Originals Image - Neumosur · 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 00.000 intervenciones,

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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.

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

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

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

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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

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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: 2531-1816

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)

200


Volume 29. Issue 4. December 2017CONTENTS

EditorialRoad safety, asthma and rhinitis: reflectionsA. Pereira-Vega .............................................................................................................................................................................................................................................................................................................. 203 OriginalsAsthma, rhinitis and road safetyJ. Gregorio Soto Campos, J. Rojas Villegas, R. Carmona García, D. del Castillo Otero, A. del Cuvillo Bernal, C. Millán González ......................................................................................................... 206 Comparison between a new nanotechnology-based agent and conventional talc in the control of malignant pleural effusionsB. Romero Romero; A. Montes Worboys, E. Arellano Orden, V. Sánchez López, L. Padrón Fraysse, J. Martín Juan, F. Rodríguez Panadero ............................................................................................. 216

Celular origin of circulating microparticles in patients with venous thromboembolism and cancerR. Otero Candelera, V. Sánchez López, T. Elías Hernández, L. Jara Palomares, E. Arellano Orden, M. Ferrer Galván, I. Asensio Cruz, J.M. Sánchez Díaz, A. González-Castro, R. Sánchez Gil, M. Chaves Conde, J. Rodríguez Martorell .......................................................................................................................................................... 226

How do medical students and family medicine residents use inhaler devices?M. Entrenas Castillo, L.M. Entrenas Costa .............................................................................................................................................................................................................................................................. 232

Home non-invasive ventilation in elderly patientsJ. Hernández Borge, M.C. García García, M.J. Antona Rodriguez, A. Sanz Cabrera, P. Pires Goncalves, P. Cordero Montero, A. M. Esquinas Rodríguez ........................................................................................................................................................................................................................................................ 238

Clinical NoteMeningeal carcinomatosis: unusual presentation of adenocarcinoma of the lungM. Pérez Morales, G. Jiménez Gálvez, C. España Domínguez, L.C. Márquez Lagos ........................................................................................................................................................................................... 247

ImageEndobronchial lesion in a female smokerG. López Muñiz, C. López Represa, T. Ruiz Albi ..................................................................................................................................................................................................................................................... 253


201201

EditorialSeguridad vial, asma y rinitis: reflexionesA. Pereira-Vega .............................................................................................................................................................................................................................................................................................................. 203 OriginalesAsma, rinitis y seguridad vialJ. Gregorio Soto Campos, J. Rojas Villegas, R. Carmona García, D. del Castillo Otero, A. del Cuvillo Bernal, C. Millán González ......................................................................................................... 206 Comparación de un nuevo agente basado en nanotecnología con el talco convencional para el control de los derrames pleurales malignosB. Romero Romero; A. Montes Worboys, E. Arellano Orden, V. Sánchez López, L. Padrón Fraysse, J. Martín Juan, F. Rodríguez Panadero ............................................................................................. 216

Origen celular de micropartículas circulantes en pacientes con enfermedad tromboembólica venosa y cáncerR. Otero Candelera, V. Sánchez López, T. Elías Hernández, L. Jara Palomares, E. Arellano Orden, M. Ferrer Galván, I. Asensio Cruz, J.M. Sánchez Díaz, A. González-Castro, R. Sánchez Gil, M. Chaves Conde, J. Rodríguez Martorell .......................................................................................................................................................... 226

¿Cómo utilizan los dispositivos inhalados los estudiantes de medicina y los residentes de familia?M. Entrenas Castillo, L.M. Entrenas Costa .............................................................................................................................................................................................................................................................. 232

Ventilación no invasiva domiciliaria en pacientes de edad avanzadaJ. Hernández Borge, M.C. García García, M.J. Antona Rodriguez, A. Sanz Cabrera, P. Pires Goncalves, P. Cordero Montero, A. M. Esquinas Rodríguez ........................................................................................................................................................................................................................................................ 238

Nota ClínicaCarcinomatosis meníngea: Forma inusual de presentación del Adenocarcinoma de pulmónM. Pérez Morales, G. Jiménez Gálvez, C. España Domínguez, L.C. Márquez Lagos ........................................................................................................................................................................................... 247

ImagenLesión endobronquial en mujer fumadoraG. López Muñiz, C. López Represa, T. Ruiz Albi ..................................................................................................................................................................................................................................................... 253

Volumen 29. Número 4. Diciembre, 2017SUMARIO


202

ASTHMA, RHINITIS AND ROAD SAFETY Gregorio Soto Campos J., et al. Accidents present “accident-causing” hu-man factors. The incidence of rhinitis and asthma are on the rise and there is an infraevaluation of the impact of these illnesses on activities that, like driving, require one’s maximum attention. Our study points to a higher incidence of accidents among those suffering from rhinitis or asthma. Rev Esp Patol Torac 2017; 29 (4): 206-213

COMPARISON BETWEEN A NEW NANOTECHNOLOGY-BASED AGENT AND CONVENTIONAL TALC IN THE CON-TROL OF MALIGNANT PLEURAL EFFUSIONS Romero Romero B., et al. We have completed a comparative in vitro study with talc and titanium dioxide (TiO2) in different cell lines. Talc is shown to be superior to TiO2 in its ability to produce mediators which favor pleurodesis for the control of malignant pleural effusions. Rev Esp Patol Torac 2017; 29 (4): 216-225

CELULAR ORIGIN OF CIRCULATING MICROPARTICLES IN PATIENTS WITH VENOUS THROMBOEMBOLISM AND CAN-CER Otero Candelera R., et al. Certain circulating microparticle (MP) popula-tions such as total MP levels and platelet-derived MP levels could differentiate between patients with venous thromboembolism (VTE) and non-VTE-asso-ciated cancer patients. Rev Esp Patol Torac 2017; 29 (4): 226-231

HOW DO MEDICAL STUDENTS AND FAMILY MEDICINE RESIDENTS USE INHALER DEVICES? Entrenas Castillo M., et al. Inhaled medication is essential for the treatment of asthma and chronic obstructive pulmonary disease (COPD) and doctors should teach patients to perform inhaler techniques. Uncontrolled asthma may be associated with misuse or improper use of inhalers. Not only is the doctor responsible for prescribing the device, but they are also responsible for tea-ching the patient how to use it. Previous studies have shown that doctors do not know how to use these devices properly, adding to the difficulty of instruc-ting patients on their handling. We used Inhalation Manager® in this study to check inhaler technique among medical students and family medicine residents. Rev Esp Patol Torac 2017; 29 (4):232-237

HOME NON-INVASIVE VENTILATION IN ELDERLY PA-TIENTS Hernández Borge J., et al. The use of home non-invasive ventilation in elderly patients seems to obtain results similar to the younger population. The objective of this work is to understand the factors determining its success in elderly patients in the long term. Rev Esp Patol Torac 2017; 29 (4): 238-246

Volume 29. Issue 4. December 2017

SUMMARIES OF THE ARTICLES

203

EDITORIAL

A. Pereira-Vega.

Hospital Juan Ramón Jiménez, Huelva.

Rev Esp Patol Torac 2017; 29 (4) 203-205

ROAD SAFETY, ASTHMA AND RHINITIS: REFLECTIONS

Received: November 20, 2017. Accepted: November 27, 2017.

Antonio [email protected]

Few communications such as the one presented at the 2017 Neumosur Congress on “Road safety, asthma and rhinitis”1 have had such a media impact. This was understandable, as it was a brilliant presentation on a particularly important topic: traffic accidents and their possible consequences, bronchial asthma and rhinitis, common illnesses and the basis of our specialty.

Traffic accidents are one of the most important causes of morbidity and mortality, mainly in developed countries2 and developing countries3.

Several factors have been attributed to the road accident rate. With regard to of the age of drivers, both young people4 (in relation to speeding, mobile phone use or alcohol or drug abuse), and those over 65 years old5 (for loss of reflexes or greater use of medication, such as benzodiazepines, opiates or tramadol) seem to have a significantly higher risk of traffic accidents. Various illnesses have been linked to traffic accidents, such as those that cause defects in vision or hearing, and cardiological (arrhythmias or ischemic heart disease), metabolic (hypoglycemia in diabetics), neurological (epilepsy) or psychiatric alterations. Among respiratory diseases, Obstructive Sleep Apnea Syndrome (OSAS) is noteworthy6, 7. There are scarce studies that refer to other respiratory pathologies, including rhinitis8 or bronchial asthma9. Similarly, different medication10 can make driving difficult by altering vision or hearing and/or intellectual or motor skills; deteriorating the state of alertness; causing

sedation, a disinhibiting affect, movement coordination and balance disorders; increasing the risk with the use of alcohol and drugs, among which cannabis has an advantage. Some noted medications are benzodiazepines5, opiates, antihistamines11, 12 and tramadol5, among others. Symptoms such as fatigue13, 14 have also been linked to driving deterioration and traffic accidents.

As Gregorio Soto et al.15 said in an article presented in this journal, as a result of the aforementioned communication1: “our study shows a higher prevalence of traffic accidents in patients with asthma and rhinitis than in a healthy population, and this accident rate is higher depending on the severity of the pathology”. This idea is based on the results of a descriptive study from an investigation with acceptable levels of reliability, in which 424 healthy people and 185 patients with asthma/rhinitis were interviewed. It was found that said patients had a significantly higher record of driving accidents than the healthy population. This data could be explained by apparently evident causes: symptoms that may cause lack of attention (coughing fits16, sneezing…) and the use of medication for these illnesses which may decrease attention (antihistamines11,12).

In my opinion, this assertion is relevant, as long as it is well founded.

The first time I had the opportunity to read it, it caused me some amazement, even disbelief. With asthma and rhinitis being as common as they are17, asthma

204 Rev Esp Patol Torac 2017; 29 (4) 203-205

A. Pereira-Vega. Road safety, asthma and rhinitis: Reflections

not being well controlled18, and the frequent use of antihistamines5… To what extent may suffering from these illnesses be a road risk for pedestrians, for the patients themselves and for the rest of the drivers?

We’re talking about things that may have consequences. A few years ago, Terán-Santos et al.6 showed that Obstructive Sleep Apnea Syndrome (OSAS) could increase the risk of traffic accidents. The authors conducted a study of cases (102 drivers that have had a traffic accident) and controls (152 subjects) in which they carried out an OSAS screening. Comparing patients without OSAS and with OSAS (AHI>10), they found that the latter had an odds ratio (OR) of 6.3 with a 95% CI of 2.4 to 16.2 (0.001) for having traffic accidents. In this way, today it’s thought that if sleep apnea syndrome isn’t diagnosed and treated7, the risks of having a traffic accident are clearly increased. As a consequence, patients with Sleep Apnea-Hypopnea Syndrome (SAHS) are now required to present a report from a competent pulmonologist when renewing their driver’s license, which shows that the treatment is working and effective19.

Perhaps we’re not talking about similar risks, but we must reflect on this. In this regard, I would like to comment that it would be interesting for the authors of the article in question15 to analyze their odds ratio (OR), a very illustrative and easy parameter to complete.

It seems like a brilliant article which establishes a clear association between asthma, rhinitis and traffic accidents in its conclusion. In terms of the consequences it could have, I think that this subject requires more in-depth exploration to avoid any type of bias, such as confounders (alcohol consumption, visual or auditory alterations, BMI and age of drivers, previous accident history, medication and associated illnesses, among others) or the interrelation of casual factors20, being very strict about the inclusion/exclusion criteria in these studies. It would be interesting to carry out new research that supports these initial results.

The research must try to clarify or demonstrate ideas, while the work of other bodies is to analyze the consequences of the research.

BIBLIOGRAPHY1. De La Cruz NP, Soto JG, Rojas J et al. Seguridad vial en asma y rinitis. Rev Esp Patol Torac

2017; 29 (1): 5-92. Página 29.2. Kassebaum, Nicholas J; Arora et al. Global, regional, and national disability-adjusted life-

years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388 (10053):1603-1658.

3. Jiang, Baoguo; Liang et al. Review: Transport and public health in China: the road to a healthy future. Lancet 2017; 390 (10104): 1781-1791.

4. Scott-Parker, Bridie; Oviedo-Trespalacios O. Young driver risky behaviour and predictors of crash risk in Australia, New Zealand and Colombia: Same but different? Accident Analysis and Prevention 2017; 99 Part A: 30-38 Part A.

5. Rudisill, Toni M.; Zhu et al. Medication use and the risk of motor vehicle collision in West Virginia drivers 65 years of age and older: a case crossover study. BMC Research Notes 2016; 9: 1-11.

6. Terán J, Jiménez-Gómez A, Cordero-Guevara J and The Cooperative Group Burgos-San-tander. The association between Sleep Apnea and the risk of traffic accidents. N Engl J Med 1999; 340: 847-851.

7. Grote, Ludger; Karimi et al. Sleep Apnea Related Risk of Motor Vehicle Accidents is Re-duced by Continuous Positive Airway Pressure: Swedish Traffic Accident Registry Data. SLEEP 2015; 38 (3): 341-349.

8. Demoly, Pascal, Maigret et al. Allergic rhinitis increases the risk of driving accidents. Jour-nal of Allergy and Clinical Immunology 2017; 140 (2): 614-616.

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A. Pereira-Vega. Road safety, asthma and rhinitis: Reflections

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J. Gregorio Soto Campos1, J. Rojas Villegas2, R. Carmona García3, D. del Castillo Otero1, A. del Cuvillo Bernal4, C. Millán González5. 1Pulmonology-Allergy CMU. Hospital de Jerez. 2Health Prevention, Promotion and Monitoring CMU. AGS Norte de Cádiz. 3Pulmonology CMU. Hospital Puerto Real. 4ENT CMU. Hospital de Jerez. 5Rhinitis and Asthma Functional Unit. Hospital de Jerez. Project financed by Beca Neumosur 5/2012.


ORIGINALS

ASTHMA, RHINITIS AND ROAD SAFETY

AbstractIntroduction: injuries from traffic accidents constitute one of the main health problems for the global population in the early 21st century. This study aims to determine if there is a grea-ter prevalence of accident-causing driving among individuals diagnosed with asthma and/or rhinitis. Method: patients visiting two health centers who were not afflicted with chronic disease were recruited consecutively over the course of three months. All participants ranged between 18 and 65 years old, and were habitual drivers. A group of ill patients with a diagnosis of asth-ma/rhinitis were also recruited from the pulmonology, allergy and ENT departments at the Hospital de Jerez. These patients were interviewed following a predetermined questionnaire, collecting demographic data, tobacco use, history of driving accidents, characteristics of the asthma and rhinitis and the Goldberg Anxiety-Depression Scale (GADS) was used to evaluate the existence of a psychiatric comorbidity. The prevalence of accidents was calculated in each group and among the patients with a diagnosis of rhinitis/asthma, as well as according to diagnosis and severity. Results: 424 healthy individuals (49.3% women) were interviewed with an average age of 38. We also interviewed 185 patients with asthma/rhinitis (52.4% women), with an average age of 45. Of those interviewed, 67.6% suffered from rhinitis with or without asthma. A total of 33.8% of the control group and 41.6% of asthmatic patients (p <0.001) reported having su-ffered traffic accidents. Patients suffering only from rhinitis (n = 125) had more accidents than the healthy population in the control group (0.48 ± 0.51 vs 0.34 ± 0.47; p < 0.001). Accidents showed a correlation with the level of asthma control and the severity of asthma and rhinitis. Conclusions: there is a higher rate of driving accidents among individuals suffering from asthma and rhinitis, which may be related to the severity of these illnesses.

Key words: Asthma, rhinitis, road safety, traffic accidents.

Received: August 28, 2016. Accepted: August 9, 2017.

