. Valme (Sevilla).1st Prize for Best Submission 2016. Project financed by Beca Fundación Neumosur 9/2009

Influence of comorbIdItIeS In Stable copd patIent mortalIty

abstract:objective: to assess the relationship between comorbidities and all-cause mortality in stable chro-nic obstructive pulmonary disease (COPD) patients, in our geographic area.methods: Prospective, multicenter, longitudinal study of patients with stable COPD. We recorded demographic characteristics, respiratory functional tests, Charlson comorbidity index and hospital anxiety and depression scale. Patients were followed up for 3 years. In the case of death it was investigated to determine the real cause of death.results: 138 patients were studied with a mean age of 66.3 ± 10.3 years and mean FEV1 of 51.3 ± 16.9%. The mean Charlson index was 4.66 ± 1.57. 17.2% had depression and 12.7% anxiety. Thirteen (9.5%) patients died, 5 of lung cancer, 5 COPD exacerbation, 1 colon cancer, another for acute myocardial infarction (AMI) and another one for congestive heart failure (CHF). In the multivariate analysis the number of comorbidities (HR 1.926; IC 95%: 1.384 - 2.680) and anxiolytic treatment (HR 4.072; IC 95%: 1.106 - 14.987) showed relationship with mortality. Kaplan-Meier suvival plots showed that patients with 2 o more comorbilities, in addition to COPD, have higher mortality than patients with 1 or no comorbidity (35.52 ± 0.2 vs 33 ± 1.3 months, p = 0,039). conclusions: The prevalence of comorbidities in patients with stable COPD was high. Mortality in these patients is related to the number of comorbidities and anxiolytic treatment. Mortality was higher in patients with 2 o more comorbidilites.

Key words: COPD, comorbidities, mortality, Charlson index.

mailto:aure152%40separ.es?subject=Influencia%20de%20las%20comorbilidades%20en%20la%20mortalidad%20de%20pacientes%20con%20EPOC%20estables%20


A. Arnedillo Muñoz et al. Influence of Comorbidities in Stable COPD Patient Mortality

Summary

IntroductIon Chronic Obstructive Pulmonary Disease (COPD) is characterized by the chronic limitation of airflow, associated with a chronic inflammatory response in the bronchial tree and lungs, primarily due to the inhalation of tobacco smoke1. This inflammatory response does not occur solely at the lung level, as COPD patients also show increased inflammatory markers at the system level and there is a theory that these inflammatory proteins move from the lung to the systemic circulation2, 3.This systemic inflammation can be seen in other diseases, which are frequently associa-ted with COPD and are known as comorbidities, and it may be implicated in their pathogenesis. These comorbidities associated with COPD include cardiovascular di-sease such as coronary heart disease, heart failure, stroke and peripheral vascular disease, neoplasms, diabetes mellitus, anxiety and depression, li-ver and kidney disease, peptic ulcers, etc. Comorbidities have a significant impact on the prognosis and morbi-mortality for COPD patients and, in fact, they constitute the primary cause of mortality among patients with mild and moderate COPD4, 5. Some studies have shown an increase in mortality among COPD pa-tients related to these comorbidities5-10. The majority of publications have used the Charlson index to quantify the impact that said comorbidi-ties have on mortality.This index includes many comorbidities/diseases, which are assigned a score. The index is an indicator of mortality in those patients11. Data published on the relationship between comorbidities and mor-tality among COPD patients vary widely and there are factors that can influence this variability such as when patient evaluation is conducted (during admission or a stable period), and the degree of obstruction pre-sent; even the geographical region where the study takes place can modify the results5-10, 12, 13. Despite the relationship existing between comorbidities and COPD prognosis, until now there has not been data available that connects sta-ble COPD patient mortality and comorbidities in the regions of Anda-lusia and Extremadura.As a result, our objective has been to study the relationship between comorbidities and mortality by any cause among stable COPD patients, as well as the influence that each of these comor-bidities has on said mortality in our geographic region.Our hypothesis is

that these comorbidities, particularly some of them, influence mortality among COPD patients.

materIal and metHodS A multi-center longitudinal prospective study was designed for a co-hort ofstable patients diagnosed with COPD in 5 hospitals in Andalusia and Extremadura. Patients must have been diagnosed with COPD and met GOLD1 crite-ria at least 6 months before their visit, and be smokers or former smokers with exposure intensity of more than 20 packs per year.Those patients presenting with a chronic respiratory disease other than COPD and tho-se who declined to participate in the study or sign the informed consent were excluded. Patients were recruited consecutively through external consults over 3 months and monitoring was carried out for 3 years, from January 2011 to December 2013. Participatinghospitalswere Hospital Universitario Puerta del Mar (Cá-diz), Hospital Universitario Virgen del Rocío (Seville), Hospital Infanta Cristina (Badajoz), Hospital Universitario Virgen de Valme (Seville) and Hospital Universitario San Cecilio (Granada). All patients completed a standardized questionnaire about demogra-phic data, tobacco use, work status, family situation and level of studies.Average dyspnea was registered using the Modified Medical Research Council (mMRC) scale. Information about current medication and co-morbidities was collected using patient medical history and a detailed interview. Comorbidity was quantified using the Charlson index11, which was de-veloped to predict mortality in patients with chronic disease.The index assigns each disease/comorbidity a score, which is proportional to the relative risk of dying from the disease.Arterial hypertension (AHT) was collected, which is not included on the Charlson index.Anxiety and de-pression are also comorbidities that are not included on the Charlson index and have been detected using the Hospital Anxiety and Depres-sion Scale, HAD14, which has been validated for detecting these diseases.Even so, information about patients’ anxiolytic and antidepressant use was collected.A hemogram, basic biochemistry, oxygen saturation measu-red by pulsioxymetry (SpO2), spirometry with a bronchodilator test and



Summary

6-minute walk test were also done.Patients were monitored over 3 years via a visit or phone call every 3 months, collecting information about the need for care facilities and death. The sample size was calculated analyzing the effect on the Charlson index, accepting a mortality of 10% for stable patients, a standard de-viation of 1.1 points on the Charlson index based on previous studies, and accepting an alpha risk of 0.05 and a beta risk of 0.2 in a bilateral contrast.A total of 11 subjects were needed for the first group and 110 for the second to detect a difference greater than or equal to 1 unit on said index. A descriptive analysis was done for all variables included in the study, using common descriptive statistics.The numerical variables were compa-red using the independent samples t-test or the Mann-Whitney test when there was abnormal distribution.The chi-square test or Fisher’s exact test was used to compare proportions between qualitative variables when they did not meet application conditions.Comparisons between individual pre-dictive variables for mortality were made using Cox regression analysis.To determine mortality indicators, all predictive variables were included in a multivariate Cox proportional hazards model.Kaplan-Meier survival cur-ves were created to see the influence of anxiolytic treatment and comor-bidities.The differences between survival curves were evaluated using the log-rank test.“P” values less than 0.05 are considered significant.Statisti-cal analysis was done using the SPSS 17.0 software package for Windows. The study was approved by the Clinical Research Ethics Committee and adheres to the principles of the Declaration of Helsinki for medical research involving human subjects.All participants were informed about the nature of the study and its objectives and agreed to participate by sig-ning an informed consent.Data was collected under strict confidentiality following Spanish Organic Law 15/1999 on the protection of personal data.

table 1. details on quantitative population variables

Quantitative variables media ± desviación estándarAge (years) 66.3 ± 10.3Packs/year 57.9 ± 34.2Body mass index 28.7 ± 5.5Post-bronchodilator (postBD) FEV1 (ml) 1417.7 ± 491.5Predicted postBD FEV1 % 51.3 ± 16.9PreBD FEV1/FVC% 50.1 ± 16.9SpO2 93.9 ± 2.81Baseline dyspnea (MRC scale) 1.10 ± 1.566-minute walk test distance (m) 398.73 ± 131.94BODE index 3.1 ± 2.1Charlson index 4.66 ± 1.57No. of comorbidities excluding COPD 0.94 ± 1.55Hemoglobin (mg/dl) 14.62 ± 1.71Total leukocytes (x103mcL) 9.062 ± 3.615Lymphocytes (% of total leukocytes) 25.8 ± 10.0Eosinophils (% of total leukocytes) 2.9 ±5.6

FEV1: maximum volume exhaled in the first second. FVC: forced vital capacity. BD: bronchodilator. SpO2: blood oxygen saturation measured by pulsioxymetry. MRC: the Medical Research Council dyspnea scale. COPD: chronic obstructive pulmonary disease.

table 2. details on qualitative population variables

Qualitative variables number (percentage)Gender- Male- Female

111 (80.4%)27 (19.6%)

Tobacco use:- Former smoker- Active smoker

98 (71.01%)40 (28.9%)



Summary

Qualitative variables number (percentage)COPD severity (GOLD)1234

8 (5.8%)58 (42.0%)61 (44.2%)11 (8.0%)

Treatment with inhaled steroids 105 (76.08%)Treatment with LABA 105 (76.08%)Treatment with LAMA 113 (81.8%)Oxygen therapy 19 (13.7%)Non-invasive ventilation 13 (9.4%)Myocardial infraction (history) 17 (12.3%)Heart failure (history) 11 (8.0%)Arterial hypertension 47 (34.1%)Depression (according to HAD) 24 (17.4%)Anxiety (according to HAD) 18 (13.04%)Antidepressant treatment 7 (5.1)%Anxiolytic treatment 16 (11.6)%Dyspnea severity (MRC)01234

11 (7.97%)55 (39.85%)45 (32.60%)22 (15.94%)5 (3.60%)

≥ 2 comorbidities (including COPD) 67 (48.6%)≥ 3 comorbidities (including COPD) 32 (23.2%)Deaths

NoYes:Lung cancer:Colorectal cancer:AECOPD:Coronary heart disease:Heart failure:

124 (90.5%)13 (9.5%)5 (3.6%) 1 (0.7%) 5 (3.6%) 1 (0.7%) 1 (0.7%)

GOLD: Global Obstructive Lung Disease. LABA: beta agonista de acción prolongada. LAMA: anticolinérgico de acción prolongada. AE-POC: Agudización de la EPOC. MRC: Escala de disnea de la Medical Research Council. HAD: Hospital anxiety and depression scale.

Table 3. Variables with statistically significant differences between deceased and living patients

Variable deceased living pHemoglobin (mg/dl) 13.43 ± 1.99 14.76 ± 1.63 0.007Charlson index 6.70 ± 2.01 5.5 ± 1.5 0.038No. of comorbidities 1.70 ± 0.94 3.46 ± 2.36 <0.001NIMV 4 (2.9%) 9 (6.5%) 0.006Antidepressant treatment 3 (2.2%) 4 (2.9%) 0.002Anxiolytic treatment 5 (3.6%) 11 (8%) 0.002AMI 5 (3.6%) 12 (8.7%) 0.003AHT 9 (6.5%) 37 (26.8%) 0.004CHF 5 (3.6%) 6 (4.3%) 0.001Values for numerical variables are expressed as average ± standard deviation. For qualitative variables they are expressed as absolute value and percentage.NIMV: non-invasive mechanical ventilation. AMI: history of acute myocardial infarction. AHT: arterial hypertension. CHF: history of congestive heart failure.

Table 4. Predictive variables for mortality. Bivariate analysis using Cox regression

Variable p rr Ic 95%lower upper

Hemoglobin (mg/dl) 0.005 0.645 0.474 0.878Charlson index 0.023 1.498 1.057 2.122No. of comorbidities <0.001 1.956 1.457 2.628NIMV 0.029 4.403 1.167 16.614

Antidepressant treatment 0.035 5.202 1.123 24.103

Anxiolytic treatment 0.008 5.285 1.546 18.067AMI 0.014 4.687 1.371 16.017AHT 0.009 5.838 1.548 22.011CHF 0.004 7.132 1.888 26.947NIMV: non-invasive mechanical ventilation. AMI: history of acute myocardial infarction. AHT: arterial hypertension. CHF: history of congestive heart failure. P: level of statistical significance. RR: risk ratio CI: confidence interval.



Summary

Table 5. Independent mortality risk, adjusted for age and gender and by interaction between risk factors. Multivariate analysis using the Cox proportional hazards model

Variable p Hr Ic 95%lower upper

Age 0.624 1.019 0.945 1.100Gender 0.757 1.308 0.239 7.160No. of comorbidities <0.001 1.926 1.384 2.680Anxiolytic treatment 0.035 4.072 1.106 14.987No.: number.P: level of statistical significance. HR: hazard ratio. CI: confidence interval.

Figure 1. Kaplan-Meier survival curves with log-rank test analysis for patients with and without anxiolytic treatment who have 3 or more comorbidities (including COPD) vs. those with fewer than 3 comorbidities.Tto: treatment. P: level of statistical significance.

reSultS The study included 138 patients, whose general data can be found in Tables 1 and 2.The majority of participants were men and a third were current active smokers.The average degree of obstruction was moderate to severe, and more than 80% of the study population belonged to these groups. The average Charlson index was high, revealing patients presented abun-dant associated comorbidities, many of which were cardiovascular as can be seen in Table 2.The HAD questionnaire was used to detect depression in 17.4% of patients and anxiety in 13.04%.Nearly 50% of patients presented with 2 or more comorbidities and almost a quarter had 3 or more, including COPD.13 patients (9.5%) passed away during monitoring. The most frequent causes of death were neoplasms and acute exacerbations of COPD (AECO-PD). Table 3 reflects the results of variables which show statistical significance in the bivariate analysis between the group of deceased patients and those who are still living. Table 4 shows the individual predictive variables for mortality in bivariate analysis using Cox regression. In the Cox multivariate analysis (Table 5), only the presence of anxiolytic treatment and the number of comorbidities were shown to be independent mortality factors, having been adjusted for age and gender. Patient survival was compared in function of the number of comorbidities and patients with 2 or more comorbidities in addition to COPD were shown to have a higher mortality than those who presented with 1 or no comorbidi-ties.The Kaplan-Meier survival curves comparing both groups can be seen in Figure 1, as well as the patients with and without anxiolytic treatment.

dIScuSSIon This study describes the relationship between comorbidities and mortality among stable COPD patients from the regions of Andalusia and Extremadu-ra for the first time.According to the results, the global mortality among stable COPD patients is related to the Charlson index; the number of comorbidities, particularly AMI, AHT, and CHF; lower hemoglobin levels and treatment with anxiolytics and antidepressants.However, in the multivariate analysis, only anxiolytic treatment and the number of comorbidities were related to higher mortality.



Summary

The first surprising piece of data is the mortality seen within the sample population, which is lower than what was expected at 9.5%.Some authors have described mortality rates one year after hospital discharge at about 28%12; but for stable patients undergoing treatment, like those in our study, the mortality rate in the TORCH study15 at 3 years was 12.6% and the UPLIFT study16 showed a 14.4% mortality rate at 4 years. These figures are closer to ours, although the studies are older.Some publications have shown a progressive decrease in mortality rates for COPD patients17, 18, a trend which may justify our lower mortality rate for stable patients at the time of recruitment. Causes of mortality for our patients are in accordance with information published in the bibliography.Many publications have shown an increased pre-valence of mortality from neoplasms, primarily lung cancer and cardiovascu-lar disease5, 19-21, in addition to deaths caused by acute exacerbations of COPD (AECOPD).The most frequent causes of death among the population of this study were neoplasms and AECOPD, with cardiovascular disease being the third most prevalent.Within cardiovascular diseases, there are authors who have observed higher mortality among patients with AMI and CHF, as seen in our study population22. With regard to the relationship between the Charlson index and COPD pa-tient mortality, published results show different findings.Antonelli-Incalzi et al.6 studied this aspect in a 270-patient cohort, although post-hospitalization.Among this population, the Charlson index did not show predictive capability in the multivariate analysis.Gronewegen et al.12 also analyzed this prognostic index in patients hospitalized for AECOPD and, although the Charlson index associated it with a significantly higher risk of death, the multivariate analysis was unable to demonstrate an independent association.On the other hand, Al-magro et al.13 studied 135 patients hospitalized for AECOPD. In this case, the Charlson index did significantly associate it with decreased survival.The mul-tivariate analysis revealed that for patients presenting a Charlson index equal to or higher than 3 (the equivalent of 2 chronic diseases or one serious disease in addition to COPD), there was a higher risk of death.In a study on stable COPD patients, Matters et al.23 also found no association between the Charl-son index and mortality after 4.2 years of follow-up.Similar to Gronewegen et al.12, the present study found a significant association between the Charlson index and a reduced survival rate in patients, but the multivariate analysis did not prove this association.In contrast, in the multivariate analysis the number of comorbidities was indeed independently associated with a higher mortality.

Additionally, we have seen that the presence of 2 or more comorbidities is associated with a higher mortality (Figure 1), similar to the results of Almagro et al.13. Mortality increased by 1.92 (CI 95%: 1.38-2.68) within the study popu-lation among those patients with 3 or more comorbidities (including COPD). However, we believe that the Charlson index was designed at a time when some of the measured parameters had a significant influence on mortality (such as AIDS, which no longer has the mortality rate it was associated with in the ‘80s when this index was created).Moreover, the index does not include other important comorbidities such as AHT, anxiety and depression.As a re-sult, we believe that new indexes should be developed which are more realistic than the Charlson index and, above all, aimed toward the specific population of COPD patients.In this sense, the recently described COTE index which uses 12 comorbidities and was developed for COPD patients is promising7. With respect to hemoglobin levels, the patients who showed higher mor-tality had significantly lower hemoglobin levels and, although this was not an independent factor for mortality in the multivariate analysis, some authors have found higher mortality among COPD patients with anemia, in addition to a poorer prognosis during hospitalization for AECOPD21, 24, 25. As far as the findings related to anxiety and depression, the prevalence varied considerably depending on the selected population.In a revision of COPD patients, selecting those studies that used the same questionnaire as that used for the present study, Maurer et al.26 describe anxiety rates of bet-ween 13 and 55% and depression rates between 7 and 32%. The prevalence in this study fell within the lower limits of those described.It is important to note the infradiagnosis and infratreatment of these patients, as only 16.6% of those the HAD questionnaire detected as being depressed were undergoing anti-depression treatment and 27.7% were undergoing treatment for anxie-ty.The present study showed no relationship between anxiety or depression and long-term mortality, but it did link mortality with undergoing anxiolytic treatment.Some authors have described higher mortality among patients with anxiety and depression, as well as longer hospital stays, worse recovery after hospitalization and a higher risk of being readmitted27-29. As far as limitations of the present study, one has been the low level of mortality that has been seen.The sample size was calculated for an estimated mortality of 10%, which is low in itself.However, if we calculate a sample for a 9.5% mortality rate, which is what we obtained, a minimum of 11 patients would be needed in the deceased group, the same number for the 10% mor-



Summary

tality rate, and 104 for the group of still living patients. As a result, this does not affect the statistic results obtained. Another limitation is that the diagnoses of anxiety or depression we made in patients were based on the HAD questionnaire without confirming whether the patients actually suffered from these diseases, rather than through a psychiatric study.However, a psychiatric study for our entire population would suppose an extra burden that would be difficult to undertake, which is the reason it was decided to use said questionnaire as it is one of the most fre-quently used for COPD patients to detect this disease and it has been properly validated.In any case, the questionnaire can give false negatives for patients who have previously been treated with antidepressants or anxiolytics who are taking medication and, in fact, of the patients the questionnaire did not diag-nose with depression, three were taking antidepressants. In the case of anxie-ty, 11 were taking anxiolytics and were not diagnosed with anxiety through the HAD questionnaire.This has likely had an influence on the infradiagnosis of the disease and the fact that anxiolytic treatment was associated with a higher mortality instead of the disease. In conclusion, there was a high prevalence of comorbidities in our popu-lation of stable COPD patients.The most frequent causes of mortality were neoplasms, acute exacerbations of COPD and cardiovascular comorbidity (CHF and AMI).In the multivariate analysis, patient mortality was associated with anxiolytic treatment and the number of comorbidities.Patients with 2 or more comorbidities in addition to COPD showed higher mortality than those who had one or no comorbidities.As a result, we believe that the early de-tection and treatment of these comorbidities could improve survival among COPD patients.

bIblIoGrafIa1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for diagnosis, ma-

nagement, and prevention of COPD. Updated 2015. Disponible en: http://www.goldco-pd.org/

2. Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010; 65: 930-6.

3. Fabbri LM, Luppi F, Beghé B et al. Complex chronic comorbidities of COPD. Eur Respir J 2008; 31 (1): 204-12.

4. Mannino DM, Watt G, Hole D et al. The natural history of chronic obstructive pulmonary

disease. Eur Respir J 2006; 27: 627-43.5. Cavaille`s A, Brinchault-Rabin G, Dixmier A et al. Comorbidities of COPD. Eur Respir

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Summary

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very and outcome of hospitalized COPD exacerbations. Eur Respir J 2013; 41: 815-823.

117

Summary

ORIGINALS


Received: February 29, 2016. Accepted: March 2, 2017.

Mercedes Sánchez [email protected]

Abstract: The transcutaneous CO2 (tcCO2) monitoring has demonstrated a good correlation with the arterial CO2 value, and is better than pulsioxymeter for to detect hypoventilation episodes. The tcCO2 monitoring is not routine in our environment. The aim of our study was to evaluate the utility of tcCO2 monitoring in our sleep unit, in basal studies and in non invasive ven-tilation settings. We performed a prospective study. We measured the tcCO2 values in basal polisomnografies (PSG) and in CPAP or BIPAP settings in patients with diagnosis of OSAS, obesity-hypoventilation Syndrome and COPD. We included 102 studies in 89 patients. There were 45 basal studies, 21 CPAP settings and 34 BIPAP settings. The most frequent pathology was OSAS. The mean pressure in CPAP settings was 9.6 H2Ocm, while in BIPAP settings the mean IPAP was 15.7 and the mean EPAP was 7.4. The mean desaturation index was 27, the mean peripheral O2 value was 91.8%, ant the mean cumuled time under 90% (CT90) of O2 peripheral saturation was 22.9%. The mean tcCO2 was 45.6 and the maximum was 49.2. Con-clusions: tcCO2 monitoring is a non invasive method for to detect hypoventilation episodes in patients with sleep pathology and in non invasive ventilation settings, although the peripheral oxygen saturation remains in normal values.

Key words: Hypoventilation, non-invasive ventilation, transcutaneous monitoring of CO2

UtilidAd de lA monitorizAción trAnScUtáneA de co2 dUrAnte el regiStro poliSomnográfico en UnA UnidAd de SUeño

resumenLos trastornos respiratorios del sueño son frecuentes en la población general y generan un alto consumo de recursos por ingresos, consultas y uso crónico de las terapias ventilatorias. La medición de CO2 transcutánea (tcCO2) ha mostrado buena correlación con la presión ar-terial de CO2 (PCO2) y es superior al pulsioxímetro para detectar hipoventilación. Su uso está poco extendido en nuestro medio. Nuestro objetivo fue valorar su utilidad en estudios de sue-ño basales y en titulaciones de CPAP y BIPAP, aplicadas a pacientes con síndrome de apneas del sueño (SAHS) y síndrome de obesidad-hipoventilación (SOH). Usamos el medidor tcCO2 en polisomnografías (PSG) basales de pacientes con sospecha de patología respiratoria del sueño y en titulaciones de CPAP o BIPAP de pacientes ya diagnosticados. Se realizaron 102 estudios a 89 pacientes. Hubo 45 estudios basales, 21 titulaciones de CPAP y 34 de BIPAP. La patología más frecuente fue el SAHS. La presión media de las titulaciones de CPAP fue de 9,6 cmH2O. En las titulaciones de BIPAP la IPAP media fue de 15,7 y la EPAP media de 7,4. El índice de desaturación (IDH) medio fue de 27. La SpO2 media fue de 91,8% y el CT90 del 22,9%. La tcCO2 media fue de 45,6 y la máxima de 49,2. No hubo efectos secundarios a la monitorización tcCO2. Conclusiones: observamos hipercapnia latente en muchos pacientes y el medidor fue bien tolerado. Creemos que la monitorización tcCO2 puede ser útil como método no invasivo para detectar hipoventilación, aun con cifras normales de SpO2.

palabras clave: Hipoventilación, ventilación no invasiva, medición transcutánea de CO2.

M. Sánchez Bommatty1, M. Merino Sánchez2, A. León Jiménez3, M.P. Foncubierta Fernández2, F. Fernández Pérez2.1Sección de neumología. Hospital Santa Bárbara, Puertollano. 2UGC de neumología, alergia y cirugía torácica. Hospital universitario Puerta del Mar, Cádiz. 3UGC de neumología, alergia y cirugía torácica. Hospitales universitarios Puerta del Mar y Puerto Real, Cádiz. Project financed by Beca Fundación Neumosur17/2011

the prActicAlity of trAnScUtAneoUS co2 monitoring dUring polySomnogrAm recording in A Sleep Unit

mailto:merchedit%40hotmail.com?subject=Revista%20Neumosur


M. Sánchez Bommatty et al. The Practicality of Transcutaneous CO2 Monitoring During Polysomnogram Recording in a Sleep Unit

Summary

introdUction Sleep-related breathing disorders are common in the general popu-lation.They generate a high use of resources for the health care system in terms of hospitalizations, addressing consults or emergencies and the chronic use of respiratory therapy.Sleep apnea-hypopnea syndrome (SAHS) is defined as a clinical picture of excessive drowsiness; cognitive-behavioral, respiratory, cardiac, metabolic or inflammatory disorders oc-curring as side effects of repeated episodes of upper airway obstruction during sleep1. It is a common disorder, present in 2-4% of the adult population2. Respiratory poligraphy or polysomnography (RP or PSG) is necessary for diagnosis. To make the diagnosis, an apnea-hypopnea index (AHI) >5 and symptoms related to the disease must be present1. Another common disease is obesity hypoventilation syndrome (OHS), defined as the combination of daytime hypercapnia (partial carbon dioxide pressu-re, PCO2 >45 mmHg) and suffering from obesity (body mass index >30 Kg/m²), in which losing weight would reverse the alterations in sleep, pulmonary hypertension and shortness of breath associated with OHS3. As we know, during PR recording sensors tracking body position,respiratory effort, airflow and pulse oximetry and other data are generally placed on the patient4. The extension of the use of pulse oximetry has allowed for the non-invasive monitoring of pulse and the oxygen in the arterial hemoglobin. Capnography, for its part, allows for the measurement of CO2 in exhaled air and non-invasive transcutaneous monitoring.The transcutaneous measurement of CO2 in humans was first described in 1960 by Severinghaus and consists of placing an electrode on the skin, which it heats to 42º C, vaporizing the capillary CO2 in the subcutaneous tissue. This is the concentration which is measured by an infrared light transceiver/reader of a specific wavelength which is absor-bed by the CO2 in the tissue. The amount of light that reaches the reader is proportional to the amount of CO2 present in the tissue.These mea-surements are read on a continuous reading monitor that is connected to the electrode5. Its use is increasingly widespread, used on patients with alveolar hypo-ventilation both in sleep units and outpatient clinics, hospital stays and neonatal and adult intensive care units where invasive and non-invasive mechanical ventilation (IMV and NIV) are used. Currently, arterial blood gas (ABG) is still the most exact method to

measure arterial oxygen pressure (PO2) and PCO2 as well as the acid-base balance, allowing us to know the degree of oxygenation in the blood and pulmonary ventilation6. Since the end of the last century, multiple studies have compared the gold standard, arterial blood gas, with transcutaneous CO2 measurement. Reviewing the literature, the highest number of studies on tcCO2 has been in neonatal7 patients and children, both in acute8 and diagnostic processes while undergoing poligraphy9.The number of studies in adults continues to increase, including the study by Moronta and Gutiérrez6 in which stable individuals went to outpatient clinics for respiratory diseases where they underwent baseline ABG and a single measurement of tcCO2. The average difference between diagnostic techniques was 1.08% and capnographic values were 1.1% (p <0.01) higher than those from blood gas.Similarly, the literature includes studies on patients in acute respira-tory failure being treated with non-invasive mechanical ventilation with continuous CO2 monitoring. In this case, while tcCO2 measurement is not recommended as a substitute for that of PCO2, there are recommen-dations for it to have a changing role and be a response to treatment. The development and extension of transcutaneous CO2 measurements draws from the premise of being a continuous nocturnal recording, in comparison with ABG which is an occasional measurement and can thus mask nocturnal hypoventilation11. Some studies have looked at tolerance for the device, initially recom-mending a change in the recording point after 4 hours and the recali-bration of the machine to avoid scalding the skin12 since, as mentioned previously, the machine increases temperature to 42 or 43ºC to work co-rrectly.However, more recent studies have measured tcCO2 over 8 hours of continuous recording, without noting discomfort or side effects such as skin burns13, 14. The objective of this study was to evaluate the practicality of trans-cutaneous monitoring as a non-invasive tool to detect hypoventilation episodes in baseline sleep studies in patients with suspected sleep-related breathing disorders as well as CPAP or BIPAP titration in patients who have already been diagnosed with a sleep-related breathing disorder. A secondary objective was to evaluate tolerance to the device and if discomfort or side effects presented at the point where the electrode was applied on patients studied during continuous nocturnal recording.



Summary

Exclusion criteria were patients declining to participate in the study and/or declining to receive nocturnal respiratory support via the infor-med consent for said treatment. Demographic data for patients was collected as well as tobacco use, presence of COPD (with spirometry values if affirmative) and the pre-sence of cardiovascular risk factors: arterial hypertension (AHT), dyslipi-demia, diabetes mellitus type 2 (DM2) and obesity.Obesity was defined as those patients with BMI >30 Kg /m². Patients were classified into three groups according to degree of obesity: moderate obesity (BMI 30 - 35 Kg/m²), severe obesity (BMI 35 - 39.9 Kg/m²) and morbid obesity (>40 Kg/m²). The Charlson comorbidity index was also included.The Epwor-th Sleepiness Scale was used for all patients. The study was nocturnal and collected the following variables for analysis: AHI, 4% IDH, average and minimum peripheral capillary oxygen saturation (SpO2), CT90, average and maximum transcutaneous CO2 values (tcCO2) throughout the night of the study. First, the characteristics and values of the aggregate sample were analyzed, followed by those based on diagnosis where patients with SAHS, OHS, COPD and neuromuscular disease were analyzed. Variables were collected based on data and analyzed using the SPSS statistics software package, version 15.0.A statistical analysis was done for all variables included in the study.Qualitative variables are expressed as absolute frequency and percentages, while the quantitative variables are expressed as averages and standard deviations.The correlation bet-ween quantitative variables was measured using Pearson’s correlation co-efficient.The chi-square was used to measure association and compare proportions between qualitative variables. The selection of independent variables for the multivariate analysis was based on the degree of statistical significance obtained in the uni-variate analysis. The presence of hypercapnia was considered to be the main variable.Differences with a p value of 0.05 or less associated with the contrast test were considered significant in all cases. The study was done respecting the ethical principles for medical re-search involving human subjects from the Declaration of Helsinki by the World Medical Association as well as applicable laws for clinical trials with medical products, having received authorization from the center’s clinical research ethics committee.

mAteriAl And methodS An observational prospective study was done on baseline polysomno-graphy and CPAP and BIPAP titration with respiratory poligraphy or po-lysomnography control done in the sleep unit at Hospital Puerta del Mar.The equipment for the sleep study incorporated the TOSCA 500 (Radio-meter Medical ApS, Copenhagen) brand transcutaneous CO2 meter.All patients were recruited from a sleep unit with a suspected sleep-related breathing disorder (SAHS, OHS) or had an existing diagnosis. Patients underwent CPAP or BIPAP titration from 1 March 2013 to 31 August 2014. The study was carried out in the sleep unit at Hospital Puerta del Mar in Cadiz.The TOSCA 500 transcutaneous CO2 meter was connected to one of the Jaeger SleepLab 1000p (Jaeger, Warwich, UK) polysomnograms at our disposal.Thus, all of the studies were carried out in the same PSG bed with the same polysomnography equipment using the same trans-cutaneous CO2 meter, after calibrating the device to avoid measurement errors.For all of the studies, the transcutaneous meter signal was obtained for three values: minimum, average and maximum tcCO2 for each patient. Our study carried out a continuous recording throughout the night, without recalibration nor change in sensor placement throughout the en-tirety of the test.

The following were inclusion criteria: adults over the age of eighteen with one of the following characteristics:

- Immunocompetent patients with obesity (BMI >30 Kg/ m²) with a suspected sleep-related breathing disorder.

- Patients diagnosed with amyotrophic lateral sclerosis (ALS) with suspected alveolar hypoventilation after a suspicious baseline noc-turnal pulse oximetry done during diagnosis or during follow-up at our ALS unit or through daytime hypercapnia detected in a baseline arterial blood gas for patients with alterations in forced vital capa-city during pulmonary function tests.

- Suspected SAHS.- Suspected OHS.- Patients diagnosed with SAHS or OHS for CPAP or BIPAP titra-

tion.



Summary

- 21 CPAP adjustment/titrations.- 34 BIPAP adjustment/titrations.- 1 volumetric ventilator titration.- 1 nocturnal O2 monitoring as separate treatment.

No cases of intolerance to the device or side effects were recorded in the area where the transcutaneous CO2 meter was applied, and thus no changes were made to sensor placement.The meter was also not recali-brated during the recording as it was not considered necessary since, in addition to not needing to change sensor placement, no data collection errors were registered in any study that would require recalibration. When analyzing disease distribution in the aggregate sample, SAHS was the most frequent (61 patients, 68.5%), followed by OHS (31 pa-tients, 34.8%), COPD (25 patients, 28%), patients diagnosed with neu-romuscular disease (4 patients, 4.4%) and patients with no sleep-related breathing disorders after completing a baseline study (7 patients, 8%). SAHS and OHS overlapped in 19 patients.Of the 25 patients with COPD, 20 of them were associated with SAHS (overlap syndrome) and 5 with OHS.Table 3 shows the distribution by disease. With regard to the data obtained in the sleep studies, the average AHI in the aggregate sample was 11.9 and the average IDH was 27. The ave-rage global SpO2 was 91.8% and the minimum was 78.8%. The average CT90 was 22.9%. Average tcCO2 values in the aggregate sample were 45.6, with maximums of 49.2. In CPAP titration, the average pressure was 9.5 cmH2O (range: 9 to 13 cmH2O). In BIPAP titration, the average IPAP was 15.7 cmH2O (range: 9 to 20) and the average EPAP was 7.4 cmH2O (range: 4 to 11). As for the patients who were not diagnosed with respiratory disease after the baseline sleep study, statistically significant differences were observed in pulse oximetry values with respect to the aggregate sample, with an average SpO2 of 94.3% (p: 0.04), a minimum value of 87.4% (p <0.001) and a CT90 value of 1.1% (p <0.001). However, no differences were ob-served in the average and maximum tcCO2 values (46.2 and 48.5, respec-tively), being very similar to those for the aggregate sample.

reSUltS

Aggregate sample analysis A total of 89 patients were included, for whom a total of 102 noc-turnal sleep studies with tcCO2 measurement were conducted.Of the 89 patients, 52.5% were women.The average age was 64 (range: 20-90). The average score on the Epworth Scale was 6.5 points. Half of the participants had a history of tobacco use, primarily among men (62.5%) versus women (37.5%), p <0.001. The average BMI was 35.7 Kg/m² (range: 16.4 to 61), with 73.7% of participants suffering from obesity.Of these, 39.5% were morbidly obese, with a BMI greater than 40. As far as other cardiovascular factors analyzed, their presence was quite significant within the sample. The prevalence of arterial hypertension was 68.8%, dyslipidemia was present in 40% and 37.5% of patients suffe-red from diabetes mellitus. With regard to the distribution of different cardiovascular risk factors between genders, males were significantly associated with tobacco use and suffering from COPD (p< 0.05), similar to obesity and tobacco use, which were more prevalent among men (54.1% and 62.5%, respectively, p <0.04). Arterial hypertension, dyslipidemia and diabetes were more fre-quent among women (58.1%, 53.1% and 53.3%, respectively). The dis-tribution of risk factors for patients involved in the study is reflected in Table 1. The presence of other comorbidities was evaluated using the Charlson comorbidity index, the average value of which was 3.8. In fact, 65% of patients had a Charlson index greater or equal to 3 points.For patients prescribed continuous home oxygen therapy, the average Charlson index was 5.08.