Jose Gregorio Soto [email protected]

ASMA, RINITIS Y SEGURIDAD VIALResumen:Introducción: Las lesiones por accidente de tráfico constituyen uno de los principales pro-blemas de salud de la población mundial en los inicios del siglo XXI. En este estudio nos planteamos estudiar si existe una mayor prevalencia de accidentalidad en la conducción en personas con diagnóstico de asma y/o rinitis. Método: Se eligieron, de forma consecutiva durante un periodo de tres meses, a pacientes que acudieron a consultas de dos centros de Salud sin aquejar patología crónica, todos ellos con un rango de edad entre 18 y 65 años, conductores habituales y a un grupo de enfermos de las consultas de neumología, alergia y ORL de Hospital de Jerez, con diagnóstico de asma/rinitis. A estos pacientes se les entrevistó siguiendo cuestionario preestablecido, reco-giéndose datos demográficos, consumo de tabaco antecedentes de siniestralidad en la con-ducción, características del asma y la rinitis y la escala Goldberg Anxiety-Depression (GADS) para la valoración de la existencia de comorbilidad psiquiátrica. Se calculó la prevalencia de accidentalidad en cada grupo y en los pacientes con diagnóstico de rinitis/asma, también en función de estos diagnósticos y su gravedad. Resultados: Se entrevistó a 424 personas sanas (49,3% mujeres) de 38 años de edad media y a 185 pacientes asmáticos/riníticos (52,4% mujeres), con edad media de 45 años. Un 67,6% de ellos padecían rinitis con o sin asma. Referían haber sufrido accidentes de tráfico un 33,8% del grupo control y el 41,6% de los pacientes asmáticos (p <0,001). Los pacientes que presentaban solamente rinitis (n = 125) concentraron más accidentes que la población sana del grupo control (0,48 ± 0,51 vs 0,34 ± 0,47; p < 0,001). La siniestralidad mostró relación con el grado de control del asma y la gravedad del asma y rinitis. Conclusiones: Existen indicios de una mayor siniestralidad en la conducción entre perso-nas asmáticas y riníticas, que podría estar relacionada con la gravedad de estas patologías.

Palabras clave: Asma, rinitis, seguridad vial, accidentes de trafico.


J. Gregorio Soto Campos et al. Asthma, rhinitis and road safety

INTRODUCTION Injuries from traffic accidents constitute one of the main health problems for the global population in the early 21st century. In the first few decades, they became one of the most prevalent health problems in developed countries, in which they represent the leading cause of death between ages 5 and 44. The health impact is even greater, as half of all serious head injuries and 60% of all spinal injuries are the result of a traffic accident. In Spain, a total of 1,348 fatal accidents were registered in 2013, resulting in 1,680 deaths. In addition, there were 89,519 accidents with victims and 10,086 serious injuries1. Human factors were identified as the cause of the accident in 71% to 93% of cases2. Within comorbidities, particular emphasis has been placed on sensory organ (sight, hearing) defects and cardiovascular (arrhythmia, coronary heart disease), metabolic (hypoglycemia in diabetics), neurological and/or psychiatric alterations. The incidence of chronic airway inflammation (rhinitis and asthma) is on the rise and, in the case of allergies, seasonality and the age affected (youth) determine an infraevaluation of the impact these illnesses have on activities that require maximum attention, such as driving. Rhinitis and sinusitis are very prevalent illnesses. In Spain, an estimated 21% of the population suffers from allergic rhinitis (of which the highest percentage corresponds to moderate-serious)3 and around 5-15% suffers chronic sinusitis, while 2% of the population has sinonasal polyposis4. Additionally, the prevalence of asthma reached 7% of the general population in the most recent studies5. As a result, for nearly the nearly 10 million people suffering from problems related to allergic processes, driving vehicles can be affected by the illness and even become dangerous. Few studies have been done on this matter, but they point to a higher incidence of accidents in people with rhinitis or asthma derived from allergic processes. In the case of asthma, upon analyzing the incidence of health factors and their influence on traffic accidents in the Community of Madrid in 2006 and 2007, Kanaan A. et al.6 found that the two entities most frequently associated with accidents were high blood pressure and asthma (detected in 6.6% of cases), followed at quite a distance by depression and epilepsy (2.8%). Previous studies have identified syncope from coughing fits as a risk factor for accidents7-9. However, recent publications indicate that patients suffering from allergic rhinitis do not have deteriorated driving reflex capacity and memory10. Nevertheless, a few years

ago, Mapfre released a report stating that allergies were responsible for 100 deaths per year in traffic accidents in Spain11. Our objective in this study is to analyze whether there is a higher rate of driving accidents in the population with asthma and/or rhinitis in our healthcare area, determining the prevalence of previous accidents this group has had. With this, we aim to shed some light on the risks of these illnesses with regard to road safety and if these illnesses can be considered risk factors affecting driving.

MATERIAL AND METHODS A cross-sectional observational epidemiological analysis was done with case and control groups from October 2013 to September 2014. For the patient group, participants with a diagnosis of rhinitis/asthma were consecutively recruited while attending an appointment at the Pulmonology/Allergy and Otolaryngology departments at the Hospital de Jerez, provided they met the requirement of being habitual drivers (at least twice a week). The asthma diagnosis was based on the criteria found in the Spanish Guide for Asthma Management (GEMA)12, with regard to compatible clinical symptoms and obstruction reversibility with FEV1 >12% and >200 ml or FeNO >50 ppm or PEF variability or positive nonspecific provocation. The rhinitis diagnosis was based on the definition from the European Academy of Allergy and Clinical Immunology’s document “Allergic Rhinitis and Its Impact on Asthma” (ARIA)13. The allergy diagnosis was based on compatible clinical symptoms with skin tests using the prick test and/or determining positive specific serum IgE for common pneumoallergens in the environment. The diagnosis of polyposis was based on imaging tests and/or ENT exams. Participants for the control group were selected consecutively from pa-tients attending appointments at two health centers in the healthcare area in northern Cádiz (La Serrana Health Center and Jerez-Norte). Participants did not suffer previous illness, ranged from 18-65 years old, and were habitual drivers. The study was carried out after approval from the respective local ethics committees and all patients gave their written consent to participate. Patients were interviewed following a pre-determined questionnaire. De-mographic data, tobacco use and history of driving accidents (number of previous accidents) were collected, as well as several characteristics of their



illness and treatment. The Goldberg Anxiety-Depression Scale (GADS) was also used14. The GADS questionnaire asks how interviewees have felt in the past month using nine anxiety items and nine for depression, to which they answer “yes” or “no”. A driving accident was defined as that which occurs on the minor roads or territory for the circulation of motor vehicles which are under traffic legisla-tion, provided this accident results in one or more deaths or injuries or only causes material damage, provided a moving vehicle is involved. Accidents with victims are considered those in which one or several people are killed or injured. Accidents with only material damage are those in which no death or injury has occurred. Participants were also asked about accidents without victims or material damage resulting from the loss of control while driving a vehicle. Injuries were considered serious when the person injured in the accident was hospitalized for longer than 24 hours. Minor injuries are those which do not meet the definition for serious injury. Those individuals who were not habitual drivers (did not drive at least two days a week), those with factors related to psychomotor driving prob-lems, a history of previous treatments that affected driving, the presence of symptoms compatible with sleep apnea syndrome, associated comorbidity or psychiatric involvement and those who consumed alcohol or psychotropic drugs were excluded. Asthmatic patients were classified according to severity and degree of control according to GINA (Global Initiative for Asthma) criteria14. Data was collected regarding exacerbations, which were considered to be those episodes requiring treatment with systemic steroids, emergency room visits or hospitalization. Patients with rhinitis were grouped according to severity, following the cri-teria in the ARIA (Allergic Rhinitis and Its Impact on Asthma) document13. For our main objective in this study, we calculated and compared the prev-alence of history of driving accidents in the active groups (patients with a di-agnosis of asthma/rhinitis) versus the control group. For the secondary ob-jectives, we calculated and compared the prevalence of history of accidents according to severity and the degree of asthma control and to the severity of the rhinitis. Statistical analysis: a preliminary analysis was done to calculate the sam-ple size. Considering a difference of 5% in accidents between the different groups, it was decided that 500 patients were needed for 95% power and level

of significance α of 0.05. All of the statistical analyses were done using the SPSS package, Chica-go Illinois, version 22. A descriptive analysis was done of all the variables included in our study sample. The results are expressed as percentages, fre-quencies and the number of observations for the qualitative variables and as averages with standard deviation for the quantitative variables. The general and secondary mental state scores in patients and control participants were calculated, comparing the averages using the Mann-Whitney U test. Com-parisons between groups were done using the χ2 test for categorical variables and with the Kruskal-Wallis test for ordinal and quantitative variables, after confirming values did not follow a normal distribution.

RESULTS A total of 424 healthy individuals were interviewed for the control group (50.7% male and 49.3% female) averaging 38 years old, with an average body mass index (BMI) of 24.7 ± 4 kg/cm2 (SD: standard deviation). Non-smok-ers accounted for 56.6% of the sample, while the percentage for smokers was 27.1% (at an average of 23 ± 20 packs/year) and former smokers made up 16.3%. A total of 33.8% reported having a traffic accident. Of these, 21% reported one accident, 9.9% two and 4.2% had had more than two prior ac-cidents. For the case group, 185 patients were interviewed averaging 45 years old (52.4% women and 47.6% men). The demographic and clinical characteristics of the patient sample with asthma and/or rhinitis are included in Table 1. The characteristics of the general sample are included in Table 2. It is worth noting that age differences were found in the control population (somewhat lower in this group and significantly different when comparing the females with the asthmatic group). Tobacco use was also different in both groups. In the group of asthmatic patients, concomitant rhinitis stands out to a greater extent at 67.6% (70.5% in men and 65% in women). Comorbidity data is included in Table 3. There were no significant differences in any of the parameters (anxiety or depression) between the control group and patients measured with the GADS. With respect to the medication used, the majority of asthmatic patients



used a combination of inhaled corticosteroids (ICS) + long-acting β2-agonist (LABA) (75.6%), ICS (10%), antileukotrienes (52.8%), omalizumab (20.7%), on-demand salbutamol (59.4%), and oral corticosteroids (5.4%). In patients with rhinitis, the most frequent treatments were antihistamines (35.7%), but a first-generation H1-antagonist was found in one case, followed by topical corticosteroids (29.7%), nasal antihistamines (83.3%) and immunotherapy (2.2%). Other drugs detected include: antiulcer drugs (22.2%), anxiolytics (16.2%), diuretics (7.6%), antidepressants (5.4%), beta-blockers (4.3%), and calcium antagonists (4.3%). With regard to the objective of the study, Table 4 shows the data from the road safety survey. The asthmatic group showed a higher prevalence of traf-fic accidents in comparison with the control group. There were also signifi-cant differences in the time at which these accidents occurred and the season of the year in which the accidents took place reached statistical significance, with more than half of accidents in the asthmatic group being concentrated in the spring and fall (Table 4). There were no significant differences in the severity of the injuries caused by the accidents, although the only case in which deaths occurred was registered in the asthmatic group. The majority of patients indicated that their illness interfered with driving vehicles and up to 77.7% associated their illness with the traffic accidents. If we analyze the patients suffering only from rhinitis (n = 125), they ex-perienced more accidents than the healthy population in the control group (0.48 ± 0.51 vs 0.34 ± 0.47; p < 0.001). A total of 47.2% of patients with rhinitis (n = 59) reported previous accidents compared to 33% in those not suffering from this condition. Within the asthmatic group, those presenting with concomitant rhinitis also showed a higher proportion of history of traffic accidents (47.2% vs 31.7% in the asthmatic group without rhinitis, n = 60; p < 0.001). If we consider the severity and control of the asthma, as well as accident rate based on the length or severity of rhinitis symptoms, we see the differ-ences in figures 1, 2, 3 and 4 (only significant differences are indicated in the charts).

Table 1. Clinical and demographic characteristics of asthmatic patients

Variable Female (n = 97)

Male (n = 88)

All (n = 185)

Average age (SD) 47 ± 11 43 ± 13 45 ± 12Average BMI (SD) 26.8 ± 4 26.8 ± 4 26.8 ± 4.0Tobacco (%)

Non-smoker 69.1 % 53.4 % 61.6%Smoker 16.5 % 18.2% 16.2%Former smoker 14.4 % 28.4% 22.2%

Packs/year 11 ± 8 14 ± 8 12 ± 8Hospitalizations due to asthma, n (%)

Patients hospitalized 9 (9.6%) 9 (10.3%) 18 (9.9%)Number of hospitalizations per patient 0.13 ± 0.42 0.1 ± 0.3 0.11 ± 0.36

Trips to the emergency room (previous year) 32 (34%) 29 (33.3%) 61 (33.7 %)Unplanned medical visits (previous year) 32 (34%) 19 (21.8%) 51 (28.2%)Years of asthma evolution (years) 8 ± 5 11 ± 9 9 ± 8Asthma control (GINA) (%)

Controlled 46.2% 52.9% 49.4% Partially controlled 34.4% 28.7% 31.7% Uncontrolled 19.4% 18.4% 18.9%

GINA SEVERITY, (%) Intermittent 8.6% 12.6% 10.6% Mild persistent 28.0% 34.5% 31.1% Moderate persistent 45.2% 40.2% 42.8% Severe persistent 18.3% 12.6% 15.5%

Spirometry (average (SD))FEV1, ml 2490 ± 765 3478 ± 1023 3014 ± 1033FEV1, % 88.1 ± 21.2 87.5 ± 22.6 87.8 ± 22FEV1/FVC % 74.6 ± 11.7 71 ± 11 73 ± 11

SD: standard deviation; BMI: body mass index, FEV1: maximum volume exhaled in the first second.



Table 2. Control group and asthmatic patient comparison

Control Group Asthma GroupAll (control) (n = 424)

Female (control) (n = 209)

Male (control) (n=215)

All (asma) (n =185)

Female (asma) (n = 97)

Male (asma) (n = 88)

Average age (SD) 38 ± 12 37 ± 13 39 ± 13 45 ± 12 47 ± 11# 43 ± 13Average BMI* (SD) 24.7 ± 4 24 ± 4 25.4 ± 4 26.8 ± 4.0 26.8 ± 4 26.8 ± 4Tobacco (%)Non-smoker 56.6 54.1 59.1 61.6% 69.1 %# 53.4 %*Smoker 27.1 28.2 26.0 22.2% 14.4 % 18.2%Former smoker 16.3 17.7 14.9 16.2% 16.5 % 28.4%

Packs/year 23.3±21 17± 15 30± 24 12 ± 8 11 ± 8# 14 ± 8*GADS* Total 4.9 ± 4.5 5.5 ± 4.7 4.4 ± 4.2 4.7 ± 4.6 4.8 ± 4.9 4.6 ± 4.2GADS* Anxiety 3.2 ± 2.7 3.4 ± 2.8 2.8 ± 2.6 3.0 ± 2.2 3.0 ± 2.7 2.9 ± 2.5GADS* Depression 1.8 ± 2.2 2.0 ± 2.2 1.6 ± 2.1 1.7 ± 2.4 1.7 ± 2.6 1.7 ± 2.2¶ Significant differences between control group and asthma group.* Significant differences between control group men and asthmatic men.# Significant differences between control group women and asthmatic women.

Table 3. Comorbidity in the asthmatic patients group

All (n = 185) Male (n = 88) Female (n = 97)Rhinitis (n, %) 125 (67.6%) 62 (70.5%) 63 (64.9%) Intermittent 25.6% 29.6% 28.5% Persistent 74.4% 70.4% 71.4% Mild 41.6% 48.4% 34.9% Moderate 54.4% 45.2% 63.5% Severe 4.0% 6.4% 1.6%Polyposis 32 (17.3%) 11 (12.5%) 21 (21.6%)Gastroesophageal reflux 28 (15.1%) 8 (9.1%) 20 (20.6%)Diabetes 10 (5.4%) 5 (5.7%) 5 (5.2%)Arterial hypertension 23 (12.4%) 8 (9.1%) 15 (15.5%)Fibromyalgia 9 (4.9%) 1 (1.1%) 8 (8.2%)Depression 13 (7.0%) 3 (3.4%) 10 (10.3%)Anxiety 37 (20.0%) 12 (13.6%) 25 (25.8%)

Table 4. Road safety

Control group (n = 424)

Asthmatic group (n = 185)

p

Have you had a traffic accident? YESn (%)

141 (33.8%) 77 (41.6%) 0.000

How many? n (%)None 276 (65.3) 107 (58.2) 0.052One 87 (20.6) 58 (31.5)Two 42 (9.9) 15 (8.2)> Two 18 (4.2) 4 (2.1)

Vehicle?Car 98 (84.5) 67 (91.8) 0.000Bus 4 (3.5) 3 (4.1)Motorcycle 14 (12) 3 (4.1)

Seasonspring 27 (24.8) 21 (28.8) 0.088summer 39 (35.8) 22 (30.1)fall 12 (11.0) 20 (27.4)winter 31 (28.4) 10 (13.7)

Day of the weekMonday 3 (3.2) 4 (5.5) 0.49Tuesday 13 (14.0) 10 (13.7)Wednesday 21 (22.6) 9 (12.3)Thursday 20 (21.5) 29 (39.7)Friday 25 (26.9) 10 (13.7)Saturday 9 (9.7) 10 (13.7)Sunday 2 (2.1) 1 (1.4)

Time1:00-10:00 18 (17.3) 0 (0.0) 0.01810:00 -14:00 28 (26.9) 23 (32.4)14:00 -17:00 19 (18.3) 20 (28.1)17:00-20:00 29 (27.9) 19 (26.8)20:00-01:00 10 (9.6) 9 (12.7)

Victims?Mild 37 (8.7) 15 (8.1) 0.12Serious 4 (0.9) 1 (0.5)Fatal 0 (0.0) 1 (0.5)



Do you think your illness influenced your traffic accident(s)? YES

56 (72.7)

Do you think your illness influences your driving? YES

84 (45.5)

Control group (n = 424)

Asthmatic group (n = 185)

p



DISCUSSIONOur study shows a higher prevalence of traffic accidents in patients with

asthma and rhinitis compared to the healthy population. This accident rate is higher based on the severity of the illness.

For chronic airway inflammation illnesses, interference with the normal ability to drive vehicles is normally not considered a possible effect of these conditions on the patient’s daily activities. It is likely that these factors constitute a significant part of the general limitations some patients experience, which further jeopardizes road safety16.

It is also important to remember that 7 in every 10 people affected by allergic processes are unaware that the use of antihistamines can affect daily activities, including driving. In most cases, these are classic or first-generation antihistamines, whose sedative effects hinder psychomotor performance; thus an allergic individual under the effects of these drugs takes longer than normal to make decisions and their ability to reason and memorize is reduced, leading

them to make incorrect decisions16-18. Some specialists believe that the risk of having a traffic accident for an allergic driver being treated with these drugs is similar to that of a person with a blood alcohol level of 0.5 grams per liter, in other words “under the influence”. In our case, only one of our patients was using this type of first-generation drug. Some authors have shown that patients with moderate rhinitis did not suffer effects in their attention or psychomotor abilities to drive under laboratory conditions, although they pointed to the fact that more severe symptoms could have had a greater repercussion19. This study was completed under laboratory conditions with a small sample, and we must keep in mind that for a patient with rhinitis, every sneeze equates to 2-3 seconds during which time a car traveling at 110 km/h covers around 600 meters with almost no control from the driver.

There are few existing studies which indicate the relationship between asthma and/or rhinitis severity and traffic accidents. Our study has limitations, given the retrospective nature and the fact the initially determined sample size was not reached, as well as due to the presence of some confusion factors like associated comorbidity (higher in the active group). It is also true that different drugs are implicated in the risk of accident, such as opioids and benzodiazepines20, and our study detected the use of anxiolytics in 16.2% of cases. All of these factors did not hide the association found between traffic accidents and asthma and rhinitis as a comorbid condition, which leads us to think that the severity of the bronchial disease and/or rhinitis seem to be related phenomena in an increased risk of accidents. There are previous publications which discuss the relationship between syncope from coughing fits and rhinitis symptoms and traffic accidents7-9, 21, which point to the veracity of the association found between the severity of the respiratory illness and accident rates in our study.

The reality is that current control and traffic accident prevention have similar bases to those used in other health problems. Human factors were identified as the cause of the accident in 71% to 93% of cases. Within comorbidities, particular emphasis has been placed on sensory organ (sight, hearing) defects and cardiovascular (arrhythmia, coronary heart disease), metabolic (hypoglycemia in diabetics), neurological and psychiatric alterations. However, we must remember that the incidence of allergies in our environment is increasingly higher at specific times of the year and, predominantly, among young drivers. These problems can make driving uncomfortable and even dangerous if they are not controlled. We believe it is necessary to educate



drivers with asthma and/or rhinitis about the repercussions these health problems have on driving (as we do with other aspects of their lives), the precautions they should take and the prevention strategies that should be put into place.

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21. Spector SL, Tan RA. Fatal consequence of allergic rinitis. J Allergy Clin Immunol 2010; 126 (5): 1077. doi: 10.1016/j.jaci.2010.07.017.

ESRD

UA00

36 N

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2015

PRIMER Y ÚNICO LAMA/LABA con eficacia desmostrada en el alivio de los SÍNTOMAS MATUTINOS, DIURNOS y NOCTURNOS de la EPOC1-4

Confianza en la EXPERIENCIA CLÍNICA DE ACLIDINIO Y FORMOTEROL, unidos en DUAKLIR® GENUAIR®3

Este medicamento está sujeto a seguimiento adicional, es prioritaria la notificación de sospechas de reacciones adversas asociadas a este medicamento.

18016_F_AD_Duaklir297x210_JMS.indd 1 05/07/16 13:34

FICHA TÉCNICA DUAKLIR® GENUAIR®

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 4.8, en la que se incluye información sobre cómo notificarlas. 1. NOMBRE DEL MEDICAMENTO. Duaklir Genuair 340 microgramos/12 microgramos polvo para inhalación. 2. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA. Cada dosis liberada (la dosis que sale por la boquilla) contiene 396 microgramos de bromuro de aclidinio (equivalente a 340 microgramos de aclidinio) y 11,8 microgramos de formoterol fumarato dihidrato. Esto corresponde a una dosis medida de 400 microgramos de bromuro de aclidinio (equivalente a 343 microgramos de aclidinio) y una dosis medida de 12 microgramos de formoterol fumarato dihidrato. Excipientes con efecto conocido: Cada dosis administrada contiene aproximadamente 11 mg de lactosa (como monohidrato). Para consultar la lista completa de excipientes, ver sección 6.1. 3. FORMA FARMACÉUTICA. Polvo para inhalación. Polvo blanco o casi blanco en un inhalador de color blanco con un indicador de dosis integrado y un botón de dosificación de color naranja. 4. DATOS CLÍNICOS. 4.1 Indicaciones terapéuticas. Duaklir Genuair está indicado como tratamiento broncodilatador de mantenimiento para aliviar los síntomas en los pacientes adultos con enfermedad pulmonar obstructiva crónica (EPOC). 4.2 Posología y forma de administración. Posología. La dosis recomendada es una inhalación de Duaklir Genuair 340 microgramos/12 microgramos dos veces al día. Si se olvida una dosis, la siguiente se debe administrar lo antes posible y la dosis posterior a esta se debe administrar a la hora habitual. No se administre una dosis doble para compensar las dosis olvidadas. Población de edad avanzada. No es necesario ajuste de dosis en los pacientes de edad avanzada (ver sección 5.2 en Ficha Técnica completa). Insuficiencia renal. No es necesario ajuste de dosis en los pacientes con insuficiencia renal (ver sección 5.2 en Ficha Técnica completa). Insuficiencia hepática. No es necesario ajuste de dosis en los pacientes con insuficiencia hepática (ver sección 5.2 en Ficha Técnica completa). Población pediátrica. No existe una recomendación de uso específica para Duaklir Genuair en niños y adolescentes (menores de 18 años de edad) para la indicación de EPOC. Forma de administración. Vía inhalatoria. Los pacientes deben recibir instrucciones sobre la forma correcta de administrar el producto. Para conocer las instrucciones detalladas, ver el prospecto. Es preciso indicar a los pacientes que deben leerlas detenidamente.

Descripción general de las instrucciones de uso de Duaklir Genuair

Tapa protectora

Indicador de dosis Botón naranja

Ventana de control con indicador de color

Boquilla

Para usar el inhalador Genuair, los pacientes deben seguir dos pasos después de retirar la tapa. Los pacientes deben sujetar el inhalador Genuair en posición horizontal, con la boquilla orientada hacia él y el botón naranja hacia arriba. PASO 1: Los pacientes deben PULSAR el botón naranja hasta el fondo (imagen 1) y, a continuación, SOLTARLO (imagen 2). Recuerde a los pacientes que NO DEBEN MANTENER PULSADO EL BOTÓN NARANJA. Los pacientes deben comprobar que el color de la ventana de control es verde. Este color indica que el inhalador está listo para su uso (imagen 3).

Imagen 1 Imagen 2 Imagen 3

VERDE. Listo para usar

VERDE

SI EL COLOR DE LA VENTANA DE CONTROL ES ROJO, LOS PACIENTES DEBEN REPETIR LAS ACCIONES DE PULSAR Y SOLTAR (VER PASO 1). PASO 2: Los pacientes deben inhalar CON FUERZA y PROFUNDAMENTE a través de la boquilla (imagen 4). Los pacientes deben seguir inspirando, incluso después de que hayan oído un “clic” del inhalador. • Los pacientes deben comprobar que el color de la ventana de control ha cambiado de verde a rojo, lo que indica que han realizado correctamente la inhalación (imagen 5).

Imagen 4 Imagen 5

ROJO. Inhalación correcta

ROJO

SI EL COLOR DE LA VENTANA DE CONTROL SIGUE SIENDO VERDE, LOS PACIENTES DEBEN VOLVER A INHALAR CON FUERZA Y PROFUNDAMENTE A TRAVÉS DE LA BOQUILLA (VER PASO 2). Recuerde a los pacientes que, una vez retirado el inhalador Genuair de la boca, deben contener la respiración mientras se sientan cómodos y, a continuación, expulsar el aire lentamente por la nariz. Tras la inhalación, los pacientes deben recordar volver a poner la tapa protectora. Algunos pacientes pueden experimentar un gusto ligeramente dulce o amargo, dependiendo del paciente al inhalar el medicamento. Los pacientes no deben tomar una dosis adicional si no notan ningún gusto después de la inhalación. El inhalador Genuair cuenta con un indicador de dosis que le muestra aproximadamente cuántas dosis quedan en el inhalador. Cada inhalador Genuair administrará al menos 60 dosis. Cuando aparece una banda a rayas rojas en el indicador de dosis, significa que se acerca a la última dosis y debe obtener un nuevo inhalador Genuair. Cuando la última dosis esté lista para inhalar, el botón naranja no recuperará su posición superior, sino que se quedará bloqueado en una posición intermedia. Cuando el botón está bloqueado, es posible inhalar la última dosis pero, después de hacerlo, el inhalador Genuair no se podrá volver a utilizar y el paciente tendrá que empezar a usar un nuevo inhalador Genuair. El inhalador Genuair no precisa limpieza pero, en caso necesario, puede limpiar la superficie exterior de la boquilla con un pañuelo o una toalla de papel secos. Recuerde al paciente que NUNCA utilice agua para limpiar el inhalador Genuair ya que podría causar daños en el medicamento. 4.3 Contraindicaciones. Hipersensibilidad a los principios activos o a alguno de los excipientes incluidos en la sección 6.1. 4.4 Advertencias y precauciones especiales de empleo. Asma. Duaklir Genuair no se debe utilizar para el tratamiento de asma; no se han realizado ensayos clínicos de Duaklir Genuair en pacientes con asma. Broncoespasmo paradójico. No se ha observado broncoespasmo paradójico en los ensayos clínicos de Duaklir Genuair a la dosis recomendada. No obstante, se ha observado broncoespasmo paradójico con otros tratamientos inhalados. En caso de producirse, se debe interrumpir el tratamiento con Duaklir Genuair y considerar otros tratamientos. No indicado para el uso en episodios agudos. Duaklir Genuair no está indicado para el tratamiento de episodios agudos de broncoespasmo. Efectos cardiovasculares. Los pacientes con infarto de miocardio en los seis meses previos, angina inestable, arritmia de nuevo diagnóstico en los tres meses previos, intervalo QTc (método de Bazett) por encima de 470 ms u hospitalización en los 12 meses previos debido a insuficiencia cardíaca de las clases funcionales III y IV según la New York Heart Association fueron excluidos de los ensayos clínicos, por tanto, Duaklir Genuair se debe utilizar con precaución en este grupo de pacientes. En algunos pacientes, los agonistas ß2-adrenérgicos pueden causar un aumento de la frecuencia de pulso y la tensión arterial, así como cambios en el electrocardiograma (ECG), como el aplanamiento de la onda T, la depresión del segmento ST y la prolongación del intervalo QTc. En caso de producirse tales efectos, es posible que sea necesario interrumpir el tratamiento. Los agonistas ß2-adrenérgicos de acción prolongada se deben usar con precaución en pacientes con antecedentes o prolongación conocida del intervalo QTc o que hayan sido tratados con medicamentos que afecten al intervalo QTc (ver sección 4.5). Efectos sistémicos. Duaklir Genuair se debe utilizar con precaución en aquellos pacientes que presenten trastornos cardiovasculares graves, trastornos convulsivos, tirotoxicosis y feocromocitoma. Es posible observar trastornos metabólicos de hiperglucemia e hipopotasemia con dosis elevadas de agonistas ß2-adrenérgicos. En ensayos clínicos de fase III, la frecuencia de aumentos considerables de la glucemia con Duaklir Genuair fue baja (0,1%) y similar a la del placebo. La hipopotasemia normalmente es transitoria y no precisa suplemento de potasio. En pacientes con EPOC grave, la hipopotasemia se puede ver exacerbada por la hipoxia y el tratamiento concomitante (ver sección 4.5). La hipopotasemia aumenta la susceptibilidad a experimentar arritmias cardíacas. Debido a su actividad anticolinérgica, Duaklir Genuair se debe emplear con precaución en pacientes con hiperplasia prostática sintomática, retención urinaria o glaucoma de ángulo estrecho (aunque el contacto directo del producto con los ojos es muy improbable). La sequedad de boca, que se ha observado con el tratamiento anticolinérgico, se puede asociar a largo plazo con caries dentales. Excipientes. Los pacientes con intolerancia hereditaria a la galactosa, insuficiencia de lactasa de Lapp o problemas de absorción de glucosa o galactosa no deben tomar este medicamento. 4.5 Interacción con otros medicamentos y otras formas de interacción. Medicamentos para la EPOC. No se ha estudiado la administración concomitante de Duaklir Genuair y otro medicamento anticolinérgico y/o agonista ß2-adrenérgico de acción prolongada y, por lo tanto, no se recomienda. Aunque no se han realizado estudios formales de interacción farmacológica in vivo, Duaklir Genuair se ha utilizado de manera concomitante con otros medicamentos para la EPOC, incluidos broncodilatadores ß2-adrenérgicos de acción breve, metilxantinas y corticoesteroides orales e inhalados, sin evidencia clínica de interacciones farmacológicas. Interacciones metabólicas. Los estudios in vitro indican que, a dosis terapéuticas, no se prevé que el aclidinio ni sus metabolitos causen interacciones con los fármacos sustratos de la glicoproteína P (P-gp) o con los fármacos metabolizados por las enzimas del citocromo P450 (CYP450) y esterasas. El formoterol, en concentraciones terapéuticas adecuadas, no inhibe las enzimas CYP450 (ver sección 5.2 en Ficha Técnica completa). Tratamientos que disminuyen el potasio. El tratamiento concomitante con derivados de la metilxantina, corticoesteroides o diuréticos no ahorradores de potasio puede exacerbar el posible efecto hipopotasémico de los agonistas ß2-adrenérgicos y, por lo tanto, es conveniente extremar la precaución en caso de uso concomitante de estos (ver sección 4.4). Bloqueantes ß-adrenérgicos. Los bloqueantes ß-adrenérgicos pueden debilitar o antagonizar el efecto de los agonistas ß2-adrenérgicos. En caso de ser necesario el uso de bloqueantes ß-adrenérgicos (incluidos colirios), es preferible utilizar bloqueantes ß-adrenérgicos cardio-selectivos, si bien estos también se deben administrar con precaución. Otras interacciones farmacodinámicas. Duaklir Genuair se debe administrar con precaución a pacientes en tratamiento con medicamentos conocidos por prolongar el intervalo QTc, como inhibidores de la monoaminooxidasa, antidepresivos tricíclicos, antihistamínicos o macrólidos. Estos medicamentos pueden potenciar la acción del formoterol, un componente de Duaklir Genuair, en el sistema cardiovascular. Los medicamentos conocidos por prolongar el intervalo QTc están asociados a un riesgo mayor de arritmias ventriculares. 4.6 Fertilidad, embarazo y lactancia. Embarazo. No existen datos disponibles sobre la utilización de Duaklir Genuair en mujeres embarazadas. Los estudios realizados en animales han mostrado fetotoxicidad solo a niveles de dosis muy superiores a la dosis humana máxima de exposición al aclidinio y efectos adversos en estudios de reproducción con formoterol en niveles de exposición sistémica muy elevados (ver sección 5.3 en Ficha Técnica completa). Duaklir Genuair solo se debe utilizar durante el embarazo si los beneficios esperados superan los posibles riesgos. Lactancia. Se desconoce si aclidinio (y/o sus metabolitos) y formoterol se excretan en la leche materna. Dado que los estudios realizados en ratas han mostrado excreción de pequeñas cantidades de aclidinio (y/o sus metabolitos) y formoterol en la leche, el uso de Duaklir Genuair por parte de mujeres lactantes se debe considerar únicamente si el beneficio esperado para la madre es superior al riesgo posible para el niño. Fertilidad. Los estudios realizados en ratas han revelado una leve reducción de la fertilidad solo con niveles de dosis muy superiores a la dosis máxima de exposición para humanos al aclidinio y el formoterol (ver sección 5.3 en Ficha Técnica completa). No obstante, se considera poco probable que Duaklir Genuair administrado a la dosis recomendada afecte a la fertilidad de los humanos. 4.7 Efectos sobre la capacidad para conducir y utilizar máquinas. La influencia de Duaklir Genuair sobre la capacidad para conducir y utilizar máquinas es nula o insignificante. La aparición de visión borrosa o mareo puede afectar a la capacidad para conducir o utilizar máquinas. 4.8 Reacciones adversas. La presentación del perfil de seguridad está basada en la experiencia con Duaklir Genuair y de sus componentes individuales. Resumen del perfil de seguridad. La experiencia de seguridad de Duaklir Genuair comprende la exposición a la dosis terapéutica recomendada durante un periodo máximo de 12 meses. Las reacciones adversas asociadas con Duaklir Genuair fueron similares a las de sus componentes individuales. Debido a que Duaklir Genuair contiene aclidinio y formoterol, cabe esperar que el tipo y la gravedad de las reacciones adversas asociadas a Duaklir Genuair sean los mismos que los de cada uno de sus componentes. Las reacciones adversas notificadas con mayor frecuencia con Duaklir Genuair fueron nasofaringitis (7,9%) y cefalea (6,8%). Tabla resumen de las reacciones adversas. El programa de desarrollo clínico de Duaklir Genuair se circunscribió a pacientes con EPOC moderada o grave. El número total de pacientes tratados con Duaklir Genuair 340 microgramos/12 microgramos fue 1.222. Las frecuencias asignadas a las reacciones adversas que se incluyen a continuación se basan en la tasa de incidencia cruda de reacciones adversas con Duaklir Genuair 340 microgramos/12 microgramos, obtenida del análisis conjunto de diversos ensayos clínicos de fase III aleatorizados y controlados con placebo de al menos seis meses de duración. La frecuencia de las reacciones adversas se define utilizando el siguiente convenio: 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) y frecuencia no conocida (no puede estimarse a partir de los datos disponibles).