The distribution of sleep studies done with transcutaneous CO2 mo-nitoring is summarized in Table 2.The 102 studies were distributed as follows:

- 45 baseline studies.- 14 split nights. Of these, 10 were BIPAP trials/titrations, 3 for CPAP

and 1 with supplementary O2, all of which were administered in the second part of the study.



Summary

More detailed results for the global parameters from the sleep studies are included in Table 4. table 1.Aggregate sample risk factor distribution

risk factors/comorbidities (%) % Women p*Obesity (BMI >30) 73.7 45.9 NSTobacco use 50 37.5 0.002Arterial hypertension 68.8 58.1 NSDyslipidemia 40 53.1 NSDiabetes mellitus 37.5 53.3 NSCOPD 28 32 0.001

(*): p values in function of different comorbidities between males and females.

table 2.distribution of sleep studies done with tcco2 recording

type of study frequency (%) Baseline PSG 45 44.1 Split night* 14 13.7 CPAP adjustment/titration 21 20.6 BIPAP adjustment/titration 34 33.3 Volumetric ventilator adjustment/titration 1 1 Separate nocturnal O2 adjustment/titration 1 1

* Split nights included CPAP or BIPAP adjustment/titration in the second half of the night.

table 3. distribution of patient disease in the aggregate sample.

distribution by disease frequency (%) OSAHS 61 68.5OHS 31 34.8 COPD 25 28 Neuromuscular 4 4.4 No disease 7 7.8

table 4. parameter values for sleep recording

Average parameter values for sleep study IAH 11.9IDH 27Average SpO2 91.8%Minimum SpO2 78.8%CT90 22.9%Average / maximum global tcCO2 45.6/49.2Baseline study average / maximum tcCO2 44.5/48.03tcCO2 in CPAP titration 45.87/49.22Average / maximum tcCO2 in BIPAP titration 45.41/49.25Patients with nocturnal O2 (with/without BIPAP) (n=12) 45.8/48.92Average CPAP 9.6Average IPAP 15.7Average EPAP 7.4

Analysis by diagnostic subgroup The results for each diagnostic subgroup are described in detail below.Ta-ble 5 shows the average values for the parameters analyzed in the study for each subgroup.

SAHS As mentioned previously, subjects with SAHS accounted for 68.5% of diagnoses, in a total of 61 patients.The average score on the Epworth Scale was 6.9 points. The average BMI was 36.6 (range: 17 to 61) Of the SAHS patients suffering from obesity, 36.8% had a BMI of >40. The average AHI in the diagnostic studies for SAHS was 34.1 (range: 5.1 to 80.9), while the average IDH was 56.84.The average global SpO2 was 90.6% and the minimum was 74.5%. The average CT90 was 33.2%. With regard to the transcutaneous CO2 values for these patients, the average value was 44.8 and the maximum



Summary

was 48.9. 77% of SAHS patients (47 patients) received nocturnal treatment.Of the-se, 22 patients (46.8%) received CPAP treatment with an average pressure of 9.9 cmH2O, while the remaining subjects (25 patients, 53.2%) received BI-PAP treatment with an average IPAP pressure of 15.9 cmH2O and an average EPAP pressure of 7.5 cmH2O.

OHS As we mentioned in the global results, the second most frequent diagnosis was OHS, occurring in 34.8% of cases (31 patients). The average score on the Epworth Scale was 5.5 points. The average BMI for patients diagnosed with OHS was 39 (range: 31 to 56), with 42.8% being morbidly obese with a BMI >40. The average AHI for these patients at the time of diagnosis was 11.2, with an IDH value of 31. The average SpO2 was 90.5, and the minimum was 76.4. The average CT90 was 38.7%. The average transcutaneous CO2 value was 45.2 and the maximum was 49.8. As for the stratification by degree of obesity, an average tcCO2 of 40.2 was observed in patients with moderate obesity, while patients with severe and morbid obesity respectively had averages of45.2 and 45.1. The same is obser-ved in maximum tcCO2 values, which were 46.68 in patients with moderate obesity, while the severely and morbidly obese had respective values of 49.5 and 49.1. Of patients diagnosed with OHS, 67.7% (21 patients) received nocturnal treatment. Of these, 3 patients received CPAP treatment with an average pressure of 13.3 cmH2O, while the 18 remaining subjects received BIPAP treatment with an average IPAP of 15.5 cmH2O and an average EPAP of 5.9 cmH2O.

COPD Of the total number of patients studied, 25 suffer from COPD, making up 28% of the total sample.For these patients, the average FEV1 was 1,042 ml (range: 590 ml to 2,130 ml), with an average obstruction percentage of 44% of the theoretical value. As a result, the majority of COPD patients had se-vere airflow limitation.Men constituted 68% of COPD patients.The majority were also obese (75%) which is a similar percentage to the number of obese patients in the aggregate sample. The average score for COPD patients on the Epworth Scale was 5.5. The

average BMI for COPD patients was 35.4 (range: 17 to 61). Of these subjects, 33% were morbidly obese.The average AHI was 21.8, with an SAHS percen-tage of 80% (20 of 25 COPD patients), while the average IDH was 36.5.The average SpO2 was 86.8 (significantly lower than the global average, p <0.05) and the minimum value was 77.2. The average CT90 was 26% without statis-tically significant differences from the aggregate sample values.The average transcutaneous CO2 value in COPD patients was 42.6 and the maximum was 49. A total of 12 patients received nocturnal treatment, making up 48% of cases.Of these, 7 patients were treated with BIPAP with an average IPAP of 16.4 cmH2O and an average EPAP of 6.8 cmH2O. Those who received CPAP treatment (5 patients) had an average pressure of 10.4 cmH2O.

Amyotrophic lAterAl ScleroSiS Throughout the time of the study, 4 patients diagnosed with amyotrophic lateral sclerosis were included, with an average age of 54 (range: 20-75).The average score on the Epworth Scale was 1.5 points. The average BMI for these patients was 20 (range: 18 to 22). Of the 4 patients with a diagnosis of ALS included in the study, 3 underwent BIPAP titration and a baseline sleep study was only done for one of them to evaluate the presence of nocturnal hypoventilation.Taking this into account, the average AHI for these patients was 11.5 and the IDH was 6.7. Significantly higher pulse oximetry values were also observed in compa-rison with the aggregate sample, with an average SpO2 of 94.2% (p: 0.05), a minimum value of 83.4% (p: 0.02) and a CT90 of 3.2% (p <0.001). Slightly higher average tcCO2 values (46.9) and maximum tcCO2 values (50.4) were also observed with respect to the global average, despite the fact that 3 out of the 4 patients underwent a BIPAP titration study, as mentioned previously.All of them received ventilation through a nasal mask, with average IPAP pressu-re of 11.5 cmH2O and an average EPAP of 5.5 cmH2O.

multivariate analysis Although significant differences were observed for some of the parameters analyzed between the different subgroups, none of the factors studied were related to the presence of hypercapnia in the multivariate analysis.



Summary

diScUSSion Although it may be considered a limitation of the study, a daytime baseline blood gas was not conducted in patients before leaving the hospital since, although it was initially a secondary objective of the study to evaluate the correlation between transcutaneous capnography and blood gas values, due to the organization of the unit and changes with regard to unit staff throughout the study, this point was carried out at the beginning of the study but was not conducted again.The results section does not refer to the comparative ABG analysis done at the end of the study for patients who underwent the test due to the limited number of patients.However, the correlation between the measurement of transcutaneous CO2 and arterial PCO2 values has already been studied in other work, such as the study by Dawson et al.15 and another by Parker and Gibson16. In the latter, the same transcutaneous CO2 meter was used as the one available in our sleep unit.Both studies found a good correlation between arterial PCO2 values and those obtained through measu-ring tcCO2. Correlation studies for both values have even been carried out in

patients hospitalized for respiratory disease17 and patients with sleep-related breathing disorders such as SAHS or OHS18, 19, obtaining good results both in basal sleep studies and CPAP and BIPAP titration. Regarding tolerance to the transcutaneous CO2 meter and the possible side effects from the device in the area where the meter was applied on the skin, this study did not register any case of discomfort or side effects, agreeing with the results obtained by other authors who have completed continuous 8-hour monitoring13, 14. If we analyze the average and maximum tcCO2 values detected in the ag-gregate sample, we find slightly elevated levels despite having a normal ave-rage SpO2. It was only among subjects who underwent a baseline study for suspected sleep-related breathing disorders and in which the test ruled out any disorder that we found normal tcCO2 values as well as higher average and minimum SpO2 values and a lower CT90. The fact that average and maximum tcCO2 values similar to the aggregate sample were seen for patients who were ultimately not diagnosed with any sleep-related breathing disorder after the baseline study may be justified because there were only 7 cases, a very small number of patients to establish differences. Obesity is a known independent risk factor for suffering from SAHS.In fact, two thirds of patients with SAHS are obese19. Additionally, 90% of hy-percapnic obese patients suffer from SAHS, while 11 to 15% of obese pa-tients with SAHS show signs of hypercapnia, a figure which increases to23-27% when BMI >4019, 20. In our study, the average and maximum tcCO2 levels were observed to be higher corresponding to higher BMI,although they did not reach statistical significance.There was a very similar distribution of di-sease among the obesity subgroups, except for ALS patients where the BMI was noticeably lower.This may be explained by the fact that when they arrive at the sleep unit to begin non-invasive ventilation, ALS patients already have a significant deterioration in muscle function as well as muscle mass. With regard to the finding that 80% of COPD patients presented symp-toms of SAHS (overlap syndrome), this may be due to several factors.First, the main indication to complete the sleep study was suspected SAHS, and thus the sample is biased. In other words, the objective of the study was not to evaluate the existence of SAHS in COPD patients in general. On the con-trary, patients who have clinical symptoms compatible with SAHS, regardless of COPD, were candidates to participate in the study.Secondly, the percen-tage of obesity among COPD patients included in the study was 75%, quite

table 5. parameter values obtained in the study for different diagnostic subgroups

SAhS ohS copd AlS* Aggregate sampleBMI 36.6 39 35.4 20 35.7Epworth Scale 6.9 5.5 5.5 1.5 6.5AHI 34.1 11.2 21.8 11.5 11.9IDH 56.8 31 36.4 6.7 27Minimum SpO2 74.5 76.4 77.2 83.4 78.8Average SpO2 90.6 90.4 86.4 94.2 91.8CT90 (%) 33.2 38.7 26 3.2 22.9Average tcCO2 44.8 45.2 42.6 46.9 45.6Maximum tcCO2 48.9 49.8 49 50.4 49.2Average CPAP pressure 9.9 13.3 10.4 - 9.5Average IPAP pressure 15.9 15.5 16.4 11.5 15.7Average EPAP pressure 7.5 5.9 6.8 5.5 7.4*The study was BIPAP titration for three out of four patients with ALS.



Summary

trastornos respiratorios del sueño. Ed Respira, Barcelona 2011. ISBN 978-84-937553-9-3. 5. Eberhard P. The design, use, and results of transcutaneous carbon dioxide analysis: current and

future directions. Anesth Analg 2007; 105 (Suppl 6): 48 –52. 6. Moronta D, Gutiérrez C. Correlación de los valores de PCO2 obtenidos por gasometría arterial y

capnografía transcutánea. Sanid. Mil. 2013; 69 (2): 82-86.7. Molloy EJ, Deakins K. Are carbon dioxide detectors useful in neonates? Review. Arch Dis Child

Fetal Neonatal Ed 2006; 91: 295-298.8. Gal S, Riskin A, Chistyakov I et al. Transcutaneous PCO2 monitoring in infants hospitalized with

viral bronchiolitis. European Journal of Pediatrics. 2015; 174 (3): 319-324. 9. Pautrat J, Khirani S, Boulé M. Carbon dioxige levels during polygraphy in children with sleep-

disorded breathing. Sleep and Breathing 2015; 19 (1): 149-157.10. Kelly AM, Klim S. Agreegment between arterial and transcutaneous PCO2 in patiends under-

going non- invasive ventilation. Respiratory Medicine. 2011; 105: 226-229. 11. Lee SK, Kim DH, Choi WA et al. Transcutaneous CO2 monitoring in determining initial mecha-

nical ventilator application in NMD. Ann Rehabil Med 2012; 36: 126-132. 12. Janssens JP, Howarth-Frey C, Chevrolet JC et al. Transcutaneous PCO2 to monitor noninvasive

mechanical ventilation in adults: assessment of a new transcutaneous device. Chest 1998; 113: 768-773.

13. Janssens, JP, Perrin E, Bennani I et al. Is continuos transcutaneous monitoring of PCO2 (tcPCO2) over 8h reliable in adults?. Respiratory Medicine 2001; 95, 331-335.

14. Storre JH, Magnet FS, Dreher M et al. Transcutaneous monitoring as a replacement for arterial PCO2 monitoring during nocturnal non-invasive ventilation. Resp Medicine 2011; 105: 143-150.

15. Dawson S, Cave C, Pavord I et al. Transcutaneous monitoring of blood gases: is it comparable with areialized aerlobe sampling?. Resp Medicine 1998; 92: 584-587.

16. Parker SM, Gibson GJ. Evaluation of a transcutaneous carbon dioxide monitor (“TOSCA”) in adult patients in routine respiratory practice. Resp Medicine 2007; 101, 261-264.

17. Herrejón A, Inchaurraga I, Palop J et al. Utilidad de la presión transcutánea del anhídrido carbó-nico en la valoración gasométrica de adultos hospitalizados con enfermedad respiratoria. Arch Bronconeumol. 2006; 42 (5): 225-29.

18. Maniscalco M, Zedda A, Faraone S et al. Evaluation of a transcutaneous carbon dioxide monitor in severe obesity. Intensive Care Med (2008) 34: 1340–1344.

19. Rabec C, De Lucas P, Veale D. Complicaciones respiratorias de la obesidad. Arch Bronconeumol 2011; 47 (5): 252–261.

20. Mokhlesi B, Tulaimat A, Faibussowitsch I et al. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007; 11: 117–24.

a high number, although the percentage was similar to the aggregate sample.Despite the fact that these patients had an average SpO2 lower than the other subgroups, with a higher CT90, the minimum SpO2 was similar to the other groups, along with average and maximum transcutaneous CO2 levels. This mild hypoxemia, without higher hypercapnia than the other groups, could be explained by these patients’ low lung function. In a study by Lee et al.11 on neuromuscular patients, which followed hospi-talization and included a baseline blood gas and later continuous recording of tcCO2, patients with normocapnia in the baseline ABG were shown to display hypercapnia in nocturnal CO2 measurements, concluding that ABG is not sufficient as the only tool to detect ventilator mechanics problems in these pa-tients.Our study was only able to recruit 4 patients with neuromuscular disease and of them, a baseline study was only done for one. The other 3 patients underwent BIPAP titration. The average tcCO2 level for these patients was 47, slightly higher than the aggregate sample, along with a maximum tcCO2 of 50.4. However, while this is a small number of patients to be able to reach conclusions, it seems that these patients may be especially interested in trans-cutaneous CO2 monitoring, as hypoventilation can often go unnoticed.

conclUSionSThe results of the study reveal that the presence of latent nighttime hyper-capnia in patients with respiratory disease is frequent while sleeping, both in diagnostic studies and in CPAP or BIPAP titration studies.In addition, we have not found problems with device tolerance stemming from continued use throughout the night.Thus, it can be used to reveal latent hypercapnia in diffe-rent diseases during adult sleep, in addition to the observed lack of discomfort and side effects at the local level.

BiBliogrAphy1. Durán-Cantolla J, Puertas-Cuesta FJ, Pin- Arboledas G et al. Documento de consenso nacional

sobre el síndrome de apneas- hipopneas del sueño. Arch Bronconeumol. 2005; 41: 1-110.2. Epstein LJ, Kristo D, Strollo PJ et al. Adult obstructive sleep apnea task force of the american

academy of sleep medicine. Clinical guideline for the evaluation, management and long- term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009; 5: 3.

3. Marín JM, Arán X, Barbé F et al. Recomendaciones SEPAR. Diagnóstico y tratamiento del sín-drome de apnea obstructiva del sueño Arch Bronconeumol. 2011; 47 (3): 146-149.

4. Miralda R, Fortuna A, Farré A et al. Poligrafía respiratoria. En: Manual de Procedimientos en

125

Summary

ORIGINALS


Abstract: Objective: To describe our cases in the field of therapeutic Interventional Bronchoscopy after 10 years of experience. Materials and Methods: We collected history, type of Tracheobronchial Pathology, techni-que, results and complications. Results: Were they performed 186 (113 male and 73 female) patients with mean age 51.3 years (range: 8-86). Had 320 procedures or techniques performed on them. Indications for the procedure: benign airway stenosis 45,69% (85/186), malignant stenosis 41.93% (78/186), tracheoesophageal and bronchopleural fistulas 5.91% (11/186), foreign bodies extracted with rigid bronchoscope 4.3% (8/186), and 3 cases of threatening hemoptysis. Among the benign stenosis secondary to intubation followed by the post-tracheotomy were the most common, 35.29% (30) and 34.11% (29) respectively. Between malignant lesions, 63 cases (80,76%) had home lung, of these, carcinoma, bronchogenic, 60 of 78 patients, was the most frequent and 3 carcinoid tumors. The rest 19,23% (15 / 78) were non bronchopulmonary tumors. The most used techniques have been laser in 100 cases, pneumatic dilatation in 65, Endoprosthesis 53 (35 metal and silicone 18), electrosurgery in 50, mechanical resection in 45 patients, 3 fistulas sealments and 3 occlusion balloon by hemoptysis. The most employed combined procedure was resection laser and mechanics more pneumatic dilation. Intraoperative complications in 11 cases (4.8%) and late in 4 (2.15%). All patients (100%) improved their symptoms after the procedure. Conclusions: The therapeutic interventionist bronchoscopy is a safe and effective procedure in the management of injuries in the airways.

Key words: Interventional pulmonology, rigid bronchoscopy, laser resection, pneumatic dilatation, bronchial electrocautery, stents.

Received: September 13, 2016. Accepted: May 1, 2017.