Sistema de clasificación de órganos Reacción adversa Frecuencia

Infecciones e infestaciones

Nasofaringitis3 Infección de las vías urinarias1 Sinusitis2 Absceso dental1

Frecuente

Trastornos del sistema inmunológicoHipersensibilidad4 RaraAngioedema4 No conocida

Trastornos del metabolismo y de la nutriciónHipopotasemia3 Poco frecuenteHiperglucemia3 Poco frecuente

Trastornos psiquiátricosInsomnio2 Ansiedad2 Frecuente

Agitación3 Poco frecuente

Trastornos del sistema nervioso

Cefalea3

Mareo3

Temblor2Frecuente

Disgeusia3 Poco frecuenteTrastornos oculares Visión borrosa2 Poco frecuente

Trastornos cardiacosTaquicardia2

QTc prolongado en el ECG2 Palpitaciones3

Poco frecuente

Trastornos respiratorios, torácicos y mediastínicos

Tos3 FrecuenteDisfonía2

Irritación de garganta3 Poco frecuente

Broncoespasmo, incluido paradójico4 Rara

Trastornos gastrointestinalesDiarrea3 Náuseas3

Sequedad bucal2Frecuente

Trastornos de la piel y del tejido subcutáneo Exantema3

Prurito3 Poco frecuente

Trastornos musculoesqueléticos y del tejido conjuntivo

Mialgia2

Espasmos musculares2Frecuente

Trastornos renales y urinarios Retención urinaria3 Poco frecuenteTrastornos generales y alteraciones en el lugar de administración Edema periférico3 Frecuente

Exploraciones complementariasElevación de creatina fosfocinasa (CPK) en sangre1 FrecuenteTensión arterial elevada3 Poco frecuente

1 Reacciones adversas observadas con Duaklir Genuair pero no notificadas en la Ficha Técnica de los componentes individuales. 2 Reacciones adversas observadas con Duaklir Genuair y notificadas en la Ficha Técnica de al menos uno de los componentes individuales. 3 Reacciones adversas notificadas en la Ficha Técnica de al menos uno de los componentes individuales, pero notificadas para Duaklir Genuair 340 microgramos/12 microgramos con una incidencia inferior o comparable a la del placebo. 4 Reacciones adversas notificadas en la Ficha Técnica de al menos uno de los componentes individuales, pero no observadas con Duaklir Genuair 340 microgramos/12 microgramos; la categoría de frecuencia corresponde a la indicada en la sección 4.8 de la Ficha Técnica del componente correspondiente.

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 nacional de notificación incluido en el Anexo V. 4.9 Sobredosis. Los datos de sobredosis con Duaklir Genuair son limitados. Las dosis elevadas de Duaklir Genuair pueden provocar signos y síntomas anticolinérgicos y/o ß2-adrenérgicos exagerados; los más frecuentes son visión borrosa, sequedad bucal, náuseas, espasmos musculares, temblores, cefalea, palpitaciones e hipertensión. En caso de sobredosis, se debe interrumpir el tratamiento con DUAKLIR Genuair y se recomienda tratamiento de soporte y sintomático. 5. PROPIEDADES FARMACOLÓGICAS (Ver en Ficha Técnica completa). 6. DATOS FARMACÉUTICOS. 6.1 Lista de excipientes. Lactosa monohidrato. 6.2 Incompatibilidades. No procede. 6.3 Periodo de validez. 3 años. Usar en los 60 días posteriores a la apertura de la bolsa. 6.4 Precauciones especiales de conservación. Este medicamento no requiere condiciones especiales de conservación. Mantener el inhalador Genuair protegido dentro de la bolsa cerrada hasta que se inicie el tratamiento. 6.5 Naturaleza y contenido del envase. El inhalador Genuair es un dispositivo multicomponente compuesto de plástico (policarbonato, acrilonitrilo-butadieno-estireno, polioximetileno, poliéster-butileno-tereftalato, polipropileno y poliestireno) y acero inoxidable. Es de color blanco con un indicador de dosis integrado y un botón de dosificación de color naranja. La boquilla está cubierta por una tapa protectora desmontable de color naranja. El inhalador se proporciona cerrado en una bolsa protectora de aluminio laminado, que contiene una bolsita de material desecante, situada dentro de un envase de cartón. Envase que contiene 1 inhalador con 60 dosis. Envase que contiene 3 inhaladores con 60 dosis cada uno. Puede que solamente estén comercializados algunos tamaños de envases. 6.6 Precauciones especiales de eliminación y otras manipulaciones. La eliminación del medicamento no utilizado y de todos los materiales que hayan estado en contacto con él se realizará de acuerdo con la normativa local. Para consultar las instrucciones de uso, ver la sección 4.2. 7. TITULAR DE LA AUTORIZACIÓN DE COMERCIALIZACIÓN. AstraZeneca AB. SE-151 85 Södertälje. Suecia. 8. NÚMERO(S) DE AUTORIZACIÓN DE COMERCIALIZACIÓN. EU/1/14/964/001. EU/1/14/964/002. 9. FECHA DE LA PRIMERA AUTORIZACIÓN/RENOVACIÓN DE LA AUTORIZACIÓN. Fecha de la primera autorización: 19/noviembre/2014. 10. FECHA DE LA REVISIÓN DEL TEXTO. 04/2015. 11. REGIMEN DE PRESCRIPCION Y DISPENSACION. Medicamento sujeto a prescripción médica. 12. CONDICIONES DE LA PRESTACION DEL SISTEMA NACIONAL DE SALUD. Aportación reducida (cícero). 13. PRESENTACION Y PRECIOS. Duaklir Genuair 340 microgramos/12 microgramos polvo para inhalación: Envase con 60 dosis. PVP= 67,55 €; PVPiva = 70,25 €. Para mayor información, consultar la Ficha Técnica completa y/o dirigirse a AstraZeneca Farmacéutica Spain, S.A., Tfno: 900 200 444. La información detallada de este medicamento está disponible en la página web de la Agencia Europea de Medicamentos http://www.ema.europa.eu 30.05.2015 (Corrección QRD Mayo 2015)/QRD (corrigendum procedure)

Referencias: 1. D’Urzo A, Rennard S, Kerwin E, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;14:123. 2. Singh D, Jones P, Bateman E, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014;14:178. 3. Ficha Técnica Duaklir® Genuair®. 4. Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16(1):92.

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216

ORIGINALS


AbstractFor this study, we used titanium dioxide (TiO2), produced using nanotechnology. To show its supe-riority with respect to talc, we completed an in vitro study comparing the pro-inflammatory response of both agents towards malignant and benign mesothelial cells; researching the possible apoptosis in-duction and possible inhibition of angiogenesis for both agents. We took a culture of cell lines derived from human mesothelioma, originating from human biphasic mesothelioma and human bronchial adenocarcinoma. The cells were cocultured with different doses of talc and TiO2 nanoparticles. The levels of different inflammatory mediators were analyzed for each culture supernatant sample. The apoptosis rate was analyzed using caspase-3 expression. The endostatin levels were determined for the angiostasis study using the ELISA technique. We observed that the viability of the benign mesothelial cells is much lower after using TiO2. In the case of malignant mesothelial cells, the same effect was observed with a high dose of TiO2. In adenocarcinoma of the lung, the viability of these cells expo-sed to talc was distinctly lower than that which was observed in the benign cell line. IL-8 production was much higher in neoplastic mesothelial cells than in benign cells and increased following a dose-dependent pattern with talc, while it decreased with TiO2. According to these results, we can see that talc is superior to TiO2 in its ability to produce mediators which favor pleurodesis for the control of malignant pleural effusions.

Key words: talc, nanoparticles, pleurodesis.

COMPARACION DE UN NUEVO AGENTE BASADO EN NANOTECNOLOGÍACON EL TALCO CONVENCIONAL PARA EL CONTROL DE LOS DERRAMES PLEU-RALES MALIGNOS

ResumenResumen: En este trabajo usamos dióxido de titanio (TiO2), fabricado mediante nanotecnolo-gía. Para demostrar su superioridad respecto al talco, realizamos un estudio in vitro comparando la respuesta pro-inflamatoria de ambos agentes sobre células malignas y mesoteliales benignas; investigando la posible inducción de apoptosis y la posible inhibición de angiogénesis también por ambos agentes. Realizamos cultivo de líneas celulares derivadas de mesotelio humano, pro-cedente de mesotelioma bifásico humano y adenocarcinoma bronquial humano. Las células se co-cultivaron con diferentes dosis de talco y de nanopartículas de TiO2. En todas las muestras de sobrenadantes de los cultivos se analizaron los niveles de diferentes mediadores inflamatorios. La tasa de apoptosis se analizó por la expresión de Caspasa-3. Para el estudio de angiostasis se determinaron los niveles de endostatina mediante técnica ELISA. Observamos que la viabilidad de las células mesoteliales benignas es mucho menor al emplear TiO2. En el caso de las células mesoteliales malignas, se observó el mismo efecto con dosis alta de TiO2. En el adenocarcinoma de pulmón, la viabilidad de estas células expuestas al talco fue netamente inferior a la que se ob-servó en la línea celular benigna. La producción de IL–8 fue mucho mayor por parte de las células mesoteliales neoplásicas que por las benignas y aumentó siguiendo un patrón dosis dependiente frente al talco, mientras que cayó con el TiO2. Según estos resultados, se demuestra que el talco es superior al TiO2 en su capacidad de producir mediadores que favorecerían la pleurodesis para el control del derrame pleural maligno.

Palabras clave: Talco, nanopartículas, pleurodesis.

Received: September 29, 2016. Accepted: June 7, 2017.

Beatriz Romero [email protected]

B. Romero Romero1, A. Montes Worboys2, E. Arellano Orden2, V. Sánchez López2, L. Padrón Fraysse1, J. T. Martín Juan1, F. Rodríguez Panadero2.1Surgical Medical Unit for Respiratory Diseases. Vírgen del Rocío Hospital in Seville. 2 Institute of Biomedicine of Seville (IBIS)

Project financed by Beca Neumosur 13/2010.

COMPARISON BETWEEN A NEW NANOTECHNOLOGY-BASED AGENT AND CONVENTIONAL TALC IN THE CONTROL OF MALIGNANT PLEURAL EFFUSIONS


B. Romero Romero et al. Comparison between a new nanotechnology-based agent and conventional talc in the control of malignant pleural effusions

INTRODUCTION

The presence of a malignant pleural effusion indicates the existence of an advanced neoplastic disease in which curative treatment is no longer possible. Within the palliative framework for this treatment, pleurodesis is especially important, which has the key role of adhering the two pleura in order for the lung to remain re-expanded, thus avoiding the accumulation of liquid in the pleural space.

Throughout history, different sclerosing agents have been used to adequately control malignant pleural effusions, with talc proving to be the most effective. While the success rate for pleurodesis with talc is indeed high and, generally, its intrapleural application is well tolerated1, important side effects have occasionally been described, both when it is applied as a slurry mixed with saline and as a powder2, 3.

Based on different published work in the literature, a close relationship is thought to exist between the particle size and shape of the talc used and its absorption through the pores of the pleura and, as a result, its systemic dissemination and the appearance of associated complications4-9.

Jannsen et al. (Talc Safety Study Group)10 studied 558 patients with malignant pleural effusion who underwent pleurodesis with talc, always using the same type of talc (with calibrated particle size, Steritalc®, Novatech, France), reaching the conclusion that its use was sufficiently safe, without observing any cases of acute respiratory distress. On average, the particles of this talc were large in size (24.5 μm) and there was a low concentration (11%) of small particles (<5 μm).

The mechanisms involved in pleurodesis are not completely explained. It is clear that there is a primary inflammatory response initiated by the meso-thelium, which is the first target of any stimulant applied in the pleural space, as well as a secondary response, which is caused by the different cells trapped in the pleural space after the first stimulation of the mesothelium and whose magnitude and complexity are not yet completely clear11. It has been shown that the addition of talc to a human mesothelium culture provokes the re-lease of a large amount of interleukin 8 (IL-8, known chemotactic factor for polymorphonuclear neutrophils) and also MCP-1 (monocyte chemoattractant

protein), which are the two types of cells that, after mesothelial stimulation, are most directly involved in the pleural inflammation process that leads to pleurodesis12-14. In recent years, two additional beneficial effects have been considered for the use of talc in malignant pleural effusions which are based on apoptosis induction after intrapleural application15 and also on angiogen-esis inhibition related to tumor progression (angiostasis) which, among other factors, would be measured by endostatin production16.

APPROACH TO PROBLEM

Until now, the role that the specific surface of the particles used in pleurodesis could play has not been researched. It is likely that smaller particles (which would have a greater contact surface area with mesothelial cells per unit of weight) are much more efficient in inducing a strong inflammatory and fibrotic response. However, these more efficient talc particles (= smaller) are also more dangerous due to the risk of systemic dissemination. If we were able to obtain big enough particles to impede systemic dissemination, but which also had a large specific surface area, we would achieve a very efficient sclerosant with few associated complications.

For our research, we used a new material (consisting of titanium dioxide, TiO2) which is produced with a controlled size and shape using nanotechnology, provided by the PERC (Particle Engineering Research Center) at the University of Florida. It is free of impurities and the size of the particles is larger and more uniform than the majority of talc used in clinical practice (Steritalc®, Novatech, France), while its width is adjusted to 50 nanometers, allowing it to maintain extensive contact with the cellular membrane for more effective activation. Additionally, these new particles can be given an antitumoral effect by coupling them with different chemotherapy agents. They can also be used in fluorescence studies, which allows quantifying the “cellular load” with nanoparticles and locating/quantifying the particles adhered to the cellular membrane, but which have not penetrated it, and those that have been internalized18, as well as also completing in vivo translocation studies19. In this way, in vitro tests can not only be done on the efficiency of inducing an inflammatory and fibrotic response, but also on the ability to slow the growth of neoplastic cells, either through apoptosis induction or angiogenesis inhibition (angiostasis).



OBJECTIVES OF STUDY In order to prove the superiority of a new agent for pleurodesis that was designed with nanotechnology, an in vitro comparative study was done with the following specific objectives:

1. Compare the pro-inflammatory/fibrotic and pro-angiogenic response of new TiO2 nanoparticles compared to calibrated talc (Steritalc®, No-vatech, France) in malignant cells (mesothelioma and adenocarcinoma) and benign mesothelial cells

2. Research possible apoptosis induction via TiO2 nanoparticles and cali-brated talc particles

3. Research possible angiogenesis inhibition (angiostasis) via TiO2 nano-particles and calibrated talc particles

MATERIAL AND METHODS1. Study on cellular viability and pro-inflammatory/fibrotic response.

1.1. Benign and malignant (mesothelioma and adenocarcinoma) cell culture, and particle stimulation.

1.1.1 Culture of the cell lines CRL-9444 (Met5-A), derived from human mesothelium, and CRL-2081(MSTO-211H), originating from human biphasic mesothelioma, obtained from the ATCC (American Type Cul-ture Collection, Rockville, MD, USA). Additionally, the cell line CRL-5911 (NCI-H2009) (human bronchial adenocarcinoma) was used, also provided by the ATCC. The cells were spread on polystyrene plates treated for cell cultures (Nunc) and were stored under constant con-ditions in an incubator at 37º C, 5% CO2 and saturation humidity. The culture medium used for the Met5A line was M-199 (Gibco Laborato-ries, Grand Island, NY). This medium contains the essential nutrients and was additionally supplemented with 10% fetal bovine serum (FBS) inactivated by heat for 1 hour at 56º C, penicillin (100 U/mL), strepto-mycin (100 mg/mL), human insulin (5.75 mg/L) (Sigma-Aldrich) and epidermal growth factor (EGF) (5.75 mg/L) (Sigma-Aldrich). The MS-TO-211H cells were cultured with RPMI-1640 supplemented with 10% heat inactivated FBS, penicillin (100 U/mL) and streptomycin (100 mg/mL).

1.1.2. In vitro stimulation of cell lines with different types of particles. The in vitro stimulation experiments were done between procedures 5 and 10, once the cultures reached confluence with the medium at 0% FBS. The cells were cocultured at different times (6, 24, 48 and 72 hours) at different doses (dose-response study) of talc (Steritalc®, No-vatech, France) and nanoparticles (TiO2) produced by the PERC (Parti-cle Engineering Research Center) at the University of Florida. The dos-es consisted of 0, 3, 6, 12 and 24 µg/cm2, according to Nasreen et al.15. Wells were prepared with benign and malignant mesothelial cells with-out particles as a control, and wells without cells as a blank. This pro-cedure was repeated 10 times (replicas) for each cell type. Experiment monitoring was done at 6, 24, 48 and 72 hours after the start of the in vitro treatment. All of the samples taken from the culture mediums were centrifuged at 1,000 rpm for 5 minutes to eliminate dead cells and the supernatant was frozen in aliquots at -80º C until later determinations. For the cellular viability and proliferation study, we analyzed the behav-ior of the cell lines incubated with talc and nanoparticles using the Try-pan-Blue exclusion test and MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-di-phenyltetrazolium bromide] assay. The cells for each tested dose were also photographed at each point in the experiment.

1.2. Pro-inflammatory and fibrotic response study. Determining cytokine levels in supernatants: levels of the following cyto-

kines were analyzed in all of the culture supernatant samples: IL-8, TNF-a, VEGF, FGFb, TGFβ-1, MCP-1. Determinations were made using ELISA (Quantikineâ R&D Systems, Minneapolis, MN, USA) following the manu-facturer’s recommendations.

2. Apoptosis induction study.The cells were cocultured with different doses of talc (0, 100, 200,

400, 500 and 800 µg/cm2, Steritalc®, Novatech, France) (dose-response study) and with 0, 3, 6, 12 and 24 µg/cm2 of TiO2 nanoparticles produced by the PERC (Particle Engineering Research Center) at the University of Florida at different times (6, 24, 48 and 72 hours), according to talc indications published by Nasreen et al.15. All of the samples taken from the culture mediums were centrifuged at 1,000 rpm for 5 minutes to eliminate dead cells and the supernatant was frozen in aliquots at -80º C



until later determinations. RNA was extracted from the cell pellet with a specific kit (Qiagen Diagnostics, GmbH) following the manufacturer’s recommendations. RNA quantity and quality was measured with a Nanodrop, ND-1000 spectrophotometer (Wilmington, DE, USA), and the RNA was retrotranscribed to cDNA with the SuperScript II kit (Invitrogen) in a conventional thermal cycler. The apoptosis rate was analyzed using levels of caspase-3 expression by the cells in the CRL-2081 and CRL-9444 lines after incubation with talc or TiO2.

3. Angiogenesis inhibition (angiostasis) study.According to the methodology followed by Nasreen et al. 16, HUVECs

(Human umbilical vein endothelial cells) (Cell Applications, Inc., San Diego, CA, USA) were cultured using the medium recommended by the cell line supply company. When they reached 60-80% confluence, they were stimulated with the supernatants obtained from the cultures described in section 1.1.2 for 24 hours, applying the following doses of conditioned medium: 10, 25, 50, 100 and 200 µg/cm2. After stimulation with supernatants for 24 hours, the HUVEC culture supernatants were extracted, aliquoted and kept frozen at -80º C until endostatin determination was made. Cell viability was analyzed using the Trypan-Blue exclusion test and proliferation was analyzed using the MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The cells for each tested dose were also photographed at each point in the experiment. The experiments were repeated 10 times (replicas) in order to obtain enough precision in the supernatant analysis results (ELISA). Later, the same analyses described in section 2 were applied and endostatin levels were determined in HUVEC culture supernatants using the ELISA technique (Chemicon International, Inc., Temecula, CA, USA).

4. Data analysis 4.1. Cytokine levels in cell culture supernatants.

- ANOVA of factor to compare levels of each of the cytokines between the cultures stimulated with TiO2 nanoparticles and talc particles, with application of the Bonferroni test (post hoc).

- T test to compare independent averages (intergroup, different cultures),

with the application of the Mann-Whitney U non-parametric test if the equality of variances requirement was not met.

- T test to compare related averages (intergroup), with the application of the Wilcoxon non-parametric test if the equality of variances require-ment was not met.

4.2. Comparative analysis of cell viability, apoptosis and necrosis. - K test for independent samples (variance of a Kruskal-Wallis fac-

tor).- Additionally, the systematic taking of a series of photographs of the

samples at all of the points when the medium was changed and super-natants were extracted allowed for a qualitative analysis of the experi-ments.

RESULTS

1. Cell viability (MTT).

1.1. CRL-9444 line (benign mesothelial cells): at 24 hours, cell prolifera-tion after coculturing with talc and TiO2 was very similar, with a mode-rate reduction in the highest does of talc and TiO2. However, viability was much lower when using TiO2 heated to 450º C (which changes its crystalline structure with regard to the other form of TiO2 used in our experiments). At 48 hours, we observed a clear drop in viability of the cells cultured with high doses of the three agents (talc, TiO2 and TiO2 heated to 450º), always noticing a more pronounced drop with TiO2 in either of its two forms (without statistically significant differences). These findings in benign mesothelial cells would put the potential use of TiO2 as a sclerosing agent at a disadvantage (Figure 1).

1.2. CRL-2081 line (malignant mesothelial cells): the viability of these cells was reduced very slightly when cocultured with talc (in relation to the con-trols), however there was a marked drop when using a >16 μg/cm2 dose of TiO2, without reaching a statistically significant difference. This could explain the scarce mesothelial response to pleurodesis in clinical practice.



1.3. CRL-5911 line (adenocarcinoma of the lung): the cell proliferation of this line of tumor cells was clearly lower in the cells stimulated with talc than with TiO2, in either of its two forms (TiO2 vs TiO2 heated to 450º). Additionally, the viability of the malignant cells exposed to talc was clearly inferior to that observed in the line of benign cells (without reaching sta-tistically significant difference) which could have interesting implications to reinforce the use of talc in pleurodesis in malignant pleural effusions due to pleural metastasis of adenocarcinoma (which is the most common).

1.4. HUVECs exposed to supernatants (related to the response to angioge-nic stimulants).

1.4.1. CRL-9444: at 24 hours, the proliferation of HUVECs stimulated with talc and TiO2 supernatants was very similar, with a slight drop at the highest doses.

1.4.2. CRL-2081: after 24 hours, the proliferation of HUVECs stim-ulated with talc, TiO2 and TiO2 heated to 450º supernatants was very similar, without statistically significant differences (Figure 1).

2. Cytokine production (related to the response to the sclerosant) by cells stimulated with different types of particles.

2.1. IL-8: its production was distinctly lower in benign mesothelial cells (CRL-9444) than in HUVECs. It increased following a dose-de-pendent pattern for talc, primarily in benign mesothelial cells, although without statistically significant differences with regard to the other cell lines. IL-8 production was greater in HUVECs exposed to superna-tant from benign mesothelial cells incubated with talc, also following a dose-dependent pattern, although the difference was also not statisti-cally significant with respect to the other cell lines studied. In contrast, IL-8 production by HUVECs exposed to supernatant from benign mesothelial cells incubated with TiO2 followed an inverse pattern in comparison to that observed with talc (a higher dose of TiO2 resulted in lower IL-8 production). The same results were observed for TiO2 heated to 450º, without finding statistically significant differences in any case (Figure 2).

Figure 1. Cell viability for benign mesothelial cells (CRL- 9444) and HUVECs stimulated with benign mesothelial cell supernatant with different agents at different doses (talc, TiO2 and TiO2 heated to 450ºC).

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2.2. FGFb and VEGF: higher levels were observed in the neoplastic me-sothelial cells stimulated with talc, and a drop was seen when cocultured with TiO2, following a pattern inversely proportional to the dose applied. A similar pattern was observed in the case of the VEGF.

3. Endostatin production (related to angiostasis) by the benign and malignant cell lines, stimulated with different types of particles.

3.1. Benign mesothelial cells (CRL-9444): endostatin levels were always lower than controls (cells not stimulated with any type of particle) both for

stimulation with talc and TiO2 or TiO2 heated to 450º, although levels in the case of talc were higher than for TiO2.

3.2. Malignant mesothelial cells (CRL-2081): endostatin production by these cells was also lower than the controls, although talc was again shown to be superior to TiO2 (without significant differences). Globally, the ma-lignant cell line produced less endostatin than the benign line for talc and TiO2 (without significant differences). This finding may explain the poor mesothelial response to pleurodesis with talc and also suggest the modulat-ing role the benign pleural mesothelium may play with regard to malignant lesions in the case of pleural mesothelioma.

4. Endostatin production by HUVECs after stimulation with supernatants from cocultures of benign and malignant cell lines exposed to different types of particles.

4.1. In the case of HUVECs stimulated with benign mesothelial cell su-pernatant, the same pattern was again observed with regard to endostatin production, both in the higher levels produced by the controls and the su-periority of the effect of supernatants from cocultures with talc compared to TiO2 (Figure 3).

4.2. A similar pattern was observed when the HUVECs were incubated with supernatants from malignant mesothelial cells (CRL-2081). However, levels were lower than in cases where the HUVECs were stimulated with benign mesothelial cell supernatant, which suggests that neoplastic cells are more resistant to angiogenesis inhibition from any of the tested agents.

5. Morphological findings with regard to different types of particles.

Photographs have been taken of all of the experiments. The most striking findings are the following:

- In general, scarce signs of cell deterioration have been observed in the benign mesothelial cells co-incubated with talc (Figure 4A, B), in agree-ment with the acceptable levels of cell viability and proliferation outlined previously. In the case of TiO2, signs suggesting a higher degree of cell

Figure 2. IL-8 production by benign mesothelial cells (CRL-9444) and HUVECs stimulated with benign mesothelial cell (CRL-9444) supernatant with different agents at different doses (talc, TiO2 and TiO2 heated to 450ºC).



damage were observed, with likely necrosis (Figure 4 A, B, C, D). - We observed that many of the TiO2 particles, which in theory were of ideal size to stimulate the cells by having a large specific surface area, broke apart until reaching sizes of 1 μm (or even smaller), and were internalized in many of the cells studied (Figure 5).

6. Apoptosis in different cell lines. We observed that at 48 hours after exposure to talc and TiO2 particles, the benign mesothelial cells expressed twice as much caspase-3 as the controls, which indicates that both talc and TiO2 induce apoptosis in these cells (Figure 6). - Greater apoptosis is induced in malignant mesothelial cells when they are

treated with talc in comparison with TiO2 particles. - In the case of human umbilical vein endothelial cells (HUVECs), talc

induces a higher rate of apoptosis than TiO2 particles.

Figure 3. Endostatin production by benign mesothelial cells (CRL-9444) and HUVECs stimu-lated with benign mesothelial cell (CRL-9444) supernatant with different agents at different doses (talc, TiO2 and TiO2 heated to 450ºC).