Francisco M. Páez [email protected]

ANÁLISIS DESCRIPTIVO DE 10 AÑOS DE BRONCOSCOPIA TERAPÉUTICA INTERVENCIONISTA

ResumenObjetivo: Describir nuestros casos en el campo de la broncoscopia terapéutica intervencio-nista después de 10 años de experienciaMateriales y métodos: Hemos recogido historia, tipo de patología traqueobronquial, técni-cas, resultados y complicacionesResultados: Fueron incluidos 186 pacientes (113 hombres y 73 mujeres), con edad media de 51,3 años (rango 8 - 86). Se han realizado 320 procedimientos o técnicas sobre ellos. Indica-ciones del procedimiento: estenosis benigna de la vía aérea 45,69% (85/186), estenosis malig-na 41,93 % (78/186), fistula traqueoesofágica y broncopleural 5,91% (11/186), extracción de cuerpo extraño con broncoscopio rígido 4,3% (8/186) y 3 casos de hemoptisis amenazante. La estenosis benigna secundaria a intubación seguida por la post traqueostomia fueron las más comunes, 35,29% (30) y 34,11% (29) respectivamente. Entre las lesiones malignas, 63 ca-sos (80,76%) estaban localizados en el pulmón, de estos, el carcinoma broncogenico, 60 de 78 pacientes, era el más frecuente y 3 tumores carcinoides. El 19,23% restante (15/78) no eran tumores broncopulmonares. La técnica más usada ha sido el laser en 100 casos, dilatación neumática en 65, endoprótesis 53 (35 metálicas y 18 silicona), electrocirugía en 50, resección mecánica en 45 pacientes, 3 sellados de fístulas y 3 oclusiones con balón por hemoptisis. El procedimiento combinado más empleado fue la resección laser más dilatación neumática. Complicaciones intraoperatorias en 11 casos (4,8%) y tardías en 4 (2,15%). Todos los pacien-tes (100%) mejoraron de sus síntomas después del procedimiento.Conclusiones: La broncoscopia terapéutica intervencionista es un procedimiento seguro y efectivo en el manejo de las lesiones de la vía aérea.

Palabras clave: Neumología intervencionista, broncoscopia rígida, resección laser, dilata-ción neumática, electrocauterio bronquial, stents.

F.M. Páez Codeso, A. Dorado Galindo, D. Jiménez Fernández, M. Arroyo Varela, M. García Rueda, J.L. de la Cruz Ríos.

Servicio de Neumología. Hospital Regional Carlos Haya. Málaga.

DESCRIPTIVE ANALySIS Of 10 yEARS Of INTERVENTIONAL ThERAPEUTIC BRONChOSCOPy

mailto:paezco64%40gmail.com?subject=Revista%20Neumosur


F. M. Páez Codeso et al. Descriptive Analysis of 10 Years of Interventional Therapeutic Bronchoscopy

Summary

INTRODUCTION Since endobronchial lasers were first used1 and pulmonologists’ redisco-very of rigid bronchoscopy2, a new discipline within this specialty been un-veiled, known as Interventional Pulmonology3, 4. Our objective is to describe our experience in this field as 2015 marked 10 years since the technique was implemented in our department.

MATERIALS AND METhODS We have performed a retrospective study, reviewing the medical his-tories of patients who have undergone interventional therapeutic bron-choscopy in the Bronchopleural Techniques Unit of the Pulmonology Department at the Hospital Regional Carlos Haya in Malaga over a 10-year period from January 2005 to December 2015.The objective is to describe our experience analyzing the case histories from this period.Endobronchial brachytherapy cases have not been included. According to 2011 data from the annual hospital report, the reference population for the hospital area is 623,301 inhabitants, and the reference for the province and Melilla reaches 1,249,290 inhabitants.We have also treated patients from other provinces such as Campo de Gibraltar (Cadiz) and El Ejido (Almeria).The Bronchopleural Techniques Unit performs approximately 600 bronchoscopies per year.With the exception of one case, we have not treated pediatric patients. In our systematic evaluation of each patient, they undergo a blood test which includes hematimetry, basic biochemistry (glucose, urea, crea-tinine and an ionogram) and hemostasis, as well as an electrocardiogram and arterial blood gas in cases which presented oxygen saturation (SatO2) of less than 92% or clear respiratory distress.Pulmonary function tests included at least one spirometry study with flow-volume loop.Imaging techniques always included computerized tomography, done in our cen-ter or the referring hospital.Said study was analyzed jointly with a ra-diologist, evaluating the lesion to be treated from different perspectives (axial, coronal, sagittal) and with virtual bronchoscopy, taking the ne-cessary measurements (length of lesion and diameter of a normal and pathological airway) in the case of stenosis lesions that were believed to result in endoprosthesis.At the same time, a flexible bronchoscopy was done in our examination room for all of the programmable (non-urgent)

cases, including those patients who had undergone the procedure in the hospital. The preoperative study was evaluated during the pre-anesthe-tic assessment, except in those cases which presented a life-threatening emergency. After informing the patients and signing the corresponding consent form, they were included on a waiting list and scheduled according to considered urgency.In this sense, we had one operating room available in the morning each month.For urgent cases, the anesthesiology team on duty was contacted.The two interventional pulmonologists planned the type of intervention appropriate for each case according to the informa-tion collected.The diseases treated were benign and malignant stenosis, tracheoesophageal and bronchopleural fistulas, foreign matter and life-threatening hemoptysis.The interventional therapy procedure was carried out in the operating room, under general intravenous anesthesia, avoiding inhalation anesthetics whenever possible.We did not have jet ventilation available for any case. The following equipment was used: a rigid bronchoscope Efer-Du-mon, comprised of a 13.20mm and 12mm tracheoscope and a 12mm and rigid bronchoscope of different diameters, which used an intermediary piece to pass through the tracheoscope when it was necessary to selecti-vely intubate the left or right bronchi. A Dumon stent loader and intro-ducer. A 5.5 straight-view rigid optics (Efer endoscopy BX 5500). Two flexible bronchoscopes were used interchangeably, one of which was a Pentax EB-1570® video bronchoscope 5.1mm in diameter with a 2mm working channel, and the other aPentax EB-1970® bronchoscope with a 2.8mm channel and 6.2mm diameter, according to the need for a lar-ger or smaller working channel.Rigid grasping forceps.Laser equipment (Biolitec®) with a cooled non-contact probe for photovaporization and another contact probe for cutting.Electrocautery (ECT) or electrosurgery equipment (Olympus PSD 30®) which has a coagulation electrode, elec-tric knife, loop diathermy and hot biopsy forceps. For pneumatic dilation, we used a balloon dilation catheter for controlled radial expansion (CRE Wireguided™) from the Boston Scientific® trading house with diameters between 6mm and 20mm.The CRE was controlled by a manometer which regulated the pressure acting on the walls of the airway in atmospheres (minimum: 3 atm, maximum: 10 atm.) The procedure was done according to applicable international recom-



Summary

With regard to personal background, 83 patients had a history of to-bacco use (44.6%), 67 had pulmonary disease (36%), there was some car-diovascular risk factor in 63 patients (33.9%), heart disease in 25 (14.5%), and history of other disease for 62 patients (33.3%). Over half, 51.07% (95/186) were patients with multiple diseases, presenting several comorbi-dities. The most frequent symptom was benign stenosis, 85 cases (45.69%), followed by neoplastic or malignant stenosis, 78 cases (41.93%), tracheo-

mendations5-7, always being done by the same staff member, from both nursing (a care assistant licensed in nursing) and medical practice (two pulmonologists).

RESULTS During the period of study, a total of 186 patients were examined, 113 males and 73 females.The average age +/- standard deviation was 51.3 +/- 18.11 (range: 10 - 86). 31.7% of patients did not belong to our health service area. Throughout the course of interventional therapeutic bronchoscopy, 320 techniques or procedures were used on the 186 patients (Table 1).

esophageal or bronchopleural fistulas,11 cases (5.91%), 8 foreign matter extractions with rigid bronchoscopy (4.3%), and 3 cases of life-threatening hemoptysis (1.61%). The majority of patients came from the Pulmonology Department, fo-llowed by the departments of Medical Oncology and Radiotherapy. The area of treatment or anatomical region was the trachea in 92 cases (49.5%), the bronchi in 85 (45%), of which 46 cases affected the right tree and 39 the left, and the tracheobronchial tree was affected in 9 cases (4.8%). Access was always obtained via the oral pathway.A rigid bronchoscope was only used as the exclusive instrument in 8 cases (4.3%), only a flexible bronchoscope was used in 40 cases (21.5%) and a combination of flexible bronchoscope through a rigid bronchoscope was used in 138 cases (74.2%). As far as benign stenosis pathology of the airway (Table 2), of 85 pa-tients, 30 cases were lesions following prolonged intubation (35.29%), there were 29 cases of post-tracheostomy lesions (34,11%), 12 cases of granu-lomas at the ends of the tracheostomy tube or implanted stent (22.64%), 7 patients (3.76%) with idiopathic tracheal stenosis (Fig.1), 2 patients with recurrent respiratory papillomatosis (2.35%), and other causes in the re-maining 5 patients (5.88%), in which we include one case for each of the following diseases: granulomatosis with polyangiitis, amyloidosis, sarcoido-sis, tuberculosis and relapsing polychondritis, each of these with severe and extensive endoluminal involvement.

Procedure Endobronchial laser 100Pneumatic dilation balloon 65Endoprosthesis 53Mechanical resection 45Electrocautery 35Argon plasma 15Fistula sealing 3Bronchial occlusion balloon 3Microdebridement 1 Total: 320

Table 1. Number and type of technique or procedure performed

Type of lesion number %PI 30 35.29PT 29 34.11 Granulomas 12 22.64ITS 7 3.76Recurrent respiratory papillomatosis 2 2.35Others+ 5 5.88

Total patients 85PI: tracheal stenosis following prolonged intubation. PT: post-tracheostomy tracheal stenosis. ITS: idiopathic tracheal stenosis. (+) Explanation in the text.

Table 2. Benign stenosis etiology



Summary

Fig. 1. Circumferential idiopathic subglottic stenosis

In the 78 cases of malignant or tumor pathology (Table 3), the lesion was predominantly intraluminal in 69 patients (88.46%) and extraluminal or from extrinsic compression in 9 cases (11.53%).Of these neoplastic lesions, 63 cases (80.76%) originated in the lungs and, of these, bronchogenic carci-noma was the most frequent tumor constituting 60 out of 78 patients, along with 3 carcinoid tumors.The remaining 19.23% (15/78) were non-broncho-pulmonary tumors which affected the lower airway through different me-chanisms including proximity infiltration, extrinsic compression and endo-bronchial metastasis.The origins were: esophagus (6) thyroid (4), mediastinal lymphoma (2), mediastinal germ cell tumor (2) and cervical carcinoma (1). Three cases of post-surgical bronchopleural fistula and eight of neoplastic tracheoesophageal fistula originating from neoplasm were also treated. We have had 8 cases of foreign matter extraction which required the use of general anesthesia and rigid bronchoscopy due to the impossibility of using flexible bronchoscopy.There were three cases of life-threatening he-

moptysis, the most severe of which occurred in a patient with cystic fibrosis, in which, after failure with artery embolization, bleeding was controlled with rigid bronchoscopy and an occlusion balloon. Within the techniques or procedures used, a laser was used in 100 patients (53.76%) using both the cooled non-contact probe and the cutting mode.Mechanical dilation with a CRE balloon was the second most frequently used procedure in 65 cases (34.94%).Mechanical resection with a bezel on a rigid tracheoscope or bronchoscope was used in 45 patients (24.19%).Elec-trocautery (ECT) was used for 35 patients (18.81%) in the different modes of electrocoagulation: electric knife, loop diathermy and hot biopsy forceps. Argon plasma was used in 15 cases (8.1%).Histoacryl® adhesive was used in 3 cases of bronchopleural fistula. Occlusion balloons implanted via rigid bronchoscopy were used in 3 more patients to manage life-threatening he-moptysis pathways. Finally, there was one case of mechanical microdebride-ment (Medtronic® microdebrider).

Neoplasm origin number %Pulmonary origin 63 80.76 Bronchogenic carcinoma 60 Bronchial carcinoid tumor 3

Extrapulmonary origin 15 19.23 Esophagus 6 Thyroid 4 Lymphoma 2 Germ cell tumor 2 Cervix 1

Total patients 78Explanation in the text.

Table 3. Malignant stenosis etiology



Summary

case of exitus during the procedure after massive blood loss when attempting to repermeabilize the main left bronchus after adenocarcinoma of the lung.Posto-perative and late complications were: a case of subcutaneous emphysema a few hours after an ECT resection of bronchial infiltration from adenocarcinoma in the main left bronchus which was resolved in 48 hours; 2 cases of silicone stent migration (Fig. 3), both occurring one week after implantation, which required removal in one case and substitution in the other; 2 patients receiving stents (3.7%) who required additional intervention months later due to the appearance of granulomas (Fig. 4) which almost entirely destroyed the distal end of the stent. The benefits of the interventional procedure in relation to survival have been very good.In general, survival of more than one year counted from the day of the interventional procedure was 80.6%, with the remaining 19.4% surviving less than one year.However, in the malignant tumor group of patients, survival rates were visibly lower.Of the 78 patients with neoplastic lesions, 48 (58.97%) survi-ved longer than one year.However, even in these cases, with the exception of the intraoperative exitus, 100% showed an immediate improvement in dyspnea

A total of 53 silicone-coated stents were used. Of these, 35 were Nitinol self-expanding metallic stents, (31 Boston Scientific® ultraflex, 3 Leufen aerstent TBY® tracheobronchial stents and 1 AERO stent Alveolus, Inc., NC, USA®).The remaining 18 were Dumon stents, 2 of which were tra-cheobronchial stents (GSSTM Y), 2 hourglass stents (Dumon ST), 1 carina stent (Dumon CB), and the rest were Dumon bronchial or tracheal stents (GSSTM BD and GSSTMTD, respectively) (Fig. 2).

Fig. 2. Dumon CB stent (special for carina). Used for a post-tuberculosis bronchostenosis of the main left bronchus. Opening of the main right bronchus (arrow).

↓ Intraoperative complications were uncommon, with a total of 4.8% consisting of: 7 cases of hemoptysis, controlled by topical measures during the procedure; a bronchial rupture while trying to place the silicone stent; a perforation in the pos-terior wall of the bronchus intermedius from the laser, requiring an emergency thoracotomy in the case of granulomatosis with polyangiitis; 1 case of airway fire ignited by the laser, which did not cause posterior problems for the patient; and 1

Fig. 3. Tracheal stenosis following prolonged intubation with malacia in the trachea wall. Distally migrated Dumon stent which needed to be re-positioned.



Summary

py has been the most frequent advice (58.06%), we can note, in accordance with the bibliography13, stenosis following prolonged intubation and post-tracheostomy stenosis which were the most habitual symptoms.Of the latter, we have seen two types: those associated with lesions on the tracheal tube once closed and more distal lesions of the trachea subjected to pressure from the endotracheal tube cuff, analogous with those caused by decubitus which provoke the ballooning of the endotracheal tube with regard to the tracheal mucosa.These stenoses result in an ischemic lesion on the mucosa and cartila-ge in the airway, which provokes malacia and loss of tracheal wall structure14. These lesions are almost always subsidiaries of endoprosthesis rather than ablative heat treatment (laser or ECT).The third most common type of be-nign stenosis was caused by stenosing granulomas in patients using a perma-nent tracheostomy tube in 10 cases and 2 cases at the distal ends of metallic endoprostheses. With regard to idiopathic tracheal stenosis, we only had 7 patients and it is noteworthy that all of them were women with an average age of 58 and that the anatomic area affected was the subglottis-trachea in all cases.While uncommon, this type of stenosis is difficult to manage endoscopically.All pa-tients were subjected to laser and mechanical resectioning with the bezel of a tracheoscope, avoiding placing the stent in the area immediately below the vo-cal cords.The first stage of the endoscopic surgery was done with a laryngeal mask and fiber laser using a flexible bronchoscope, intubating with a rigid ins-trument for resection in the second stage.Mitomycin C was applied at the end of the procedure in each case.Of the 7 patients with idiopathic subglottic tra-cheal stenosis, 4 were treated with bronchoscopy just once, without recurren-ce, in follow-up since 2010 for the oldest bronchoscopy treatment and since July 2015 for the most recent.In contrast, in the 3 remaining cases, recurrence has been the standard, with the average time until the first restenosis being 20 months (8-32).All patients underwent open surgery after an average of 3.3 (2-4) laser procedures.One of the patients who underwent thoracic surgery passed away 4 days after surgery from a Montgomery stent obstruction, which was implanted to aid the trachea.The other two patients to undergo thoracic surgery (one at our center and one at the Hospital Clínico de Valencia) have been free of disease during follow-up since 2011 and 2012, respectively.There is still no clear explanation as to why idiopathic stenosis recurs after the use of laser.Based on our experience, after the second restenosis we believed we should consider stopping ablative heat endoscopy (laser or ECT) and consider

DISCUSSION Interventional therapeutic bronchoscopy has proven, in general, to be very effective in improving symptomatology in patients affected by airway steno-sis8. This is especially true in the case of benign stenosis, for which it can be a decisive and definitive method, avoiding open surgery which is a much more invasive procedure and is not without the possibility for significant compli-cations9. However, cases must be studied and evaluated together with pul-monologists, thoracic surgeons and otolaryngologists in order to select the most appropriate initial treatment for each patient.However, in the case of malignant airway stenoses, endoscopic treatment is always done as palliative care10-11, thus obtaining poorer results regarding medium to long-term survi-val12, although there are immediate benefits for patients’ quality of life. Among the benign stenoses in our study, for which therapeutic endosco-

Figure 4. Tracheal metallic stent with formation of granulomas at its distal end.



Summary

open surgery when possible, as recurrence is highly likely, especially in cases of early restenosis. Within benign stenoses, a numerous group of systemic inflammatory di-seases of unknown etiology are worth mentioning which, occasionally, exten-sively and severely affect the tracheobronchial tree.Our experience is limited in this field as we have treated 5 patients in total.The patient with granuloma-tosis with polyangiitis presented multiple stenoses in the bilateral peripheral bronchi, pseudomembranes, mucosal ulcerations and the characteristic lesions described as submucosal tunnels (pinhole like)15-17.She underwent repermea-bilization with broncholaser and balloon dilation on 8 occasions (from 2009 to 2011), occasionally with rigid bronchoscope under general anesthesia and other times with flexible bronchoscope and conscious sedation, with satisfac-tory but transient results.On one occasion, laser perforation of the stenosed bronchus intermedius required an emergency thoracotomy.We can note that, in spite of the serological management of the disease with the normalization of renal function and negativization of anti-neutrophil cytoplasmic antibodies (C-ANCA) with immunosuppressive treatment (steroids and cyclophospha-mide), airway lesions continued to progress until endobronchial involvement spontaneously stabilized from October 2011 to the present.Since then, we have done non-invasive monitoring with occasional spirometry and clinical examinations. Stenosing tumors have been the second most frequent symptom of thera-peutic bronchoscopy in our study (nearly 42%).We can highlight bronchopul-monary origin and bronchogenic carcinoma as the most frequent, present in more than 80% of cases, and a miscellany of non-bronchopulmonary tumors that affect the airway, predominantly from the esophagus and thyroid.Indica-tions in these cases of malignant disease are generally palliative.Exceptions to cases of tumors in which treatment can be curative, such as photodyna-mic therapy, are still under debate and are the cause of controversy in the literature18.Carcinoid tumors are among these exceptions19-20 with exclusively endobronchial involvement.In our experience, we have treated 3 typical ca-ses of carcinoid tumors without detected metastasis in scans with octreotide (octreoscans) in which 2 cases were completely resected with loop diathermy and had no recurrence after follow-up of more than 5 years in the first case and more than 2 in the second.However, in the third case a complete resec-tion of the tumor was not possible and, after repermeabilizing the main right bronchus which was completely stenosed provoking atelectasis, the patient

underwent a pneumonectomy.Carcinoma in situ is another exception, an un-common occurrence in clinical practice, but which allows for local endosco-py treatment.In our study, we have only recently treated 1 case,using ECT without tumor recurrence after 3 months. Massive or life-threatening hemoptysis constitutes one of the emergencies most feared by pulmonologists21-22.The use of rigid bronchoscopy allows us to simultaneously secure the airway and ventilation and, along with the possi-bility of breathing with large diameter tubes, achieve immediate hemostasis of bleeding areas and insert Fogarty endovascular catheters or bronchial balloon catheters, which are specifically made for this purpose (Olympus B5-2C 5F and B7-2C 7F). The 5F Fogarty catheter used on our patients provides an in-flated diameter of 11mm, which is more than sufficient to occlude segmental and lobular bronchi, even the bronchus intermedius in its distal third.It can be inserted through a working channel, which does not allow us to extract the bronchoscope later, or parallel with the bronchoscope, helping it with biop-sy forceps inserted in the channel which grip the distal end of the catheter, allowing us to direct it to the desired bronchial area. The management of fistulas in the airway is very complex23.Bronchopleu-ral fistulas can be treated with different methods.We have used an n-butyl 2 cyanoacrylate adhesive substance in the three cases, resolving the escape of air in two cases. An additional surgical procedure was required due to seal fai-lure in the third case.Other proposed methods include Watanabe Spigots25-26 and finally shut-off valves27.For their part, tracheoesophageal fistulas28 suppo-se an even more complex problem.The 8 cases in the study originated from neoplasms and a silicone or metallic stent was placed in the trachea in each case. The fistula output only managed to be completely reversed in one case.Treatment must be accompanied by sealing the fistula through the digesti-ve tract with a self-expanding metallic stent, which was not possible for the Digestive Department in half of the cases.To this complexity we can add a patient with a very advanced-stage neoplastic process with poor general me-tabolic conditions due to nutritional problems given that, until the fistula was fixed, they had to be fed through parenteral or enteral nutrition (percutaneous endoscopic gastrostomy (PEG) tube)29. With regard to the different types of interventional procedures, during bronchoscopy it is common to not perform a single procedure, but rather several.In this sense, the combination of techniques that was most commonly used in our study was laser and mechanical resection, followed by pneumatic



Summary

dilation in 37 cases and laser and mechanical resection accompanied by pneu-matic dilation and endoprosthesis placement in 13 of the cases with malignant infiltrative stenosing lesions.Finally, for the first time in Spain, we had the opportunity to use mechanical microdebrider bronchoscopy for the resection of granulomas in a metallic stent30-31.

CONCLUSIONS We can end this 10-year descriptive analysis of airway intervention at our center by concluding that the procedure is safe in general, with a low compli-cation rate, and it is in line with information published in similar studies.The benefits of the technique can be curative in some cases of benign lesions.In the case of malignancies, if the patients are appropriately selected, they can also benefit from an alleviation of symptoms with improved quality of life for a large majority32.As for the benefits interventional procedures have had for other types of diseases we have treated (systemic diseases which affect the airway, fistulas, etc.), we cannot draw any definitive conclusions as the results have not always been satisfactory and there have been a small number of ca-ses.

Acknowledgments To Doctors Andrés Cosano from Córdoba and Enrique García from Gra-nada, our teachers. And our closest teacher José Luis de la Cruz

BIBLIOGRAPhy1. Díaz Jiménez P, Rodríguez AN. Broncoscopia láser. En Díaz Jiménez JP, Rodríguez AN,

editores. Neumología intervencionista. Barcelona: Ediciones Gea; 2000. p .31-57.2. Díaz Jiménez P, Rodríguez AN. Broncoscopia rígida. En Díaz Jiménez JP, Rodríguez AN,

editores. Neumología intervencionista. Barcelona: Ediciones Gea; 2000. p. 1-16.3. Seijo LM, Stermann DH. Interventional pulmonology. N Engl J Med. 2001; 344:740-748.4. Shulimzon TR. Interventional Pulmonology: A New Medical Specialty. IMAJ. 2014; 16:

379–384.5. Bolliger CT, Mathur PN, Beamis JF et al. ERS/ATS statement on interventional pulmono-

logy. Eur Respir J 2002; 19: 356–373.6. Ernst A, Silvestri GA, Johnstone D. American College of Chest Physicians. Interventional

pulmonary procedures: guidelines from the American College of Chest Physicians. Chest 2003; 123: 1693-1717.

7. Du Rand I A, Barber P V, Goldring J et al. British Thoracic Society guideline for advanced

diagnostic and therapeutic flexible bronchoscopy in adults. Thorax. 2011; 66: 1-21.8. Cosano Povedano A, Muñoz Cabrera L, Cosano Povedano FJ et al. Cinco años de expe-

riencia en el tratamiento endoscópico de las estenosis de la vía aérea principal. Arch Bron-coneumol. 2005; 41 (6): 322-327.

9. Li YQ, Li Q, Baj C et al. Causes of bening central airway stenoses and the efficacy of inter-ventional treatments through flexible bronchoscopy. Zhonghua Jie He He Hu Xi Za Zhi. 2008; (5): 364-368.

10. Bacon JL, Patterson CM, Madden BP. Indications and interventional options for non-re-sectable tracheal stenosis. J Thorac Dis. 2014; (3): 258–270.

11. Okiror L, Jiang L, Oswald N et al. Bronchoscopyc management of patients with symp-tomatic airway stenosis and prognostic factors for survival . Ann Thorac Surg. 2015; (5): 1725-1730.

12. Prashant N, Somandin S, Baty F et al. Therapeutic bronchoscopy for malignant airway stenoses: Choice of modality and survival. J Cancer Res Ther. 2010; (6): 204-209.

13. Cotton RT. Management of subglottic stenoses. Otolaryngologic. Clinic of North Am 2000; 33: 111-131.

14. Babarro R, Martínez A, Martínez J et al. Resection with End-to-End Anastomosis for Post-Intubation Tracheal Stenosis. Acta Otorrinolaringol Esp. 2007; 58 (1): 16-9.

15. Daum TE, Specks U, Colby TV et al. Tracheobrochial involvement in Wegener´s granulo-matosis. Am J Respir Crit Care Med. 1995; 151: 522-526.

16. Polychronnopoulos VS, Prakash UBS, Golbin JM et al. Airway involvement in Wegener´s granulomatosis. Rheum Dis Clin N Am. 2007 (33); 755-775.

17. King TE. Respiratory tract involvement in granulomatosis with polyangiitis and microsco-pic polyangiitis. Up to date May 10, 2016.

18. Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nature Reviews Cancer 2003; 3 (5): 380–387.

19. Porpodis K, Karanikas M, Zarogoulidis P et al. A case of typical pulmonary carcinoid tumor treated with bronchoscopic therapy followed by lobectomy. J Multidiscip Healthc. 2012; 5: 47–51.

20. Hadda V, Madan K, Mohan A et al. Successful Flexible Bronchoscopic Management of Dynamic Central Airway Obstruction by a Large Tracheal Carcinoid Tumor. Case Reports in Pulmonology. 2014, 1-4.

21. Cordovilla R, Bollo de Miguel E, Nuñez A et al. Diagnóstico y tratamiento de la hemoptisis. Arch Bronconeumol. 2016; 52 (7): 368-377.

22. Sakr L, Dutau H. Massive hemoptysis: An update on the role of bronchoscopy in diagnosis and management. Respiration. 2010; 80: 38–58.

23. Mora G, de Pablo A, García- Galloa CL et al. ¿Es útil el tratamiento endoscópico de las fístulas bronquiales? Arch Bronconeumol. 2006; 42 (8): 394-398.

24. Hirata T, Ogawa E, Takenaka K et al. Endobronchial closure of postoperative broncho-pleural fistula using vascular occluding coils and n-butyl-2- cianoacrylate. Ann Thorac Surg. 2002; 74: 2174-5.

25. García Polo C, León Jiménez A, López-Campos Bodineau JL et al. Nuevas técnicas de oclusión bronquial para el tratamiento endoscópico de fístulas broncopleurales. Arch Bron-coneumol. 2005; 41 Supl:129.



Summary

26. García Polo C, León Jiménez A, López-Campos JL et al. Oclusión bronquial endoscópica con prótesis de silicona de Watanabe y pegamento biológico para el tratamiento de fístulas broncopleurales. Rev Esp Patol Torac 2011; 23 (3): 200-207.

27. Cordovila R, Torracchi AM, Novoa N et al. Válvulas endobronquiales para el tratamiento de la fuga aérea persistente, una alternativa al tratamiento quirúrgico. Arch Bronconeumol 2015; 51: 10-5.

28. Herth FJF, Peter S, Baty F et al. Combined airway and oesophageal stenting in malignant airway–oesophageal fistulas: a prospective study. European Respiratory Journal 2010; 36: 1370-1374.

29. Adler DG, Baron TH, Geels W et al. Placement of PEG tubes through previously placed self-expanding esophageal metal stents. Gastrointest Endosc 2001; 54: 237–241.

30. Meléndez J, Cornwell L, Green L et al. Treatment of large subglottic tracheal schwannoma with microdebrider bronchoscopy. J Thorac Cardiovasc Surg. 2012; 144: 510–2.

31. Páez FM, Dorado A, Simó J. Resección de granulomas en prótesis metálica con microde-bridador broncoscópico. Arch Bronconeumol. 2016; 52 (8): 438-446.

32. Tanigawa N, Sawada S, Okuda Y et al. Syntomatic improvement in disnea following tra-cheobronchial metallic stenting for malignat airway obstruction. Acta Radiol. 2000; (5): 425-8.

Summary

Summary

En 2016 OXIMESA cumple 50 años atendiendo a domicilio a pacientes con patología respiratoria.

OXIMESA, empresa proveedora de Terapias Respiratorias Domiciliarias, presta sus servicios de atención sanitaria en el domicilio del paciente desde 1966 con un único objetivo: el bienestar de todos sus pacientes.

La compañía es una de las referencias dentro del campo de las terapias respiratorias, que se esfuerza día tras día en ofrecer todos sus servicios de una manera responsable y profesional.

En 1993, OXIMESA pasó a formar parte de la multinacional PRAXAIR, una de las empresas más innovadoras y líder del suministro de gases para el sector sanitario en todo el mundo.

Todo ello incide y refuerza el compromiso de calidad de OXIMESA con sus pacientes y clientes, que goza además de las más importantes certificaciones de Calidad y Seguridad, tanto laboral como medioambiental.El compromiso de calidad de OXIMESA garantiza a sus pacientes tiempos de respuesta reducidos, cuidado individualizado con visitas periódicas de seguimiento y atención permanente gracias a su servicio de atención telefónica de las 24 horas del día, los 365 días al año.

OXIMESA, desde su nacimiento ha atendido aproximadamente a 2.500.000 de pacientes, si bien a lo largo de un año se realizan más de 1.000.000 intervenciones, siendo estas el número de actuaciones sanitarias necesarias para atender actualmente a los más de 200.000 pacientes, tanto en el domicilio como en los diferentes hospitales en los que la compañía presta servicio en la actualidad.

Para mantener los estándares de calidad y reducir los plazos de atención al paciente, OXIMESA cuenta con 17 delegaciones repartidas por toda España, 33 almacenes de distribución autorizados y 12 Laboratorios de fabricación y llenado de especialidades farmacéuticas certificados por la Agencia Española del Medicamento y producto sanitario

Además, dispone de cuatro centros de atención telefónica especializada para los pacientes, dos de ellos con servicio de 24 horas,correos electrónicos de contacto exclusivo por área y un servicio de solicitud de asistencia mediante el envío de Mensajes de Texto entre otros.

OXIMESA cuenta con una extensa plantilla multidisciplinar formada por los mejores profesionales en su campo, destinando gran cantidad de recursos en el desarrollo de programas personalizados de formación continuada (on line y presenciales) que permiten aumentar sus conocimientos, mejorando el servicio prestado a los pacientes.

136

Summary

SPECIAL ARTICLE


Received: April 10, 2017. Accepted: May 10, 2017.

Aurelio Arnedillo Muñ[email protected]

A, Arnedillo Muñoz1, F. Carboneros de la Fuente2, F. Casas Maldonado3, J.D. García Jiménez2, R. Gimeno Galván4, A. Hidalgo Molina1, C. Merinas López5, E. Molina Ortiz6, G. Pérez Chica7, M.A. Sánchez Quiroga8, J.G. Soto Campos2, A. Valido Morales9, E. Vázquez Gandullo4.1UGC de Neumología, Alergia y Cirugía Torácica. Hospital U. Puerta del Mar. Cádiz. 2UGC de Neumología. Hospital U. de Jerez. Cádiz. 3UGC de Neumología. Hospital U. San Cecilio. Granada. 4UGC de Neumología. Hospital Punta Europa. Algeciras. Cádiz. 5Servicio de Neumología. Hospital U. de Ceuta. 6Servicio de Neumología. Hospital U. Infanta Cristina. Badajoz. 7UGC de Neumología. Complejo Hospitalario Ciudad de Jaén. 8Unidad de Neumología. Hospital Virgen del Puerto de Plasencia. Cáceres. 9UGC de Neumología. Hospital U. Virgen Macarena. Sevilla.

Algorithm for the WithdrAWAl of inhAled CortiCoSteroidS in CoPd

with criteria for ACO, certified by the GOLD (Global Obstructive Lung Disease) guide and GesEPOC (Guía Española de la EPOC)2,

3, although the criteria we have chosen to define ACO are those from the document of recommendations for the diagnosis and treatment of COPD in Andalusia7(Table 1).

- EFor the second criterion we have included wheezing in the stable phase, which is a clinical criterion based on experts’ experience.We believe that patients who present nearly constant or frequent wheezing, especially predominant at night and not just during exa-cerbations, are not candidates for ICS withdrawal.

The number of eosinophils has also been included in this section, ba-sed on several publications which have shown a decrease in exacerbations in patients treated with ICS when there is an elevated eosinophil count in peripheral blood8, 9. In our case, we considered a value of ≥300 eosi-nophils/µL in peripheral blood, as withdrawal of ICS in these cases has been shown to be accompanied by an increase in the number of exacer-bations10.

The use of inhaled corticosteroids (ICS) along with long-acting β2-agonists (LABA) has been common for COPD (Chronic Obstructive Pul-monary Disease) patients for years, based on studies which have shown a decrease in exacerbations compared to bronchodilators or ICS separately1. This trend has continued over time, in spite of new evidence referenced in guides which has limited the indications for ICS in the treatment of COPD2,

3. Several studies have shown an overprescription of ICS for COPD patients if we look at the current indications included in the guides4, 5,in addition to showingthe continued use of ICS is associated with several complications, notably pneumonia1, 6. This algorithm (Figure 1) integrates a series of recommendations to select those patients who do not have an indication for ICS, in addition to providing guidelines for follow-up once they have been withdrawn.

1. Starting criteria:- The first, presence of criteria for the ACO (asthma COPD overlap)

phenotype, is based on the better response to ICS from patients

mailto:aurelioarnedillo%40neumosur.net?subject=Revista%20Neumosur


A. Arnedillo Muñoz et al. Algorithm for the Withdrawal of Inhaled Corticosteroids in COPD

Summary

- The third criterion, not having had severe exacerbations or having fewer than 2 moderate exacerbations in the previous year, is also based on the cri-teria from current guides which classify these patients as being at low risk of exacerbations2, 3.

If the patient meets the initial assessment criteria, ICS can be stopped and substituted by double bronchodilation (DBD). If the initial criteria are not met, if it is due to having ACO criteria and/or presenting frequent wheezing in the stable phase and/or having a peripheral blood eosinophil count of ≥300 cells/µL, ICS will not be withdrawn and the initial dosage will be maintained. If criteria are not met because the patient has had a severe or more than 1 moderate exacerbation, if he or she is receiving a high dosage of ICS an attempt can be made to move down to a medium dosage (recommended do-sages shown in Table 2) and also maintain DBD, especially if the patient has a history of pneumonia.In these cases, alternative treatments with ICS can be considered, such as those shown in Table 3.

main criteria (mandatory)

feV1* reversibility ≥12% (and greater than 200 ml in absolute values)

and at least 2 of the following cri-teria:

1. Personal or family history of asthma or atopy2. Frequent wheezing, especially predominant at night and not only during exacerbations3. Elevated IgE4. Peripheral blood eosinophil count of ≥300 cells/µL without another justifying cause

*FEV1: maximum volume exhaled in the first second

table 1: ACo (Asthma COPD Overlap) criteria. Taken from the document of recom-mendations for the diagnosis and treatment of Chronic Pulmonary Obstructive Disease in Andalusia7

drug Low dosage(mg/day)

medium dosage(mg/day)

High dosage(mg/day)

Extra fine beclomethasone 100 – 200 201 - 400 >400 Fluticasone propionate 100 – 250 251 - 500 501 - 1,000 Budesonide 200 – 400 401 - 800 801 - 1,600

- Fluticasone furoate: the only available dosage for EPOC is 92 mg/day.*Only ICS combined with LABAs that are approved in the COPD fact sheet are shown.