Figure 4: Benign mesothelial cells (CRL-9444) cocultured with talc (panels A and B) and with TiO2 (C, D). The larger size of talc particles can be observed in comparison with those of TiO2, and there are also signs of greater deterioration when mesothelial cells are cocultured with TiO2.

Figure 5. Internalization of small TiO2 subparticles after coculturing the benign mesothelial cells (CRL -9444) with this type of particle.

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DISCUSSION At present, talc is the safest and most efficient sclerosant in the treatment of relapsing malignant pleural effusions. The majority of the complications described when used in this type of effusion are related to morphology (length, shape, width of different talc particles). Keeping in mind that talc is a naturally occurring mineral, its characteristics cannot be precisely controlled, thus the particles are subject to source extraction and processing conditions.

With the major developments achieved by nanotechnology, it is possible to design particles with characteristics which are in theory ideal to induce suc-cessful pleurodesis.

TiO2 is produced with a controlled size and shape using nanotechnology. It is free of impurities and the original size of the particles is larger than the majority of talc used in clinical practice (Steritalc®, Novatech, France), while its width is adjusted to 50 nanometers, allowing it to maintain extensive contact with the cellular membrane for more effective activation. On top of that, the crystalline state and micro/nanoporosity of this new material can be adjusted (it is well-accepted as a biocompatible material and has been used in human implants for decades) which, from the theoretical perspective, gives it great behavior versatility according to its on-demand design.

The ideal agent for pleurodesis in malignant effusions should, at least, meet the following characteristics:

a) induce a good fibrotic response in the pleural space, with the objective of eliminating the pleural space though the adhesion of the visceral and parietal layers of the pleura, eliminating the possibility of the reaccumu-lation of pleural liquid.

b) inhibit the proliferation of neoplastic cells, respecting the proliferation of benign mesothelial cells to the degree possible.

c) inhibit the angiogenesis that commonly accompanies invasive tumors.d) have the physical properties to impede their passage from the pleural

space to systemic circulation.

In the viability studies completed in our work, we observed that the viability of benign mesothelial cells is much lower after applying TiO2, which would detract from its use as a sclerosing agent from the outset. The mechanisms implied in pleurodesis are not completely explained and, although it is known that practically all sclerosing agents provoke acute inflammation in the pleural space, there are few studies that have researched the specific mechanisms involved in this process21. The role of the mesothelium seems essential, because it clearly initiates a primary response, which is the first target of any stimulant applied in the pleural space. There is also a secondary response, which is caused by the different cells trapped in the pleural space after the first stimulation

Figure 6. Caspase-3 expression in benign mesothelial cells (CRL–9444) without exposure to any agent (control), and exposed to talc and TiO2.



of the mesothelium and whose magnitude and complexity are not yet completely clear.

In the case of malignant mesothelial cells, the same effect was observed, primarily with the high dose of TiO2 (greater than 16 micrograms/cm2). The scarce decrease in the viability of these malignant mesothelial cells treated with talc could explain the limited mesothelial response to pleurodesis with talc in clinical practice. On the other hand, malignant mesothelioma usually extensively and diffusely affects the majority of the pleural cavity, thus the modulating response a non-tumorous mesothelium could have is voided or greatly reduced, which again contributes to explaining the limited or non-response that a malignant pleural mesothelioma usually has to pleurodesis or any other of the treatments commonly attempted with this type of neoplasm.

In adenocarcinoma of the lung, the viability of the cells exposed to talc was clearly inferior to that observed in the line of benign cells, which could have interesting implications to reinforce the use of talc in pleurodesis in malignant pleural effusions due to pleural metastasis of adenocarcinoma (which is the most common).

IL-8 (known chemotactic factor for polymorphonuclear neutrophils) and MCP-1 (monocyte chemoattractant protein) are known to be the two types of cells that, after mesothelial stimulus, are most directly involved in the pleural inflammation process that leads to pleurodesis13,14. In our study, IL-8 production was much higher in neoplastic mesothelial cells than in benign cells and increased following a dose-dependent pattern with talc, while it decreased with TiO2, with a pattern inversely proportional to the applied dose of TiO2. Similar results were found for VEGF production. According to these results, we can see that talc is superior to TiO2 in its ability to produce mediators which favor pleurodesis for the control of malignant pleural effusions.

The line of malignant mesothelioma cells proved particularly resistant to the angiostatic action of talc in previous studies16 as well as in our in vitro experiments, showing a clear correspondence with the clinical results previously published by our Group which show that this tumor has the worst results in pleurodesis attempts. On the contrary, adenocarcinoma has proven to be more sensitive to talc than to the other two agents tested with regard to the inhibition of angiogenesis measured by endostatin16.

The results obtained show that talc (sterile with calibrated particles) is currently the most efficient sclerosant used in the control of relapsing malignant pleural effusions and the in vitro results obtained for the use of

TiO2 are clearly inferior. In our study, we have seen that the TiO2 particles had broken apart, reaching sizes under 1 mm, having been internalized in many of the cells studied (Figure 4 A, B, C, D and Figure 5). This can explain some of the negative effects observed in our TiO2 experiments and invalidate its potential as a sclerosing agent in humans (at least in its current form) due to the risk of systemic dissemination. We still do not have an explanation for this unexpected finding which supposes a clear limitation for the use of this agent, which seems to be stronger for TiO2 heated to 450º C, although this is likely related to certain instability in its crystalline structure, which will need to be studied in the future.

This is an experimental “in vitro” study performed with cultures of cell lines, thus these preliminary results with TiO2 cannot be extrapolated to “in vivo” studies. However, we continue to think that nanotechnology offers great future design possibilities for an agent which obtains better results than talc. We believe it is necessary to continue to perform additional studies to obtain a sclerosing agent with the ideal characteristics.

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8. Sánchez Gutiérrez C, Marchi E, Mañes N et al. Side effects and effectiveness of different sizes of talc particles in pleurodesis. Am J Respir Crit Care Med. 2002; 165,8: A609.

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11. Gill AJ, Mathur MN, Tattersall S. Systematic response to talc pleurodesis. Am J Respir Crit Care Med. 2004; 169,9: 1074-1075.

12. Montes-Worboys A, Rodriguez-Portal JA, Arellano-Orden E et al. Interleukin-8 activates coagulation and correlates with survival after talc pleurodesis. Eur Respir J. 2010; 35: 160-166.

13. Nasreen N, Hartman DL, Mohammed KA et al. Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells. Am J Respir Crit Care Med. 1998; 158: 971-8.

14. Psathakis K, Calderón-Osuna E, Romero-Romero B et al. The neutrophilic and fibrinolytic response to talc can predict the outcome of pleurodesis. Eur Respir J.2006; 27: 817-821.

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ORIGINALS


Received: June 6, 2016. Accepted: October 10, 2017.

Remedios Otero [email protected]

Abstract: Microparticles (MPs) are extracellular vesicles considered to be powerful cellular effectors. They are present in healthy individuals and are elevated in pathological conditions such as in-flammatory and neoplastic diseases, and thrombosis. The relationship between venous throm-boembolism (VTE) and cancer has been well established. MPs are thought to be a pathogenic connection between the two entities. If confirmed, they could be used as biomarkers.Our aim was to characterize the MPs in both diseases according to their cellular origin (cellular, endothelial, platelet, leukocyte and those that exhibited mucin 1 on their surface). Functional parameters such as D-dimer (DD) and soluble P-selectin (sPsel) were also studied.96 patients with idiopathic VTE and 85 with advanced lung, stomach or pancreatic neopla-sia were considered. All of them were followed clinically for two years and those who were diagnosed with cancer in the VTE group or those who developed thrombosis in the group of neoplastic patients were excluded from the study. Finally, 82 VTE patients and 68 cancer patients were analyzed.In our results, we found that total MPs and platelet-derived MPs differentiated both patient groups. Additionally, significantly greater numbers of DD and sPsel (p <0.001) were determi-ned in the VTE group.The differences found between both groups, taking into account the origin of the MPs, could be caused by the prothrombotic characteristics of the neoplastic group and their sequestration within active clots in the VTE group.

Key words: microparticles, cancer, deep vein thrombosis, pulmonary embolism, coagulation.

ORIGEN CELULAR DE MICROPARTÍCULAS CIRCULANTES EN PACIEN-TES CON ENFERMEDAD TROMBOEMBÓLICA VENOSA Y CÁNCER

ResumenLas micropartículas (MPs) son unas vesículas extracelulares consideradas potentes efectores celulares. Están presentes en individuos sanos y se encuentran elevadas en estados patológi-cos como enfermedades inflamatorias, neoplásicas y trombosis. La relación entre enfermedad tromboembólica venosa (ETV) y cáncer está bien establecida. Se piensa que las MPs serían una conexión patogénica entre ambas entidades. De confirmarse, podrían utilizarse como biomarcadores.Nuestro objetivo fue caracterizar las MPs en ambas patologías atendiendo a su origen celular (celular, endotelial, plaquetar, leucocitario y las que exhibían en su superficie mucina 1). También se estudiaron parámetros funcionales como el dímero D (DD) y la P-selectina soluble (sPS).Se consideraron 96 pacientes con ETV idiopática y 85 con neoplasias avanzadas de pulmón, gástrico o páncreas. A todos ellos se les realizó un seguimiento clínico de dos años en el que se excluyeron del estudio aquellos que fueron diagnosticados de cáncer en el grupo de ETV o que desarrollaron trombosis en el grupo de pacientes neoplásicos. Finalmente, se analizaron 82 pacientes con ETV y 68 con cáncer.En nuestros resultados encontramos que las MPs totales y las MPs de origen plaquetar di-ferenciaban ambos grupos de pacientes. Además, se determinaron cifras significativamente mayores de DD y sPS (p <0,001) en el grupo de ETV.Las diferencias encontradas entre ambos grupos, teniendo en cuenta el origen de las MPs, podrían estar causadas por las características protrombóticas del grupo neoplásico y por el secuestro de las mismas dentro de los coágulos activos en el grupo de ETV.

Palabras clave: Micropartículas, cáncer, trombosis venosa profunda, embolia pulmonar, coagulación.

R. Otero Candelera1, V. Sánchez López1, T. Elías Hernández1, L. Jara Palomares1, E. Arellano Orden1, M. Ferrer Galván1, I. Asensio Cruz1, J.M. Sánchez Díaz1, A. González-Castro1, R. Sánchez Gil1, M. Chaves Conde3, J. Rodríguez Martorell2.1Biomedical Institute of Seville (IBIS), Medical-Surgical Unit for Respiratory Diseases. 2Hematology Service. 3Oncology Service of Virgen del Rocío University Hospital/CSIC/Univer-sity of Seville. 4Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Spain. Virgen del Rocío University Hospital, Seville.

CELULAR ORIGIN OF CIRCULATING MICROPARTICLES IN PATIENTS WITH VENOUS THROMBOEMBOLISM AND CANCER


R. Otero Candelera et al. Celular origin of circulating microparticles in patients with venous thromboembolism and cancer

INTRODUCTION Microparticles (MPs) are microvesicles measuring between 0.1 and 1 µm, released by cells during activation, damage or apoptosis1-5. Initially, they were considered to be devoid of any biological function, but now they are considered to be involved in various pathophysiological processes, such as hemostatic processes, inflammation or cell migration6-9. MPs are present in healthy individuals, but are found in high levels in patients with different inflammatory, neoplastic and vascular diseases, including arterial and venous thrombosis9-13. Experimental studies with animal models have shown that certain types of MPs can accelerate thrombus formation in vivo14. High levels of MPs have been found in neoplastic patients 15 and it has been postulated that these could largely explain the association between the occurrence of thrombotic phenomena and cancer. This association has been firmly established and there has been data to support it for many decades now1, 2. Venous thromboembolism (VTE) is involved in comorbidity and mortality in cancer patients. In fact, pulmonary embolism (PE) is the second leading cause of death among neoplastic patients, only behind neoplasia itself16. Not all neoplasia has the same risk of thrombosis. Advanced stage adenocarcinomas of pancreatic, gastric or pulmonary origin are high risk profiles.5. In addition, up to 15% of idiopathic VTE precede a cancer diagnosis, which could cause thrombosis. The search for biomarkers for the early diagnosis of neoplasia in thrombosis patients and/or that can predict the risk of VTE in cancer patients is of great clinical interest. D-dimer (DD) is a fibrin degradation product and therefore a direct marker of fibrinolysis whose values are elevated in thrombotic processes in which fibrinolysis is activated. DD is included among the diagnostic algorithms for VTE in the general population, but its role as a biomarker of thrombosis in cancer patients has not been demonstrated. MPs are other possible biomarkers that have garnered the interest of researchers and clinicians, although they have yet to be implemented. We believe that characterizing MPs in both these diseases—VTE and cancer—could provide useful information for future designs of prospective studies which could look into the predictive role of MPs in terms of diagnosis of thrombotic complications in cancer patients and diagnosis of hidden cancer in idiopathic VTE. We consider that an initial approximation could be evaluating MPs according to the cellular origin of these diseases of disparate etiopathogenesis but associated in medical practice.

Our objective was to compare the characterization of MPs according to their cellular origin in idiopathic VTE patients and non-VTE-associated cancer patients, aside from determining other functional parameters.

MATERIALS AND METHODS Design: prospective observational study of two patient groups; one made up of idiopathic VTE patients and another made up of patients with advanced lung, stomach or pancreatic cancer not associated with VTE. Circulating MP levels and their cellular origin were quantified in both populations. Patients:

Group of VTE patients

Inclusion criteria: ambulatory patients diagnosed with deep vein thrombosis (DVT) or patients diagnosed with PE who were not diagnosed with cancer during the two-year follow-up. Patients who started anticoagulant therapy up to 72 h prior to inclusion in the study were admitted.Exclusion criteria: patients diagnosed with neoplasia during the follow-up period. The search protocol for hidden neoplasia in VTE patients was the one according to Jara-Palomares et al17.

Group of cancer patients

Inclusion criteria: patients with a cytological and histological diagnosis of Stage IV or IIIB non-small cell lung carcinoma, with pleural or pericardial effusion, or with stomach or metastatic pancreatic carcinoma, from outpatient oncology consultations. These patients had not had any previous VTE-related events and were not on treatment or prophylaxis with low-molecular-weight-heparins.

Exclusion criteria: cancer patients diagnosed by means of objective testing for VTE (DVT and/or PE) or arterial thrombosis during the follow-up period.



Determination of D-dimer and soluble P-selectin: D-dimer (DD) was determined using the immunoturbidimetric method STA-Liatest D-Di (Diagnostic Stago, Parsippany, New York, USA), using an STA-R analyzer. Results were expressed in mg/mL. The levels of soluble P-selectin (sPsel) in plasma were detected using ELISA (Human sP-selectin/CD62P Immunoassay; RD Systems, Minneapolis, MN, USA). Results were expressed in ng/mL. Statistical analysis: quantitative results were expressed as mean and standard deviation while qualitative results were expressed as absolute values and frequencies. The paired Student’s T-test was used for the comparison of quantitative variables between different clinical groups, while the Chi-squared test was used for the comparison of qualitative variables. A significance level of p < 0.05 was used. The results were analyzed using the SPSS 22 statistical software package for Windows.

RESULTS From January 2011 to November 2013, 181 patients were recruited. There were 96 in the group of VTE patients, of which 14 were finally excluded owing to a diagnosis of neoplasia during the two-year follow-up, and there were 85 patients in the neoplastic group, of which 17 were excluded due to the development of a thrombotic process during the follow-up period. Therefore, 82 patients with idiopathic VTE and 68 patients diagnosed with cancer were analyzed. In the latter group, 56 (82.4%) died during the follow-up period. None of them had an episode of VTE during follow-up and thrombosis was not the cause of death. The cancer patients were younger (p = 0.026), predominantly male (p = 0.018), smokers (p <0.001) and more frequently had a drinking habit (34%). At the time of recruitment, 45 (66 %) were undergoing different chemotherapy regimens. The idiopathic VTE patients were older, with hypertension (p = 0.001), with 45% being women. Table 1 summarizes the clinical characteristics of both populations. With regard to the MP populations studied, total MP levels that were significantly higher were found in the neoplastic patients in comparison to the patients diagnosed with VTE (cancer: 26,454x103 ± 4,238x103; VTE: 14,787x103 ± 1,146x103; p = 0.01). A similar pattern was observed in the

All patients considered for the study signed informed consent forms.