Table 2. Inhaled corticosteroid dosage*

drug indication

Roflumilast For patients with the chronic bronchitis phenotype and FEV1* <50%.

Theophylline For patients with the emphysema phenotype

Azithromycin Severe and very severe COPD with frequent exacerbations that require several antibiotic treatments, despite an optimum treatment.

*FEV1: maximum volume exhaled in the first second.

Table 3: Other treatment alternatives



Summary

Figure 1. Algorithm for the withdrawal of inhaled corticosteroids (ICS) in COPD.*ACO:asthma COPD overlap. See Table 1. **: See Table 2. ***: See Table 3. LAMA: long-acting muscarinic antagonist. LABA: long-acting β2-agonist. FEV1: maximum volume exhaled in the first second.mMRC: Modified Medical Research Council Dyspnea Scale.

Algorithm for Withdrawal of Inhaled Corticosteroids in COPDInitial criteria:

1. No ACO criteria*2. No wheezing in stable phase, nor eosinophil blood count ≥300 cells/μL.3. No severe COPD exacerbations or >1 moderate in the previous year.

FULFILLED THE FOLLOWING CRITERIA:1. No worsening of dyspnea (mMRC without change)2. No wheezing in stable COPD phase.3. No increase as-needed BD (≤20%)4. No severe COPD exacerbations.5. No worsening in lung function: decrease FEV1pbd ≤12% and

<200ml)

START IC MEDIUM DOSES

By criterion 3

MAINTAIN LAMA+LABA

MAINTAIN TREATMENT

By criterion 1 y/o 2MAINTAIN ICNO YES

NO YESYESINCREASE IC HIGH DOSES

FULFILLED CRITERIA

NO

Review after 3 months

IC WITHDRAWALADD LAMA+LABA

If high doses of IC, change to medium doses**+ LAMA+LABA, and/or assess other alternatives according to

phenotypes***

NO

YES Review after 6 months

Review after 3 months



Summary

ml. If the patient’s FEV1 falls below this level after withdrawing the ICS, they would meet significant reversibility criteria, indicating they would likely benefit from ICS and that at the time of evaluation they were not influenced by bronchodilator treatment for some reason.

It is not common to see worsening in only one of these progress criteria, thus worsening in patient’s progress after withdrawing ICS is usually accom-panied by the worsening of more than one criterion, which reinforces intro-ducing new ICS treatments. Those patients for whom we have withdrawn ICS and who meet the pro-gress criteria for stability will receive follow-up at 6 months, after which they will be reevaluated with the same criteria. For patients who do not meet the progress criteria for stability, ICS at a me-dium dosage can be resumed, if they had been suspended, or higher dosages of ICS can be prescribed if the patient had been lowered to a medium dosage.

BiBliogrAPhY1. Calverley PM, Anderson JA, Celli B et al; TORCH investigators. Salmeterol and fluticasone

propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356(8): 775-89.

2. Guía de Práctica Clínica para el Diagnóstico y Tratamiento de Pacientes con Enfermedad Pulmonar Obstructiva Crónica (EPOC) - Guía Española de la EPOC (GesEPOC). Arch Bronconeumol 2012; 48 (Supl 1): 2-58.

3. Global Strategy for Diagnosis, Management, and Prevention of COPD – 2017 Report. Disponible en: http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/

4. Miravitlles, M. Barrecheguren, M. Román-Rodríguez et al. Frequency and characteristics of different clinical phenotypes of chronic obstructive pulmonary disease. International Journal of Tuberculosis and Lung Disease 2015; 19 (8): 992-8.

5. Izquierdo JL, Martín A, de Lucas P et al. Misdiagnosis of patients receiving inhaled thera-pies in primary care. Int J Chron Obstruct Pulmon Dis. 2010; 5: 241-9.

6. Iannella H, Luna C, Waterer G. Inhaled corticosteroids and the increased risk of pneumo-nia: what’s new? A 2015 updated review. Ther Adv Respir Dis. 2016; 10 (3): 235-55.

7. Casas Maldonado F, Arnedillo Muñoz A, López-Campos JL et al. Documento de reco-mendaciones para el diagnóstico y tratamiento de la Enfermedad Pulmonar Obstructiva Crónica en Andalucía. Rev Esp Patol Torac (en prensa).

8. Pavord ID, Lettis S, Locantore N et al. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax 2016; 71 (2): 118–25.

9. Pascoe S, Locantore N, Dransfield MT et al. Blood eosinophil counts, exacerbations, and

2. Progress criteria. In any of the cases, both withdrawing and reducing the ICS dosage, the patient will be examined after 3 months and, if they meet the progress criteria, treatment will be maintained.The following are the criteria we have selected to determine whether progress has been favorable.

- No worsening from baseline dyspnea: if the patient shows worsening of the baseline dyspnea after three months according to the mMRC (Modified Medical Research Council) scale, which is not justified by other reasons, ICS will have to be reintroduced, especially when the dyspnea, and lung function, is a parameter which improves with DBD compared to LABA+ICS treatment.

- Appearance of frequent wheezing in the stable phase: this will be a cri-terion we feel is a clinical indication of bronchospasm and very likely in-dicates the existence of bronchial hyperreactivity, thus ICS would need to be reintroduced.This is a clinical criterion based on experts’ opinions.

- Increase in rescue medication: although this parameter is difficult to quantify, a significant increase in rescue medication will force us to con-sider reintroducing ICS.The quantification of the increase in rescue me-dication is based on the results of the FLAME study11, which showed a 25% reduction in the use of rescue medication (average reduction of 1 daily inhalation), using patients with an average of 4 inhalations per day as the baseline.We believe that changing treatment to DBD should reduce the use of rescue medication, but if there is a 20% increase in its use, we believe progress is not favorable.However, this parameter is difficult to quantify. As a result, this criterion must be evaluated with caution.

- No severe acute exacerbations of COPD (AECOPDs): although fo-llow-up is only 3 months, if the patient has a severe AECOPD, especia-lly if it is non-infectious, we must consider reintroducing ICS.If there is only one case of moderate AECOPD, reintroducing ICS will not be necessary.The FLAME study11 has shown that DBD is better than the LABA+ICS combination in patients with a single moderate AECOPD.If there were more than one moderate AECOPD, we would need to consider reintroducing ICS at a medium dosage, although 3 months is likely a short time for 2 moderate AECOPDs to occur.

- Drop in lung function: we have set a limit of 12% and always above 200

http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/

http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/



Summary

response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3 (6): 435-42.

10. Watz H, Tetzlaff K, Wouters EFM et al. Blood eosinophil count and exacerbations in se-vere chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016; 4 (5): 390-8.

11. Wedzicha JA, Banerji D, Chapman KR et al.; FLAME Investigators. Indacaterol-Glyco-pyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016; 374 (23): 2222-34.

141

Summary

E. Moya Sánchez1, N. Romera Romera2, E. Ruiz Carazo1.1Servicio de Radiodiagnóstico. Complejo Hospitalario Universitario Granada. Granada. 2Servicio de Radiodiagnóstico. Hospital Universitario Río Carrión. Palencia.


Received: August 28, 2016. Accepted: February 12, 2017.

Elena Moya Sá[email protected]

Pulmonary Tumor ThromboTic microangioPaThy, an uncommon Form oF breaST cancer PreSenTaTion

IMAGE

clinical caSe A 31-year-old woman, without personal or family history of interest, who went to the Emergency Department suffering from dyspnea with minimal exertion and chest pain.A chest CT angiogram was done, which showed centrilobular nodules and branching linear opacities in the lung parenchyma (arrows in Fig. 1A and 1B). Incidentally, signs of diffuse infiltration of the right breast stand out by densities with a nodular and reticular appearance (arrow in Fig. 1C) with skin thickening (arrow tip in Fig. 1C). Three days later, she was admitted to the ICU for signs of acute respiratory distress, where she underwent another chest CT angiogram (Fig. 1D) in which we observed a marked increase in the right chambers of the heart, with inversion of the interventricular septum in comparison with the previous study (Fig. 1C), indicating severe right-sided heart fai-lure. Pulmonary tumor thrombotic microangiopathy is a relatively unknown form of pulmonary tumor embolism which is most frequently associated with choriocarcinoma and neoplasms in the breast, liver, stomach, and kidney1. The CT findings characteristic of pulmonary tumor embolism are di-lation and tortuosity of the subsegmental pulmonary arteries and pulmo-nary infarction1, although we are often faced with a chest x-ray or chest

CT which shows no evidence of parenchymal lung or lymphatic disease2. The intraarterial spread of tumors is an uncommon form of non-thrombotic pulmonary embolism3. In this case, the CT findings consist of centrilobular nodules and branching vascular structures: “tree-in-bud” pattern1. Diffuse vascular occlusion increases pulmonary vascular resistance with resulting ventricular failure and cardiovascular collapse. These image findings are based on the metastasis of small groups of tumor cells to the arterial system, activating the coagulation cascade and triggering inflammatory mediators which cause fibrin microthrombi and arterial intimal hyperplasia, reactivating the tumor embolism.This patho-logical basis determines the reference clinical presentation in our case: rapidly progressive dyspnea (found in 70% of cases), hypoxemia, cough and pulmonary hypertension4. The diagnosis is difficult and is often only detected after the autopsy, with an estimated incidence of 3-26% in patients with solid tumors2. It is important to recognize the clinical presentation and associated radiologi-cal findings in the context of a patient with an unknown neoplasm, since, when infratreated, tumor thrombotic microangiopathy is often fatal. The chosen treatment consists of quickly beginning cytotoxic treatment of the main tumor, in this case the breast cancer5.

mailto:elemoya89%40gmail.com?subject=REVISTA%20NEUMOSUR


E. Moya Sánchez et al. Pulmonary Tumor Thrombotic Microangiopathy, an Uncommon Form of Breast Cancer Presentation

Summary

bibliograPhy1. Giménez A, Franquet T, Hidalgo A. Manifestaciones intratorácicas del cáncer de mama.

Radiología 2011 Jan-Feb; 53 (1): 7-17.2. Robert KE, Hamele-Bena D, Saqi A et al. Pulmonary tumor embolism: a review of the

literatura. Am J Med 2003; 115: 228-232.3. Franquet T, Giménez A, Prats R et al. Thrombotic microangiopathy of pulmonary tumors:

a vascular cause of tree-in-bud patternon CT. AJR Am J Roentgenol 2002 Oct; 179 (4): 897-9.

4. Pinckard KJ, Wick MR. Tumor related thrombotic pulmonary microangiopathy: review of pathologic findigs and pathophysiologic mechanisms. Ann Diagn Pathol 2000 Jun; 4 (3): 154-7.

5. Vlenterie M, Desar IME, Van Herpen CML et al. Fatal microscopic pulmonary tumour embolisms in patients with breast cancer: necessary knowledge for future medical practice.Neth J Med 2014 Jan; 72 (1): 28-31.

Figures 1A and 1B: Chest CT. Reconstruction of lung parenchyma. Small peripheral and branching linear centrilobular nodules: “tree-in-bud” pattern (arrows).

Figures 1C and 1D: Chest CT angiogram.

Figure 1C: Diagnostic CT done on patient’s arrival, in which the incidental finding of diffuse infiltration of the right breast (arrows) and skin thickening (arrow tip) can be seen.

Figure 1D: Follow-up CT angiogram after 3 days in whichthe enlargement of the right heart chambers as a result of pulmonary hypertension comparatively stands out.

143

Summary


ProcedimienToS de eSTadiFicación no quirúrgicoS en el cáncer de Pulmón

resumenEl estudio del cáncer de pulmón precisa de una correcta estadificación para optimizar la terapéutica y establecer pronósticos, siguiendo las recomendaciones de la última edición de la Asociación Internacional para el Estudio del Cáncer de Pulmón (IASL 7ºth ed.), con un abordaje diagnóstico escalonado con el fin de evitar riesgos añadidos.

Palabras clave: Cáncer de pulmón, estadificación, ecoendoscopia.

Received: February 27, 2016. Accepted: October 30, 2016.

Miguel Henrique Reyes [email protected]

M.H. Reyes Cotes, J.M. Sánchez Nieto.

Departamento de Neumología. Hospital Morales Meseguer. Murcia.

non-Surgical ProcedureS For lung cancer STaging

RESIDENTS’ PRESENTATION

inTroducTion Given the relevance of lung cancer and the natural course it entails, achieving correct staging is fundamental for appropriate management and treatment of the disease, whether it be surgical, medical or radiothe-rapeutic.The first step in staging is using non-invasive methods (clinical and imaging tests) which allow for the identification of affected areas, both locally and remotely.In most cases diagnostic confirmation will be necessary, collecting cytohistological samples through invasive methods according to a staggered approach as necessary.Selection of the type of

test will be made according to doctor criteria and the patient’s clinical presentation. The different types of non-surgical procedures currently done for lung cancer staging are presented below, according to recommendations from the International Association for the Study of Lung Cancer published in its 7th edition (IASLC 7th ed. 2009)1 and other more recent recommen-dations awaiting publication in the IASLC 8th ed.expected this year2.

abstractSummary: Nonsurgical staging in lung cancer. The study of lung cancer requires a correct sta-ging to optimize the treatment and to establish a disease prognosis, following the recommen-dations of the latest edition of the International Association for the Study of Lung Cancer (IASLC 7ºth ed.) with a stepwise diagnostic approach to avoid additional risks.

Key words: Lung cancer, staging, echoendoscopy.

mailto:doctormiguelreyes%40gmail.com?subject=REVISTA%20NEUMOUSUR


M.H. Reyes Cotes et al. Non-Surgical Procedures for Lung Cancer Staging

Summary

non-inVaSiVe STaging ProcedureS

clinical: approximately 10% of lung cancer patients do not present symptoms at the time of diagnosis; the disease is detected through a rou-tine chest x-ray3. The rest of patients present a clinical variable according to location, extent and the type of tumor.A correct medical history and physical examination must be done in order to collect data at an early stage and thus optimize time and resources to study it.The most com-mon clinical findings were cough (50-75%), hemoptysis (30-50%) and constitutional syndrome (30%)4, 5.There are clinical scales which provide guidance regarding the patient’s general state including the Karnofsky Performance Scale Index which starts at an optimal level, 100% (asymp-tomatic patient), and decreases according to clinical severity (ex: 10% for a dying patient, 0% for a deceased patient).Another useful scale is the E.C.O.G. (East Cooperative Oncology Group) which ranges from grade 0 (asymptomatic patient) to grade 4 (permanently disabled or terminal patient), the latter scarcely undergoing palliative measures, for whom cli-nical diagnosis based on non-invasive measures and sputum cytology to confirm the diagnosis are proposed.The latter has a sensitivity (Sn) of around 66% (R: 43-97%) and a specificity (Sp) of 99% (R: 68-100%)6.

imaging tests: a chest x-ray is the most frequently used radiological technique in thoracic studies and should be indicated from two views: posteroanterior and lateral.The presence of a tumor (T) can be discove-redby its location (single or multiple, central or peripheral) and its effects (atelectasis, consolidation, elevated diaphragm, pleural effusion, bone ti-tration), although this is limited to nodules larger than 7mm in diameter7. Lymph node assessment (N) is problematic and suspected in cases of mediastinal and/or hilar widening.Due to the low sensitivity of a chest x-ray, additional study with other imaging tests such as chest computed tomography (CT) is recommended to identify adenopathy and for the morphological characterization ofpulmonary nodules.

chest cT: the use of thin-slice CT (high-resolution or helical) is re-commended, which includes upper abdominal slices.The use of intrave-nous contrast is recommended (although this would in theory make it a minimally invasive test), which would serve to distinguish the lymphatic

ganglion structures of the vessels. Currently, iodinated contrast (I-131) is the most commonly used.CT provides us with information about the characteristics, the size and density of the tumor (speculation, ground glass opacity, calcification); the degree of parenchymal spread; additional nodules or “satellites”; and invasion of mediastinal, pleural and chest wall structures.Additionally, it can assess the presence of metastasis (M) at the abdominal (liver and adrenal glands) and bone level.An abnormal lymphatic ganglion (adenopathy) is defined as one which has a diameter greater or equal to 1cm on a short axis2. It is estimated that 40% of me-diastinal adenopathies suggesting malignancy according to CT are benign and that 20% of the supposedly benign adenopathies are indeed not8. For this reason, lymph node staging should not be based solely on CT results given its low sensitivity and specificity (Table 1), thus cytohisto-logical confirmation is recommended.Upper abdominal slices will help to identify hepatic lesions, where the majority will be benign cysts and hemangiomas. CT and magnetic resonance imaging (MRI) with contrast and/or ultrasound will be useful to study stages.A percutaneous biopsy will be done when diagnostic certainty is required to establish a diagnosis.Additionally, CT will help to evaluate the adrenal glands. The criteria for benignity (adenoma) are: size (lesions larger than 3cm are more likely to be metastatic, but benign disease is still possible), well-defined contours, low attenuation (fat density) <10 Hounsfield Units with simple CT (Sn 71%, Sp 98%)2. Thus, if criteria for benignity are met, follow-up may be chosen (simple CT, IV contrast or MR-IV gadolinium will be used for limited fat content).If a single metastasis is suspected, we will consider a PET/CT (Sn 97%, Sp 91%)2 or a percutaneous adrenal biopsy, which is a relatively safe and efficient means of obtaining a diagnosis in borderline cases.When the results are indeterminate, the test should be repeated or an adrenalectomy should be considered for a curative diagnosis.

Positron emission tomography (PeT): a nuclear imaging study which uses the physioanatomical traces of protons given off by low molecular weight isotopes, which translates to metabolic activity.For neoplastic studies of the lung, the most frequently used radioisotope is fluorodeoxyglucose (FDG), synthesized with radioactive fluorine (18F), a comparable D-glucose, which is phosphorylated after cell intake, ac-cumulating intracellularly rather than being metabolized.As cancerous



Summary

lung cells have a higher glycolytic rate and overexpress glucose transpor-ters, there is a preferential accumulation of FDG in the main tumor and potentially metastatic lesions.The criteria for an abnormal PET scan is either a standardized uptake value (SUVmax) of more than 2.5 or uptake in the lesion which is greater than the background mediastinal activity 8.9 (keeping in mind that the heart and brain uptake a great deal of FDG).PET scans are not convenient to assess malignant lesions smaller than 1.0 cm in diameter9. On the other hand, the combination of CT and PET offers higher diagnostic precision than doing either of the scans separa-tely (Table 1), which supports their use for pulmonary neoplasm staging.PET scans can show distant metastatic disease in the bones, the liver and the adrenal glands which are not detected with CT (11%)10. If the PET mediastinal evaluation result is negative, it is considered acceptable to proceed to treatment without prior invasive tests, except in the following situations8:

a) centrally-located tumors, frequently in contact with the mediastinumb) tumors with low metabolic activityc) apparent N1 involvementd) when the chest CT detects ganglia whose shortest axis is > 15 mm,

whose probability of malignancy (N2) is 21%8,10

Given their elevated sensitivity, when available, a PET or PET/CT scan should be done on patients who will potentially benefit from treatment in order to detect hidden distant metastases (Stage I 8%, III 24%)8, thus avoiding unnecessary thoracotomies and improving the treatment plan.We must keep in mind that in the case of a positive mediastinal PET re-sult, continuing with lymph node evaluation or possible resection mustn’t be rejected, given the possibility of obtaining false positives (inflamma-tory or infectious lesions).PET/CT FDG-18 has proven superior (Sn 92%, Sp 98%) to bone scans with technetium 99MDP (Sn 86%, Sp 88%)2 in the study of bone metastasis, in addition to the fact that the latter is not able to recognize bone marrow infiltration in the early stages.For these reasons, bone scans are no longer used in the study of lung cancer metastases to bone.In general, unless there is clinical and overwhelming imaging test evidence, image findings suggesting metastasis, especially

regarding a single lesion with hyperuptake, should not exclude patients from potentially curative treatments until malignancy is confirmed with a cytohistological sample.Other uses for PET/CT include: marking the area to irradiate (complementary cases of external radiotherapy, radiofre-quency (SBRT), and/or local brachytherapy), atelectasis of questionable origin (Figure 1) and iodinated contrast allergy11.

magnetic resonance: its use is limited by its scarce availability as well as having a limited diagnostic value without the additional data of the chest CT, except in the case of superior sulcus tumors, given its superiority in evaluating vessel, brachial plexus and medullary cavity infiltration, with diagnostic accuracy that can reach 94% compared to the 63% of CT8. Additionally, it is useful in assessing cerebral, liver and adrenal metastasis.With regard to the diagnosis of cerebral metastasis, a head CT or mag-netic resonance imaging (MRI) scan must be done if there are any symp-toms or suspicious neurological signs, as well as in asymptomatic Stage III patients for whom the possibility of radical treatment is being con-sidered (surgery or thoracic radiation therapy)8.Dynamic MRI has been proposed to differentiate visceral pleural invasion from parietal pleural invasion with a sensitivity of 100% and a specificity of 70%2.

Thoracic ultrasound: its importance stems from its low cost, the fact it doesn’t give off radiation, and the ease with which it can be moved and used.It can be used to evaluate the presence of pleural effusion which, if confirmed, will require cytology at the very least to classify it as metastatic effusion (M1a), according to the most recent classification (7th IASLC). Additionally, thickening of the pleura (if >1cm) or diaphragm (>0.7cm) and the pleural nodules can be identified, the presence of which is highly suggestive of a malignant disease12. Finally, the thoracic wall and supra-clavicular and axillary adenopathies can be evaluated.



Summary

non-Surgical inVaSiVe STaging ProcedureS This section includes exploratory procedures which involve tissue disrup-tion (ex: punctures) or entering the organism through a natural orifice (endos-copy), with the aim of examination and collecting samples for cytohistological analysis (without requiring surgery).These include: endoscopic examination: this allows us to obtain samples using fine needle aspiration (FNA) through bronchoscopy and/or esophagoscopy (see yield in Table 1). bronchoscopy: considered highly useful, both for the diagnosis and staging of lung cancer, as lesions at the endobronchial level can be seen. It allows samples to be collected through bronchial suction, bronchial brus-hing, and bronchial and transbronchial biopsies whether they be blind, use radioscopy or include the new use of electromagnetic navigation (automa-

Procedure Sn% Sp% nPV PPV accu-racy

PreVa-lence

Mediastinum evaluation:Non-invasive:CT 47-54 84-88 47-96 30-95 63-83 28PET 50-89 77-90 50-100 43-100 69-89 29PET/CT 47-89 60-100 85-99 37.5-100 62-93 52Invasive, non-surgical:Blind TBNA 79-95 99 - - - 75EBUS with linear FNA 79-95 99-100 86.99 100 97-98 53.2EUS 86 96-98 73-83 97-99 - 61Extrathoracic metastasis evaluation: CT 18 98 89 71 88 -PET 50-79 75-100 89 75 89 -PET/CT 92 98 98 89 97 -EUS 85-93 100 - - 97-99 -Mediastinal restaging.Yield CT 59 62 53 66 60 -PET 71 69 64 75 70 -PET/CT 77 92 75 93 83 -EBUS-FNA 75-77 100 18-22 100 - 76-79 Taken and adapted from J. Sánchez de Cos et al / ArchBronconeumol. 2011;47(9):458

Table 1. diagnostic yield of non-surgical tests in lung cancer staging

Figura 1. Imágenes comparativas entre TC torácico (izquierda) y PET-TC (derecha) permitiendo definir las zonas hipercaptantes (adenopatías y masa tumoral infiltrante). Imágenes cedidas por Dr. Renato Salguero, Oncología, Hospital Morales Meseguer. Murcia.

Figure 1. Image comparison of chest CT (left) and PET/CT (right) allowing the definition of hyperuptake areas (adenopathy and infiltrating tumor masses). Images provided by Dr. Renato Salguero, Oncology, Hospital Morales Meseguer. Murcia.



Summary

tic or manual).Additionally, it plays a fundamental role in determining lymph node involvement (N), obtaining samples through FNA in two ways: blind or ultrasound-guided (EBUS). The upper station mediastinal lymph nodes (2, 3p, 4), subcarinal nodes (7) and intrapulmonary hiliar (10) and lobar (11) nodes can be accessed.The importance of having an experienced cytopathologist when undergoing testing has been proven.With their help, an adequate lymph node sample can be taken, identifying the satisfactory samples (presence of lymphocytes, atypical cells) and avoiding more invasive procedures such as mediastinoscopy, mediastinotomy and thoracotomy.The standard method of mediastinal lymph node study is based on blind transbronchial FNA (also called TBNA).To complete the procedure, a prior chest CT (and PET scan ac-cording to availability) is recommended, which will guide us to the most invol-ved lymph node group in order to take samples.Time management is essential for various reasons (patient comfort, safety, sedation).A plateau in malignancy yield has been proven to be achieved after seven TBNA procedures13.

echobronchoscopy (ebuS): a relatively safe procedure which can be done on an outpatient basis to collect samples from mediastinal and hiliar lesions.It is recommended:

1) to explore and biopsy all lymph nodes that were suspicious in the PET/CT scan, sequentially dismissing N3, N2 and N1 by their therapeutic implications.

2) to examine the N3 lymph node stations in all cases with a radical curati-ve aim and to biopsy lymph nodes ≥5mm in diameter.

In the case of adenopathy detected by CT or PET scan, as well as when im-mediate cytopathological diagnosis is available, the Sn of the test increases to values of 94% and 97%, respectively.In the absence of an onsite pathologist, the diagnostic yield is based on the number of FNA procedures done for each lymph node station. Diagnostic yield does not increase when more than 3 procedures are done (1st procedure Sn: 69.8%, NPV: 86.5%; 2nd procedureSn: 83.7 NPV: 92.2%; and 3rd procedure Sn: 95.3%, NPV: 97.6%)8, 14. The ultra-sound image allows us to differentiate the lymph nodes suggesting malignancy from those suggesting benignity (Figure 2)15. Collecting lymph node samples using EBUS can avoid between 30 and 56% of mediastinoscopies8, 16. An EBUS result is considered negative when there is no evidence of malignancy

after 3 biopsies with the presence of perioperative lymphocytes.At the same time, if the sample is contaminated, necrotic, insufficient or contains blood, it would be considered indeterminate and a negative result for malignant cells would have to be confirmed with surgical techniques (Figure 3).

esophagoscopy: a transesophageal FNA is normally done guided by ul-trasound (EUS), allowing us to reach the lower left paratracheal stations (4L) and other areas that are not accessible through EBUS such as the subaortic (5), paraesophageal (8) and pulmonary ligament (9) stations.It is also possible to access the 7, 4R, 2R and 2L mediastinal regions. EUS-FNA also allows us to detect left-hand pleural effusions, subdiaphragmatic metastases (left adre-nal gland, celiac artery and liver lymph nodes, the left lobe and part of the right lobe) and evaluate the presence of mediastinal invasion of the tumor (T4) much more accurately than radiological techniques (Sn: 98%, Sp: 98%, FN: 1%, and FP: 30%)8. It reduces the number of unnecessary thoracotomies from 25% to 9%8, 16. The combined use of EBUS and EUS allows access to all of the mediastinal lymph node stations, except region 6, with efficacy that is no less than the gold standard (mediastinoscopy)17. The Sn for this combi-nation (EBUS + EUS) is 93%, with a NPV of 97%8.

Figure 2. Echoendoscopic characteristics of the lymphatic ganglion. Taken and adapted from Jujiwara et al. CHEST 2010; 138(3):643. Note: The data in the lower line is indicative of ma-lignancy. On the right, EBUS and echoendoscopic image with FNA (A) of adenopathy with malignant characteristics, note the distal end of the needle (B) and the edges of the adeno-pathy (arrows).



Summary

TranSThoracic bioPSieS Thoracentesis: cytology of the pleural liquid will accurately confirm the presence of atypical cells, thus proving there is a metastatic effusion (M1a, IASLC7th ed.) with Sn 72% (R: 49-91%) after at least 2 serialized cytologies12,

18. A pleural effusion should not be assumed to be metastatic until there is cytohistological confirmation, as it may be a paraneoplastic effusion (transu-date or exudate) or a parapneumonic effusion (exudate).Tumor markers have poor specificity.

Pleural biopsy: a closed pleural biopsy has lower efficacy than a diagnostic thoracentesis, with a Sn around 50%, but higher in cases with a low pH and low glucose (indicative of advanced disease)18. Success depends on pleural area, the number of samples taken and the experience of the person taking the sample.This procedure is recommended in cases when the first cytology is not diagnostic and the effusion has not been identified19.Even then, only 7-12% of patients with negative cytology who actually have a malignant effu-sion are diagnosed exclusively with this technique. A CT-guided pleural biopsy has an efficacy of 85%18 and medical thoracoscopy with pleural biopsy has a sensitivity of around 97%19.

image guided lung biopsy: this consists of taking a sample at the thoracic level. In many cases, it is chosen for peripheral lesions. In general it is guided by real-time computed tomography. Two techniques can be included under this name: on one hand, fine needle aspiration (FNA), which has a diameter of less than 20G and, on the other, core needle biopsy (CNB) with a diameter larger than 20G.CT-guided CNB is the most effective. It has a specificity of approximately 90% and a risk of pneumothorax of 12-30%, of which only 3-15% require a chest tube to be inserted20. This risk is elevated in patients with emphysema and bullas.There is also a risk of bleeding, which is generally self-limited, although there is a higher risk in patients with pulmonary hyper-tension.

concluSion For patients diagnosed with or suspected of suffering from lung cancer, cli-nical assessment continues to be the first step in obtaining information about their status and proceeding to optimize the therapeutic diagnostic approach

Taken and edited from J. Sánchez de Cos et al / ArchBronconeumol. 2011;47(9):461.Observations:1 Cranial study for patients with neurological focality and/or candidates for radical Stage III treatment. 2Surgical techniques include simple and/or extended cervicalmediastinoscopy,thoracoscopy, mediastinal lymphadenectomy: transcervical extended (TEMLA) and video-assisted (VAMLA). *EBUS combined with EUS, if available, or EBUS alone8, 21. **TBNA adenopathy transbronchial needle aspiration. A limit of 1cm for mediastinal lymph nodes is traditionally used.If a PET scan is available, the lower limit will be 1.5cm if there is no hyperuptake.



Summary

15.- Fujiwara, T, Yasufuku K, Nakajima T et al. The utility of sonographic features during en-dobronchial ultrasound-guided transbronchial needle aspiration for lymph node staging in patients with lung cancer; a standard endobronchial ultrasound image classification system. Chest 2010; 138 (3): 641-647.

16.- Larsen SS, Vilmann P, Krasnik M et al. Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: preliminary results from a ran-domised trial. Lung Cancer 2005; 49: 377–85.

17.- Berania I, Kazakov J, Khereba M et al. Endoscopic Mediastinal Staging in Lung Cancer is Superior to “Gold Standard” Surgical Staging. Ann Thorac Surg. 2016; 101 (2): 547-50.

18.- Villena-Garrido V, Cases-Viedma E, Porcel-Pérez JM et al, Normativa SEPAR. Diagnósti-co y tratamiento del derrame pleural. Arch bronconeumol 2014; 50 (6): 235-249.

19.- Jiménez HL, Bravo JB, Zapatero G. Diagnóstico y manejo del derrame pleural maligno. Rev Patol Respir 2007; 10(3): 140-145.

20.- Donado JR, Paz-Ares L, Bartolomé A et. al. OncoSur. Diagnóstico y tratamiento Cáncer de Pulmón. Fundación Médica Mutua Madrileña 2007; 1-49. Disponible en: http://www.seom.org/seomcms/images/stories/recursos/sociosyprofs/colectivos/grupocooperati-vo/2006/oncosur/guia_clinica_oncosur_cancerpulmon.pdf.

21.- Vilmann P, Clementsen PF, Colella S et al. Combined endobronchial and esophageal en-dosonography for the diagnosis and staging of lung cancer: European Society of Gas-trointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). Endoscopy 2015; 47: 545–559.

22.- Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Pro-posals for Revision of the TNM Stage Groupings in Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorarc Oncol. 2016; 11 (1): 39-51.

which will have phases.The 8th edition of the IASLC TNM Classification for Lung Cancer is expected to be published by the end of the year.The published proposals call for changes to T and M22, maintaining the approach to study for now.PET/CT is considered the imaging test with the highest diagnostic value.The combination of EBUS + EUS is ideal for the study of mediastinal adenopathy, as it allows us to obtain lymph node material guided by a real-time ultrasound and, in indeterminate cases, it will lead to surgical methods.

bibliograPhy1.- Goldstraw, P. IASLC staging manual in thoracic oncology. 1st ed. Orange Park (FL). Rx

Press; 2009.2.- De Groot PM, Carter BW, Betancourt Cuellar SL et al. Staging of lung cancer”. Clin Chest

Med 2015; 36 (2): 179-196.3.- Kocher F, Lunger F, Seeber A et al. Incidental diagnosis of asymptomatic non-small-cell

lung cancer: A registry-based analysis. Clin Lung Cancer 2016; 17 (1): 62-7.4.- Thomas KW, Gould MK, Jett JR et al. Overview of the initial evaluation, diagnosis, and

staging of patients with suspected lung cancer. Literature review. Uptodate; 2015 [acceso 03 de noviembre de 2015]. Disponible en: http://www.uptodate.com.

5.- Álvarez-Sala Walther JL, Casan Clara P, Rodríguez de Castro F et al. Neumología Clínica. Elsevier; España 2010: 466-494.

6.- Rivera MP, Mehta AC: Initial diagnosis of lung cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd ed). Chest 2007; 132 (Suppl 3): 131S–148S.

7.- Ketai L, Malby M, Jordan K et al. Small nodules detected on chest radiography: does size predict calcification? Chest 2000; 118 (3): 610-4.

8.- Sánchez de Cos J, Hernández JH, López MF et al. Normativa SEPAR sobre estadificación del cáncer de pulmón. Arch Bronconeumol. 2011; 47 (9): 454-65.

9.- Sobin LH, Gospodarowicz MK, Wittekind C. International Union Against Cancer: TNM Classification of Malig¬nant Tumours, 7º ed. Oxford, UK. Wiley-Blackwell, 2009.

10.- De Langen AJ, Raijmakers P, Riphagen I et al. The size of mediastinal lymph nodes and its relation with metastatic involvement: a metaanalysis. Eur J Cardiothorac Surg 2006; 29: 26–9.

11.- Silvestri GA, Gonzalez AV, Jantz MA et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013; 143 (Suppl 5): e211S–50S.

12.- Qureshi NR, Rahman NM, Gleeson FV. Thoracic ultrasound in the diagnosis of malignant pleural effusion. Thorax 2009; 64: 139–143.

13.- Chin R, McCain TW, Lucia MA et al: Transbronchial needle aspiration in diagnosing and staging lung cancer. Am J Respir Crit Care Med 2002; 166: 377–381.