Blood sampling: all patients had their blood drawn using a 21-gauge needle, without using compression or with minimal venous occlusion, in plastic blood collection tubes with 0.109 M of buffered trisodium citrate solution (Vacutainer ®, BD Biosciences, Erembodegem, Belgium) discarding the first 3 mL. The samples were processed within the first hour after extraction; they were centrifuged at 1,500 g for 30 min at 4°C with no brake to obtain plasma containing MPs and platelet-free plasma (PFP). The PFP was divided into aliquots and stored at -80 ºC until their analysis. Quantification and characterization of MPs by flow cytometry: the levels of total MPs and platelet-derived MPs in plasma were determined in all patients using the LSRFortessa flow cytometer (BD Biosciences, Erembodegem, Belgium). For detection of total MPs, annexin V conjugated with CF Blue (Immunostep, Salamanca, Spain), was used. It recognizes and binds to phosphatidylserine present on the microparticle surface. For detection of platelet-derived MPs (PDMPs) and endothelial cell-derived microparticles (EDMPs), the human antibodies anti-CD31 and anti-CD41 conjugated with fluorescein isothiocyanate (FITC) and phycoerythrin cyanine 7 (PECy7), respectively (Beckman Coulter, Marseille, France), were used. For detection of leukocyte-derived MPs (LDMPs), the human antibody anti-CD45 FITC (Beckman Coulter, Marseille, France) was used. For detection of MPs with mucin 1 expression on the surface (MPs-MUC1+), the human antibody anti-CD227 FITC (BD Biosciences, Erembodegem, Belgium) was used. Flow cytometer calibration for MP detection was done using the mix of Megamix-Plus SSC fluorescent beads (Biocytex, Marseille, France), according to the manufacturer’s specifications. The MPs were defined as events collected within the established region for MPs and positive for annexin V. The PDMPs were identified as positive MPs for the anti-CD31 and anti-CD41 antibodies; the EDMPs as positive MPs for CD31 and negative for CD41; the LDMPs as positive MPs for CD45; and the MPs-MUC1+ as positive MPs for CD227. As a negative control, the isotype controls corresponding to each antibody were used. Counting beads (6 μm) with a concentration of around 1,000 beads/µL (Perfect-Count Microspheres; Cytognos, Salamanca, Spain) were used to calculate the concentration of MPs from the absolute counts of cells. Results were expressed as events/mL.



number of PDMPs (cancer: 22,263x103 ± 3,973x103; VTE: 11,118x103 ± 1,004x103; p = 0.008). No differences were seen for the rest of the cellular origins studied (endothelial and leukocyte) and for the MPs-MUC-1+ (Table 2). With regard to the levels of DD and sPsel, both parameters were found to be significantly higher in the group of VTE patients in comparison to the cancer patients (p <0.001; Table 2).

Characteristics Idiopathic VTE (n = 82) Cancer (n = 68)Age, years (mean ± SD) 63.4 ± 14.5 62.3 ± 11.3Masculine gender n (%) 45 (54.9) 50 (73.5)BMI (kg/m2) (mean ± SD) 31.0 ± (5.4) 26.6 ± 5.6Smoker, n (%) 27 (32.9) 52 (76.5)Alcohol consumption, n (%) 10 (12.2) 23 (33.8)Hypertension, n (%) 44 (53.7) 17 (25.0)Dyslipidemia, n (%) 22 (26.8) 23 (33.8)Diabetes, n (%) 13 (15.9) 9 (13.2)Chronic respiratory disease, n (%) 20 (24.4) 15 (22.1)Ischemic cardiomyopathy , n (%) 7 (8.5) 2 (2.9)Chronic renal insufficiency, n (%) 5 (6.1) 6 (8.8)Dementia, n (%) 13 (16.0) 6 (8.8)

Table 1. Clinical characteristics of patients with idiopathic venous thromboembo-lism (VTE) and cancer. BMI: body mass index; SD: standard deviation.

Parameters VTE (n = 82) Cancer (n = 68) P valueTotal MPs/mL (x103 ) 14787 ± 1146 26454 ± 4238 0.01EDMPs/mL 27027 ± 3170 25432 ± 2056 0.687PDMPs/mL (x103) 11118 ± 1004 22263 ± 3973 0.008LDMPs/mL 98705 ± 9104 96818 ± 9147 0.885MPs-MUC1+/mL 135118 ± 41377 251606 ± 91310 0.239D-dimer (µg/L) 6869 ± 944 1327 ± 227 < 0.001sP-selectin (ng/mL) 58.92 ± 3.21 40.80 ± (2.06) < 0.001

Table 2. Circulating microparticles (MPs) of cellular origin and other functional parameters in patients with venous thromboembolism (VTE) and cancer. EDMPs: Endothelial-derived MPs; PMPs: Platelet-derived MPs; LDMPs: Leukocyte-derived MPs; MPs-MUC1+: MPs that exhibited mucin 1 on their surface; sP-selectin: Solu-ble P-selectin. The results were expressed as the mean ± standard deviation. Signi-ficance level: p < 0.05.

DISCUSSION In the present study, we compared the levels of different MP populations between two patient groups—one made up of patients diagnosed with idiopathic VTE and another one made up of non-thrombosis-associated cancer patients. Additionally, DD and sPsel levels were also compared. In our results, we observed total MP and PDMP levels that were surprisingly much higher in the group of cancer patients than in the VTE group, and DD and sPsel levels that were much higher in the thrombosis group than in the cancer group. The PDMPs are considered to be procoagulant microparticles that are involved in the initiation and propagation of venous thromboembolism18, 19. PDMPs are known to be elevated in VTE patients20. Nevertheless, several authors point out that finding elevated levels in VTE depends on the group with which the comparison is made21. These authors compared PDMP levels in a group of patients diagnosed with PE with healthy subjects, with and without cardiovascular risk factors. They only found significant differences between PE patients and healthy subjects with no cardiovascular risk factors. In the group with PE, blood was drawn right before starting anticoagulant treatment.



This does not coincide with our study, in which blood was drawn up to 72 hours after the start of anticoagulant treatment. In our context, it would not have been viable to use a study design in which blood was drawn before the start of anticoagulant treatment, as clinical practice guidelines allow for the start of treatment prior to the confirmation of diagnosis22. In addition, the patients comprising our cancer group were those who had the highest number of procoagulant MPs in other published series23. Therefore, the difference found in our study should not be considered in absolute terms. Several aspects must be taken into account, such as comparison with a group of cancer patients with high procoagulant risk, the time of blood sampling, which may be within 72 hours of anticoagulant treatment of the VTE patient, or that a large part of circulating PDMPs in patients with an active thrombotic process may be trapped in the clots, leading to a false decrease in circulating PMs. Although the MPs-MUC1+ did not refer to any specific cell lineage, they were determined in order to identify the MPs derived from tumor cells, particularly adenocarcinoma. It has been described that tumor cells can overexpress at the MUC1 membrane level, so MPs with this origin could be identified using this type of antigen. Nevertheless, we found no differences between the VTE group and the cancer group in our results. Other authors found higher levels of MPs-MUC1+ in cancer patients24. This discrepancy could be due to the patient profile chosen for each study, the type of neoplasia or the stage, which could affect MUC1 expression in tumor cells. In addition, although tumor cells can overexpress MUC1 on the surface, this protein is not exclusive to tumor cells. Other types of cells can give rise to MPs-MUC1+, as this protein is also involved in the immune system, trapping pathogens25. DD is one of the markers used in diagnostic algorithms for VTE, both in their DVT and PE expression. Clinical trials and prospective studies26 with thousands of patients support the high negative predictive value of DD. However, the diagnostic value of DD in cancer patients is called into question. Although DD is highly sensitive for thrombosis, it is not specific at all, as it can also be elevated in pro-inflammatory and neoplastic situations. Particularly, doubt has been cast as to whether the cut-off level of 500 mg/L is suitable for a population with cancer. In our group of patients with cancer without VTE, mean DD was 1.327 ± 227 mg/L. This may suggest that a cut-off point above 1,000 mg/L is

perhaps more suitable for this group. sPsel is a protein involved in cell adhesion functions, stored in intracytoplasmic granules of platelets and endothelial cells. When these cells are activated, Psel is translocated to the plasma membrane, enabling interaction with its ligands27. It plays a fundamental role in the initial migration of leukocytes to the focus of inflammation, but it is also important in platelet aggregation through platelet-fibrin and platelet-platelet bridges to the area of vascular damage28. Thrombin is one of the stimuli for Psel to be secreted by the endothelial cells. But the role of Psel in tumor metastatic processes, facilitating the process of migration and dissemination of tumor cells, has also been recognized29. In our study groups, the determination of sPsel has a behavior similar to that of DD, which indicates that, although it could be elevated in patients with metastatic cancer, it is also significantly elevated in acute VTE. All our patients were in the advanced stages of their neoplasia, although we do not know the specific cancer treatment they were undergoing and whether this could affect the sPsel levels. The potential role of this protein in VTE diagnosis has been suggested30. Other authors have pointed out its predictive role in VTE diagnosis in cancer patients31. Adding biomarkers such as DD and sPsel to the Khorana prediction scale improved diagnostic precision. The authors advocate two cut-off points for both biomarkers with potential value in predicting thrombotic events in cancer patients; DD ³1,440 mg/L and sPsel ³53.1 ng/mL. These figures are consistent with the means we obtained in our sample of cancer patients without VTE, which were below them. Based on our results, we can say that certain populations of circulating MPs such as total MP levels and PDMP levels could differentiate between patients with idiopathic VTE and non-VTE-associated cancer patients. These observations would need to be validated in future cohort studies with cancer patients and VTE patients focused on the role of MPs as biomarkers of thrombotic events in cancer patients and hidden neoplasia in VTE patients. When interpreting our results, it is important to bear in mind that it is a preliminary study with a small sample size, in which VTE patients who were already undergoing anticoagulant treatment—although for less than 72 h—at the time of blood sampling, were admitted.



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ORIGINALS

Received: June 5, 2017. Accepted: October 26, 2017.

Marta Entrenas [email protected]

Abstract: Purpose: To check inhalation therapy techniques among fourth-year students of the Faculty of Medicine at the University of Córdoba and family and community medicine residents affi-liated with the teaching unit of Córdoba.Methods: Prospective study of two unselected groups. 80 participants were included: the first group was made up of 41 fourth-year students of the Faculty of Medicine at the University of Córdoba, while the second group consisted of 39 family and community medicine residents affiliated with the teaching unit of Córdoba. The use of a pressurized cartridge (MDI) as com-pared with a state-of-the-art dry-powder inhaler (Spiromax®) was analyzed, without either group having received any prior instruction regarding their handling. Inhalation Manager® showed whether the maneuver was adequate depending on how each device was handled and the pulmonary drug deposition obtained.Results: In the group of students, 98% used an adequate technique with the state-of-the-art dry-powder inhaler, as compared with the 58% who used the pressurized cartridge correctly. The low pulmonary drug deposition obtained meant poor technique with both devices. The percentage of family and community medicine residents affiliated with the teaching unit of Córdoba which used Spiromax® correctly (97%) was considerably higher than that for the MDI (33%). The level of pulmonary drug deposition obtained in this group was not ideal either. Correct use of the pressurized cartridge in the group of students (58%) was signifi-cantly better than that of the group of residents (33%). The most common error in using the pressurized cartridge was breathing too early in both groups. The only error observed in using the dry-powder inhaler was exhaling instead of inhaling in both samples.

Key words: COPD, asthma, inhaler device, Inhalation Manager, medical student, GPs trai-nees, education.

¿CÓMO UTILIZAN LOS DISPOSITIVOS INHALADOS LOS ESTUDIANTES DE MEDICINA Y LOS RESIDENTES DE FAMILIA?

ResumenObjetivo: Comprobar la técnica de la terapia inhalada en estudiantes de cuarto curso de la Facultad de Medicina de la Universidad de Córdoba y residentes de medicina familiar y co-munitaria adscritos a la unidad docente de Córdoba.Métodos: Estudio prospectivo de dos grupos no seleccionados. Se incluyeron 80 partici-pantes: el primer grupo estaba formado por 41 estudiantes de cuarto curso de la Facultad de Medicina de la Universidad de Córdoba, mientras que el segundo grupo lo componían 39 residentes de medicina familiar y comunitaria adscritos a la unidad docente de Córdoba. Se analizó la utilización del cartucho presurizado (MDI) frente a un dispositivo de polvo seco de última generación (Spiromax®), sin que ningún grupo hubiera recibido instrucción previa alguna sobre su manejo. Inhalation Manager® muestra si la maniobra es adecuada en función del manejo de cada dispositivo así como del depósito pulmonar obtenido.Resultados: En el grupo de los alumnos el 98% realizaron una técnica adecuada con el dis-positivo de polvo seco de última generación, frente al 58% que utilizaron de forma correcta el cartucho presurizado. El escaso depósito pulmonar obtenido se traduce en una mala técnica de ambos dispositivos. El porcentaje de residentes de medicina familiar y comunitaria ads-critos a la unidad docente de Córdoba que utilizó de forma correcta Spiromax® (97%), fue significativamente mayor que con el MDI (33%). El nivel de depósito pulmonar obtenido en este segundo grupo tampoco fue el idóneo. El uso correcto del cartucho presurizado en el grupo de estudiantes (58%) fue significativamente mejor que en el grupo de residentes (33%). El error más común en la utilización del cartucho presurizado fue realizar la inhalación de forma prematura en ambos grupos. El único error observado en el uso del cartucho de polvo seco fue exhalar en vez de inhalar en ambas muestras.

Palabras clave: EPOC, asma, dispositivo de inhalación, Inhalation Manager, estudiantes de medicina, médicos residentes, educación.

M. Entrenas Castillo1, L.M. Entrenas Costa1, 2.1Pulmonology CMU, Hospital Universitario Reina Sofía, Córdoba, Spain. 2Faculty of Medicine and Nursing , University of Córdoba.

HOW DO MEDICAL STUDENTS AND FAMILY MEDICINE RESIDENTS USE INHALER DEVICES?



M. Entrenas Castillo et al. How do medical students and family medicine residents use inhaler devices?

Inhaler technique was analyzed consecutively in both groups, without having received any kind of prior instruction. First, while using the pressurized cartridge (MDI) and, afterwards, the state-of-the-art dry-powder inhaler (Spiromax®) through the Inhalation Manager® device. It consists of a pneumotachometer to which the device to be studied is attached using a specific adapter and which, through the right software, is capable of analyzing the start of the inhalation maneuver, the flows and their completion. For the MDI, it determines the exact moment when the device is activated. Information on the maneuver provided by the software not only includes suitability of inhaler technique, but also, upon measuring post-inspiratory apnea, provides data on maneuvers which facilitate pulmonary drug deposition7. For this study, handling of the device was considered to be correct when the report generated was considered to be good or optimal. The results were expressed as absolute frequencies and percentages. To determine the differences, a comparison of percentages was made and the confidence interval (CI) was determined. Statistical significance was set at p ≤0.05. The statistical package SPSS v. 8.0. The results of this work are found within the framework for the assessment of a training project on inhalation therapy8 which received approval from the hospital’s Ethics Committee.