14.- Lee HS, Lee GK, Lee HS et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspira-tions per target lymph node station? Chest 2008; 134: 368–74.

http://www.seom.org/seomcms/images/stories/recursos/sociosyprofs/colectivos/grupocooperativo/2006/oncosur/guia_clinica_oncosur_cancerpulmon.pdf.%0D



Summary

▼Este medicamento está sujeto a seguimiento adicional, lo que agilizará la detección de nueva información sobre su seguridad. Se invita a los profesionales sanitarios a notificar las sospechas de reacciones adversas. Ver la sección “Reacciones adversas”, en la que se incluye información sobre cómo notificarlas. NOMBRE DEL MEDICAMENTO Ultibro Breezhaler 85 microgramos/43 microgramos polvo para inhalación (cápsula dura) COMPOSICIÓN CUALITATIVA Y CUANTITATIVA Cada cápsula contiene 143 µg de maleato de indacaterol equivalente a 110 µg de indacaterol y 63 µg de bromuro de glicopirronio equivalente a 50 µg de glicopirronio. Cada dosis liberada (la dosis que libera la boquilla del inhalador) contiene 110 µg de maleato de indacaterol equivalente a 85 µg de indacaterol y 54 µg de bromuro de glicopirronio equivalente a 43 µg de glicopirronio. Excipiente(s) con efecto conocido: Cada cápsula contiene 23,5 mg de lactosa (como monohidrato). Para consultar la lista completa de excipientes, ver sección “Lista de excipientes” FORMA FARMACÉUTICA Polvo para inhalación (cápsula dura) Cápsulas con tapa de color amarillo transparente y cuerpo incoloro transparente conteniendo un polvo blanco o casi blanco, con el código «IGP110.50» del producto impreso en azul bajo dos barras azules en el cuerpo y el logo de la compañía ( ) impreso en negro en la tapa. DATOS CLÍNICOS Indicaciones terapéuticas Ultibro Breezhaler está indicado para el tratamiento broncodilatador de mantenimiento, para el alivio de los síntomas en pacientes adultos con enfermedad pulmonar obstructiva crónica (EPOC). Posología y forma de administración Posología La dosis recomendada consiste en la inhalación del contenido de una cápsula una vez al día, utilizando el inhalador de Ultibro Breezhaler. Se recomienda que Ultibro Breezhaler se administre a la misma hora cada día. Si se olvida una dosis, se debe administrar tan pronto como sea posible en el mismo día. Se debe indicar a los pacientes que no se administren más de una dosis al día. Poblaciones especiales Pacientes de edad avanzada Ultibro Breezhaler puede utilizarse a la dosis recomendada en pacientes de edad avanzada (a partir de 75 años de edad). Insuficiencia renal Ultibro Breezhaler puede utilizarse a la dosis recomendada en pacientes con insuficiencia renal de leve a moderada. En pacientes con insuficiencia renal grave o enfermedad renal terminal que requieren diálisis, debe utilizarse únicamente si el beneficio esperado supera el riesgo potencial (ver”Advertencias y precauciones especiales de empleo”). Insuficiencia hepática Ultibro Breezhaler se puede utilizar a la dosis recomendada en pacientes con insuficiencia hepática de leve a moderada. No se dispone de datos sobre el uso de Ultibro Breezhaler en pacientes con insuficiencia hepática grave, por lo tanto se debe tener precaución en estos pacientes. Población pediátrica No existe una recomendación de uso específica para Ultibro Breezhaler en la población pediátrica (menores de 18 años) para la indicación de EPOC. No se ha establecido la seguridad y eficacia de Ultibro Breezhaler en niños. No se dispone de datos. Forma de administración Para vía inhalatoria exclusivamente. Las cápsulas no deben tragarse. Las cápsulas deben administrarse únicamente con la ayuda del inhalador de Ultibro Breezhaler (ver “Precauciones especiales de eliminación y otras manipulaciones”). Se debe instruir a los pacientes sobre como administrar el medicamento correctamente. A los pacientes que no presenten mejoría en la respiración se les debe preguntar si están tragando el medicamento en lugar de inhalándolo. Para consultar las instrucciones de uso del medicamento antes de la administración, ver “Precauciones especiales de eliminación y otras manipulaciones”. Contraindicaciones Hipersensibilidad a los principios activos o a alguno de los excipientes incluidos en la “Lista de excipientes”. Advertencias y precauciones especiales de empleo Ultibro Breezhaler no se debe administrar conjuntamente con medicamentos que contienen otros agonistas beta-adrenérgicos de larga duración o antagonistas muscarínicos de larga duración, grupos farmacoterapéuticos a los que pertenecen los componentes de Ultibro Breezhaler (ver “Interacción con otros medicamentos y otras formas de interacción”). Asma Ultibro Breezhaler no se debe utilizar para el tratamiento del asma debido a la ausencia de datos en esta indicación. Los agonistas beta

2-

adrenérgicos de larga duración pueden aumentar el riesgo de acontecimientos adversos graves, incluyendo muertes, relacionados con el asma, cuando se utilizan para el tratamiento del asma. No para uso agudo Ultibro Breezhaler no está indicado para el tratamiento de episodios agudos de broncoespasmo. Hipersensibilidad Se han notificado reacciones de hipersensibilidad inmediatas tras la administración de indacaterol o glicopirronio, los cuales son los componentes de Ultibro Breezhaler. Si se producen signos que sugieran una reacción alérgica, en particular, angioedema (dificultad para respirar o tragar, hinchazón de la lengua, labios y cara) urticaria o erupción cutánea, se debe interrumpir inmediatamente el tratamiento e instaurar una terapia alternativa. Broncoespasmo paradójico Al igual que con otros tratamientos inhalatorios, la administración de Ultibro Breezhaler puede producir broncoespasmo paradójico que puede ser potencialmente mortal. Si esto ocurre, se debe interrumpir inmediatamente el tratamiento e instaurar una terapia alternativa. Efectos anticolinérgicos relacionados con glicopirronio Glaucoma de ángulo estrecho No se dispone de datos en pacientes con glaucoma de ángulo estrecho, por lo tanto, Ultibro Breezhaler se debe utilizar con precaución en estos pacientes. Se debe informar a los pacientes a cerca de los signos y síntomas del glaucoma de ángulo estrecho agudo y de que deben interrumpir el uso de Ultibro Breezhaler si se desarrolla alguno de estos signos o síntomas. Retención urinaria No se dispone de datos en pacientes con retención urinaria, por lo tanto, Ultibro Breezhaler se debe utilizar con precaución en estos pacientes. Pacientes con insuficiencia renal grave En pacientes con insuficiencia renal de leve a moderada se observó un aumento promedio moderado en la exposición sistémica total (AUC

last) a glicopirronio de hasta 1,4 veces y de hasta 2,2 veces en pacientes con

insuficiencia renal grave y enfermedad renal terminal. En pacientes con insuficiencia renal grave (tasa de filtración glomerular estimada inferior a 30 ml/min/1,73 m2), incluyendo los de enfermedad renal terminal, que requieren diálisis, Ultibro Breezhaler debe utilizarse únicamente si el beneficio esperado supera el riesgo potencial. Se debe monitorizar estrechamente a estos pacientes por la posible aparición de reacciones adversas. Efectos cardiovasculares Ultibro Breezhaler debe utilizarse con precaución en pacientes con trastornos cardiovasculares (insuficiencia coronaria, infarto agudo de miocardio, arritmias cardiacas, hipertensión). Los agonistas beta

2-adrenérgicos pueden producir efectos cardiovasculares clínicamente significativos en algunos pacientes, determinado por el incremento de la frecuencia del pulso, la presión sanguínea y/o los síntomas. Si aparecen estos efectos con este medicamento, puede ser necesario interrumpir el tratamiento. Se ha

notificado, asimismo, que los agonistas beta-adrenérgicos producen alteraciones en el electrocardiograma (ECG), como el aplanamiento de la onda T, prolongación del intervalo QT y depresión del segmento ST, si bien se desconoce la significación clínica de estos hallazgos. Por lo tanto, los agonistas beta2-adrenérgicos de

larga duración se deben utilizar con precaución en pacientes con conocimiento o sospecha de prolongación del intervalo QT o tratados con medicamentos que afectan al intervalo QT. Los pacientes con cardiopatía isquémica inestable, insuficiencia ventricular izquierda, antecedentes de infarto de miocardio, arritmia (excluyendo fibrilación atrial estable crónica), antecedentes de síndrome de QT largo o aquellos con prolongación del intervalo QTc (>450 ms) (método Fridericia), se excluyeron de los ensayos clínicos, y por lo tanto, no se dispone de experiencia en este grupo de pacientes. Ultibro Breezhaler debe utilizarse con precaución en este grupo de pacientes. Hipocaliemia Los agonistas beta

2-adrenérgicos pueden inducir en algunos pacientes una hipocaliemia significativa, capaz de provocar efectos adversos cardiovasculares. El descenso del potasio sérico es generalmente transitorio y no requiere administrar suplementos. En pacientes con EPOC grave, la

hipocaliemia puede acentuarse por la hipoxia y por el tratamiento concomitante, lo que puede aumentar la susceptibilidad a las arritmias cardiacas (ver” Interacción con otros medicamentos y otras formas de interacción”). No se han observado efectos clínicamente relevantes de hipocaliemia en los ensayos clínicos de Ultibro Breezhaler a la dosis terapéutica recomendada. Hiperglucemia La inhalación de dosis elevadas de agonistas beta

2-adrenérgicos puede inducir un aumento de la

glucosa plasmática. Tras el inicio del tratamiento con Ultibro Breezhaler, deben vigilarse estrechamente los niveles de glucosa en sangre en pacientes diabéticos. Durante ensayos clínicos de larga duración, la mayoría de los pacientes tratados con Ultibro Breezhaler experimentaron alteraciones clínicamente considerables de la glucemia (4,9%) a la dosis recomendada comparado con placebo (2,7%). No se ha investigado el uso de Ultibro Breezhaler en pacientes con diabetes mellitus no controlada. Alteraciones generales Ultibro Breezhaler se debe utilizar con precaución en pacientes con trastornos convulsivos o tirotoxicosis, y en pacientes que responden de forma inusual a los agonistas beta

2-adrenérgicos. Excipientes Los pacientes con intolerancia hereditaria a galactosa, insuficiencia de lactasa de Lapp

o problemas de absorción de glucosa o galactosa no deben tomar este medicamento. Interacción con otros medicamentos y otras formas de interacción La administración concomitante de indacaterol y glicopirronio por vía inhalatoria oral, en condiciones de estado estacionario de ambos componentes, no afectó a la farmacocinética de cada uno de ellos. No se realizaron estudios de interacción específicos con Ultibro Breezhaler. La información sobre el potencial de interacciones está basada en el potencial de cada uno de sus dos componentes. Uso concomitante no recomendado Bloqueantes beta-adrenérgicos Los bloqueantes beta-adrenérgicos pueden debilitar o antagonizar el efecto de los agonistas beta

2- adrenérgicos. Por ello, Ultibro Breezhaler no debe administrarse junto con bloqueantes

beta-adrenérgicos (incluidos colirios) a menos que su uso esté claramente justificado. Cuando sean necesarios, es preferible utilizar bloqueantes beta-adrenérgicos cardioselectivos, aunque éstos también deben administrarse con precaución. Anticolinérgicos No se ha estudiado la administración concomitante de Ultibro Breezhaler con otros medicamentos conteniendo anticolinérgicos y por lo tanto, no está recomendada (ver “Advertencias y precauciones especiales de empleo”). Agentes simpaticomiméticos La administración concomitante de otros agentes simpaticomiméticos (solos o como integrantes de un tratamiento de combinación) puede potenciar los acontecimientos adversos de indacaterol (ver “Advertencias y precauciones especiales de empleo” ). Precaución necesaria con el uso concomitante Tratamiento hipocaliémico La administración concomitante de tratamiento hipocaliémico con derivados de la metilxantina, corticoides o diuréticos no ahorradores de potasio pueden intensificar el posible efecto hipocaliémico de los agonistas beta

2-adrenérgicos, por lo tanto se debe utilizar con precaución (ver

“Advertencias y precauciones especiales de empleo”). Para tener en cuenta con el uso concomitante Interacciones asociadas al metabolismo y a transportadores La inhibición de los agentes principales del metabolismo de indacaterol, CYP3A4 y la glicoproteína P (P-gp) aumenta hasta dos veces la exposición sistémica del fármaco. La magnitud de la exposición aumenta debido a las interacciones, si bien no afecta a la seguridad de acuerdo con la experiencia adquirida con el tratamiento con indacaterol en los ensayos clínicos de hasta un año de duración y utilizando dosis de hasta el doble de la dosis máxima recomendada de indacaterol. Cimetidina u otros inhibidores del transportador de cationes orgánicos En un ensayo clínico en voluntarios sanos, la cimetidina, un inhibidor del transportador de cationes orgánicos, la cual se cree que contribuye a la excreción renal del glicopirronio, incrementó la exposición total (AUC) a glicopirronio en un 22% y disminuyó el aclaramiento renal en un 23%. En base a la magnitud de estos cambios, no se espera una interacción de los fármacos clínicamente relevante cuando el glicopirronio se administra conjuntamente con cimetidina u otros inhibidores del transportador de cationes orgánicos. Fertilidad, embarazo y lactancia Embarazo No existen datos sobre la utilización de Ultibro Breezhaler en mujeres embarazadas. Los estudios en animales no sugieren efectos perjudiciales directos ni indirectos en términos de toxicidad para la reproducción a una exposición clínicamente relevante. El indacaterol puede inhibir el parto debido al efecto relajante sobre el músculo liso uterino. Por lo tanto, Ultibro Breezhaler debe utilizarse únicamente durante el embarazo si el beneficio esperado para el paciente justifica el riesgo potencial para el feto. Lactancia Se desconoce si indacaterol, glicopirronio y sus metabolitos se excretan en la leche materna. Los datos farmacocinéticos/toxicológicos disponibles muestran que indacaterol, glicopirronio y sus metabolitos se excretan en la leche de ratas lactantes. Únicamente se debe considerar el uso de Ultibro Breezhaler por mujeres en periodo de lactancia, si el beneficio esperado para la mujer es mayor que cualquier posible riesgo para el lactante . Fertilidad Los estudios de reproducción y otros datos en animales no indican ningún problema con respecto a la fertilidad en machos o hembras. Efectos sobre la capacidad para conducir y utilizar máquinas La influencia de este medicamento sobre la capacidad para conducir y utilizar máquinas es nula o insignificante. Sin embargo, la aparición de mareo puede influir sobre la capacidad para conducir y utilizar máquinas (ver “Reacciones adversas”). Reacciones adversas La presentación del perfil de seguridad está basada en la experiencia con Ultibro Breezhaler y los componentes individuales. Resumen del perfil de seguridad La experiencia de seguridad con Ultibro Breezhaler comprende hasta 15 meses de exposición a la dosis terapéutica recomendada. Ultibro Breezhaler mostró un perfil de reacciones adversas similar a los componentes individuales. Como contiene indacaterol y glicopirronio, se puede esperar en la combinación, el tipo y gravedad de las reacciones adversas asociadas con cada uno de estos componentes. El perfil de seguridad se caracteriza por los síntomas beta-adrenérgicos y anticolinérgicos típicos relacionados con los componentes individuales de la combinación. Otras reacciones adversas más frecuentes relacionadas con el producto (al menos el 3% de los pacientes para Ultibro Breezhaler y también superior a placebo) fueron tos, rinofaringitis y cefalea. Tabla de reacciones adversas Las reacciones adversas detectadas durante los ensayos clínicos y de fuentes post-comercialización se enumeran según la clasificación de órganos del sistema MedDRA (Tabla 1). Dentro de cada clase de órganos del sistema, las reacciones adversas se clasifican por frecuencias, incluyendo primero las más frecuentes. Dentro de cada grupo de frecuencias, las reacciones adversas se especifican por orden decreciente de gravedad. Además, la correspondiente categoría de frecuencia para cada reacción adversa se basa en la siguiente convención: muy frecuentes (≥1/10); frecuentes (≥1/100 a <1/10); poco frecuentes (≥1/1.000 a <1/100); raras (≥1/10.000 a <1/1.000); muy raras (<1/10.000); frecuencia no conocida (no puede estimarse a partir de los datos disponibles). Descripción de reacciones adversas seleccionadas La tos se observó de forma frecuente, pero por lo general era de intensidad leve. Notificación de sospechas de reacciones adversas Es importante notificar sospechas de reacciones adversas al medicamento tras su autorización. Ello permite una supervisión continuada de la relación beneficio/riesgo del medicamento. Se invita a los profesionales sanitarios a notificar las sospechas de reacciones adversas a través del Sistema Español de Farmacovigilancia de medicamentos de Uso Humano: https://www.notificaram.es. Sobredosis No existe información acerca de la sobredosificación clínicamente relevante con Ultibro Breezhaler. Una sobredosis puede producir de forma exagerada los efectos típicos de los estimulantes beta

2-adrenérgicos, es decir, taquicardia, temblor, palpitaciones, cefalea, náuseas, vómitos, mareo, arritmias ventriculares, acidosis

1 Reacción adversa observada con Ultibro Breezhaler, pero no con los componentes individuales.

2 Informes recibidos de la experiencia post-comercialización; sin embargo, las frecuencias se han calculado en base a los datos de los ensayos clínicos.

Reacciones adversas Frecuencia

Trastornos respiratorios, torácicos y mediastínicos

Tos Frecuente

Dolor orofaríngeo incluyendo irritación de garganta Frecuente

Broncoespasmo paradójico Poco frecuente

Disfonía2 Poco frecuente

Epistaxis Poco frecuente

Trastornos gastrointestinales

Dispepsia Frecuente

Caries dental Frecuente

Gastroenteritis Poco frecuente

Sequedad bucal Poco frecuente

Trastornos de la piel y del tejido subcutáneo

Prurito/erupción cutánea Poco frecuente

Trastornos musculoesqueléticos y del tejido conjuntivo

Dolor musculoesquelético Poco frecuente

Espasmos musculares Poco frecuente

Mialgia Poco frecuente

Dolor en las extremidades Poco frecuente

Trastornos renales y urinarios

Obstrucción de la vejiga y retención urinaria2 Frecuente

Trastornos generales y alteraciones en el lugar de administración

Pirexia1 Frecuente

Dolor torácico Frecuente

Edema periférico Poco frecuente

Fatiga Poco frecuente

Reacciones adversas Frecuencia

Infecciones e infestaciones

Infección de las vías respiratorias altas Muy frecuente

Rinofaringitis Frecuente

Infección del tracto urinario Frecuente

Sinusitis Frecuente

Rinitis Frecuente

Trastornos del sistema inmunológico

Hipersensibilidad Frecuente

Angioedema2 Poco frecuente

Trastornos del metabolismo y de la nutrición

Hiperglucemia y diabetes mellitus Frecuente

Trastornos psiquiátricos

Insomnio Poco frecuente

Trastornos del sistema nervioso

Mareo Frecuente

Cefalea Frecuente

Parestesia Rara

Trastornos oculares

Glaucoma1 Poco frecuente

Trastornos cardiacos

Isquemia coronaria Poco frecuente

Fibrilación auricular Poco frecuente

Taquicardia Poco frecuente

Palpitaciones Poco frecuente

Tabla 1: Reacciones adversas

FT_pmsa_ULTIBRO_282x211_090617.indd 1 15/6/17 13:57

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