RESULTS Students: records from 41 fourth-year students, (24 males, 58% and 17 females, 42%) were obtained. Figure 1 summarizes the handling of both devices in this group. With regard to MDI, 24 students (58%) handled it properly while 17 (42%) handled it improperly. The reasons for improper handling were: pressing too early (n = 12), not pressing the device (n = 3) and poor coordination between pressing and breathing (n = 2) (Figure 2). Pulmonary drug deposition could be compromised, at least from a theoretical perspective: in 24 cases, for not performing post-inspiratory apnea; in 23, as inspiratory flow was too fast; and in 2 cases, as inspiratory flow was insufficient (Figure 1). It is worth pointing out that none of them were able to both handle the device properly and achieve proper pulmonary drug deposition, which would have ensured receiving an optimal dose with the MDI.

INTRODUCTION Inhalation therapy plays a prominent role in guidelines for the treatment of asthma and COPD. The Spanish Guidelines on the Management of Asthma (GEMA)1 and the Spanish COPD Guidelines (GesEPOC)2 opt for this route as a choice in their different therapeutic schemes. Improper inhaler technique is equivalent to unconscious noncompliance with treatment3, which much of the loss of asthma control is attributable to. In an ideal clinical practice setting, a nursing professional should teach and check inhaler technique during each patient visit. However, clinical reality shows that, as there are no specific staff for this, it falls on the doctor to take on this task at the practice itself4, while generally not having any additional time for it. In previous works5, we already pointed out that the lack of specific training on this matter during undergraduate education results in theoretical lack of knowledge for a large number of students who are about to begin their medical practice without having acquired this ability. But with the start of professional practice, there is also no guarantee that the resident will know proper inhaler technique6. The emergence of devices such as Inhalation Manager®7, which records inspiratory parameters and is thus capable of objectively determining the suitability of inhaler technique for different devices with no observer variability, makes it possible to address the problem from a perspective that has not been analyzed to date. The purpose of this work is to conduct a practical study of inhaler technique for devices among medical students and resident doctors in family and community medicine.

MATERIALS AND METHODS From November 1 to 30, 2015, a prospective study was conducted among two unselected groups. The first group was made up of 41 fourth-year students of the Faculty of Medicine at the University of Córdoba, which is the year when they take up the subject of respiratory diseases, and the second group was comprised of 39 family and community medicine residents affiliated with the teaching unit of Córdoba, who were selected after giving their consent upon attending a training session given by the teaching unit. An exclusion criteria was having previously taken up another specialty.



With regard to Spiromax®, 40 students (98%) handled it properly while only 1 (2%) handled it improperly (Figure 1). The only case of improper handling was for exhaling through the device (Figure 3). Pulmonary drug deposition could be compromised in 40 cases for not performing post-inspiratory apnea and in 24 for not prolonging inspiration long enough (Figure 1). In this case, there were also no students able to both handle the device properly and perform a maneuver that theoretically ensured proper pulmonary drug deposition. The percentage of students who were able to use Spiromax® correctly without having received any prior instruction was significantly higher than for the pressurized cartridge (98%, CI: 93%-102% vs. 59% CI: 43%-74%, p <0.000001). Residents: records from 39 resident doctors (25 males, 64% and 14 females, 36%). Figure 4 summarizes the handling of both devices in this group. With regard to the MDI device, 13 doctors (33%) handled it properly while 26 (67%) handled it improperly. The reasons for improper handling were pressing too early (n = 16), poor coordination (n = 5), not pressing the device (n = 3) and pressing several times (n = 2) (Figure 2). Pulmonary drug deposition was compromised, at least from a theoretical perspective, in 13 cases for not performing post-inspiratory apnea and in 11 as inspiratory flow was too fast (Figure 4). None were able to both handle the device properly and achieve proper pulmonary drug deposition (Figure 4). With regard to Spiromax®, it was properly handled in 38 cases (97%) while it was improperly handled in 1 (3%) case (Figure 4). As with the group of students, this was for exhaling through the device. Pulmonary drug deposition could be compromised in 37 cases for not performing post-inspiratory apnea and in 18 for not prolonging inspiration long enough (Figure 1). None were able to both handle the device properly and achieve proper pulmonary drug deposition. The percentage of resident doctors who were able to use Spiromax® correctly was significantly higher than for the pressurized cartridge (97%, CI: 92%-102% vs. 33% CI: 19%-48%, p <0.000001).

Figure 1: Students. The figure shows the results obtained by the students in handling both devices (Spiromax® and MDI). The columns indicate the results for each of the devices. In the top row, and separated according to device, the percentages are shown for each group that properly or improperly handled each device. The size of each circle is proportional to the value. In the bottom row and separated according to device, the reasons that can interfere with proper pulmonary drug deposition are shown.



DISCUSSION The results from our work clearly show inhaler device handling errors, which already appear in medical literature, while providing a dual perspective. The students, who did not receive any prior instruction, can be representative of a population of young patients to whom a device is prescribed, but with the additional element of—in a few years—being the ones who will have to prescribe medication that they do not know how to use, as there is no specific training for this during undergraduate education. These results are consistent with previously published data on both medical students9 and pharmacy students10. In the case of the resident doctors, and in view of the results that were Figure 3: Errors made in handling Spiromax® by both groups.

Figure 2: Errors made in handling MDI by both groups.

Figure 4: Residents. The figure shows the results obtained by the resident doctors in handling both devices (Spiromax® and MDI). The columns indicate the results for each of the devices. In the top row, and separated according to device, the percentages are shown for each group that properly or improperly handled each device. The size of each circle is proportional to the value. In the bottom row and separated according to device, the reasons that can interfere with proper pulmonary drug deposition are shown.



When transferring this knowledge to the patient, the ideal situation would be to have specific staff for this, perhaps a nursing consultation. In our setting, and despite the fact that nearly 90% of the primary care doctors say that they have placebo inhaler devices at their practice to teach patients how to use them, 60% of them do not have any staff to do this, so it must be assumed that this is done by the primary care doctor themselves during visits4. This study, in contrast to previous works that focused on theoretical knowledge, took an objective look at how the different devices were handled, as Inhalation Manager® made it possible to measure something that is normally difficult to subjectively evaluate such as the press-and-breathe action for MDI devices, which determines pulmonary drug deposition. When choosing the devices to study, we had to select one, as there are numerous types available on the market today, which, in general, can be classified into pressurized cartridges (MDI) and dry-powder inhalers17. For the latter type, we opted for one that simplified inhaler technique to three steps (open-breathe-close) to try to see whether doing away with maneuvers in the inhalation technique would improve its handling. The choice of Spiromax® was decided as it had the required adapter for the pneumotachometer of Inhalation Manager®. In view of the results and in a real clinical practice setting, it is foreseeable that training in inhaler devices will continue, at the very least, at its current poor level. In the undergraduate course, there is no subject that provides regulated education on inhalation therapy and device handling, which is why it would be important to add this subject to the program curriculum. Future primary care doctors also do not seem to demonstrate optimal knowledge of the technique that they will have to teach in real-life visits shortly, which is why we should consider specific training for the residents, particularly for those who will manage these diseases as they will be the ones who will have to teach patients. It has yet to be demonstrated whether using state-of-the-art dry-powder inhalers, which simplify handling by reducing the number of steps necessary for breathing (open-breathe-close) and release the appropriate dose under almost any circumstance of use18 is a solution to the problem. In our study, both groups achieved a significant number of correct maneuvers as compared to the MDI. But it is very important to point out that neither group, with either of the two inhalers used, was able to perform maneuvers that ensured optimal pulmonary drug deposition, particularly post-inspiratory apnea. This data shows that teaching future educators of patients how to handle devices

obtained, we should not assume that the lessons learned during their residency will be enough to ensure knowledge of inhaler technique. Overall, it can be estimated that half of patients with asthma11 or COPD12 do not undergo inhalation therapy. But if we also add the factor of improper handling of the device, we can understand the situation of these two diseases as the improper use of inhaler devices is associated with a loss of asthma and COPD control13, which leads to an increase in the consumption of resources, and consequently, health expenditure14. In our setting, in a series of asthma and COPD patients who were studied for compliance with medication, both groups had a high rate of noncompliance. But upon analyzing the unconscious type of noncompliance, which is caused by improper handling of the device, we found that this was the case for 31.2% of COPD patients and for 22.8% of asthma patients15. Regardless of the considerations about socio-demographic differences between patients with one disease or the other, we can affirm that overall, one out of every three COPD patients, as well as one out of every four asthma patients, handles the device improperly. If we also consider that the only factor capable of rectifying errors in taking inhaled medication is supervision by health professionals14, we can understand the importance of providing proper instruction. In an attempt to remedy these defects, inhaler devices that seek to improve pulmonary drug deposition have been gradually developed16 and the different scientific societies have published guidelines and recommendations to improve inhaler technique17. These stress the importance of proper instruction in handling the device which, aside from delivering a higher percentage of dispensed medication to the airway (the further the better), seeks to minimize oropharyngeal drug deposition, which tends to cause most of the significant side effects of these drugs and which in practice encourages its disuse.But to impart knowledge, one has to have it first, and examples abound in literature which clearly show a deficient level of knowledge, in both theory and practice, on inhaler devices by the professionals directly involved in the education of patients. In an assessment of the steps necessary to handle the device according to the guidelines, Madueño-Caro et al. found that the pressurized cartridge, the pressurized cartridge with holding chamber or spacer, Turbuhaler® and Accuhaler® were properly handled by only 9.7% of practicing primary care doctors, 4.8% of resident doctors in family and community medicine, and by none of the undergraduate medical students6.



14. Melani AS, Bonavia M, Cilenti V et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011; 105 (6): 930-8.

15. Plaza V, López-Viña A, Entrenas LM et al. Differences in Adherence and Non-Adherence Behaviour Patterns to Inhaler Devices Between COPD and Asthma Patients. COPD. 2016; 13: 547-54.

16. Roche N, Dekhuijzen PN. The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices. J Aerosol Med Pulm Drug Deliv. 2016; 29: 311-27.

17. Área de asma de SEPAR, Área de enfermería de SEPAR, Departamento de asma ALAT. Consenso SEPAR-ALAT sobre terapia inhalada. Arch Bronconeumol. 2013; 49 (Supl 1): 2-14.

18. Canonica GW, Arp J, Keegstra JR et al. Spiromax, a New Dry Powder Inhaler: Dose Con-sistency under Simulated Real-World Conditions. J Aerosol Med Pulm Drug Deliv. 2015; 28: 309-19.

cannot be neglected to ensure that they convey this knowledge properly. The maneuver does not just involve simple inhalation/exhalation; the patients themselves have to perform inspiratory apnea to ensure pulmonary drug deposition and, although technological development of devices has been able to solve certain problems with handling, a certain level of collaboration from the patient is still necessary, which makes proper instruction of the maneuver absolutely essential.

BIBLIOGRAPHY1. Comité ejecutivo de GEMA. GEMA4.2. Guía española para el manejo del asma. Disponi-

ble en: http://www.gemasma.com/profesionales/.2. Miravitlles M, Soler-Cataluña JJ, Calle M et al. Guía española de la enfermedad pulmonar

obstructiva crónica (GesEPOC) 2017. Tratamiento farmacológico en fase estable. Arch Bronconeumol. 2017; 53: 324-35.

3. Plaza V, Fernández-Rodríguez C, Melero C et al. Validation of the ‘Test of the Adherence to Inhalers’ (TAI) for Asthma and COPD Patients. J Aerosol Med Pulm Drug Deliv. 2016; 29: 142-52.

4. Entrenas Costa LM, Arenas de Larriva MS, Fernández Delgado L et al. Situación del asma en Andalucía. Rev Esp Patol Torac. 2015; 27: 5-6.

5. Ordóñez Dios IM, Chica Galiano MJ, Roldán Reguera B et al. Rev Esp Patol Torac. 2015; 27: 50.

6. Madueño Caro AJ, Martín Olmedo PJ, García Martí E et al. Evaluación del conocimiento teórico-práctico de los sistemas de inhalación en médicos de atención primaria, posgrados en formación y pregrado. Aten Primaria. 2000; 25: 91-9.

7. Kamin WE, Genz T, Roeder S et al. The inhalation manager: a new computer-based device to assess inhalation technique and drug delivery to the patient. J Aerosol Med. 2003; 16: 21-9.

8. Moscoso Jara A, Entrenas Costa LM, Pérula de Torres LA et al. Conocimientos sobre la co-rrecta utilización de inhaladores por parte de los médicos residentes de atención primaria e impacto de una intervención formativa. Educ Med. 2017. (in press). Disponible en: http://dx.doi.org/10.1016/j.edumed.2016.12.007

9. Dominelli GS, Dominelli PB, Rathgeber SL et al. Effect of different single-session educa-tional modalities on improving medical students’ ability to demonstrate proper pressurized metered dose inhaler technique. J Asthma. 2012; 49:434-9.

10. Basheti IA. The effect of using simulation for training pharmacy students on correct device technique. Am J Pharm Educ. 2014; 78:177.

11. Bozek A, Jarzab J. Adherence to asthma therapy in elderly patients. J Asthma. 2010; 47:162-5.12. Cecere LM, Slatore CG, Uman JE et al. Adherence to long-acting inhaled therapies among

patients with chronic obstructive pulmonary disease (COPD). COPD. 2012; 9: 251-8.13. Giraud V, Allaert FA. Improved asthma control with breath-actuated pressurized metered

dose inhaler (pMDI):The SYSTER survey. Eur Rev Med Pharmacol Sci. 2009; 13: 323-30.

238

ORIGINALS


Received: August 13, 2016. Accepted: November 4, 2017.

Jacinto Hernández [email protected]

Abstract: Introduction: The aim of this study was to evaluate the outcome-including long term effects of Non-invasive Domiciliary Ventilation (NIDV) in our elderly patients and to assess what factors were associated with their survival.Material and methods: Prospective study that included all patients of our Service who star-ted NIDV at 75 years of older (January 2002 - April 2015). Analysis of survival was under-taken using Kaplan-Meier method and Cox regression.Results: 82 patients were included (72% women, mean age: 79.9 ± 3,7 years). 67% had more than three comorbidities. The most frequent causal diseases were: Obesity hypoventilation syndrome (65,9 %) and restrictive diseases (17,1 %). Significants improvements were obtained in diurnal blood gases at discharge (PaO2, PaCO2, ph) and in the follow-up (PaCO2) as well as a significant decrease in the number of hospital admissions. The mean compliance was 8.7 ± 3.2 h/day although tolerance at home was considered to be deficient in 50 %. In the end of the follow-up (median 15 months; range 0 - 135) the mortality was 70.7 %. The estimated survival at 1º year, 2 º year and 3 º year was 63 %, 56 % and 44 %, respectively. Survival was independently associated with: good compliance, restrictive disease, lower EPAP level and lower dyspnea level (mMRC) in the follow-up.Conclusions: The results of the NIDV in elderly patients are satisfactory improving arterial blood gases, hospital readmissions and achieving long survival. Survival was better in “good compliance” patients, in restrictive diseases and with lower dyspnea level at follow up.

Key words: Non-invasive domicilary ventilation; respiratory failure; elderly; survival.

VENTILACIÓN NO INVASIVA DOMICILIARIA EN PACIENTES DE EDAD AVANZADA

ResumenIntroducción: Conocer la evolución a largo plazo de pacientes ancianos en ventilación no invasiva domiciliaria (VNID) y qué factores se asocian a la supervivencia de los mismos.Material y métodos: Estudio prospectivo de los pacientes >75 años que han iniciado VNID en nuestro centro en un periodo de 12 años (2002 - 2014). Se realizó un análisis univariado (Kaplan-Meier) y multivariante de supervivencia (Cox).Resultados: Se incluyeron 82 pacientes. Un 67% tenían >3 comorbilidades, iniciándose la ventilación en situaciones agudas en el 76,8%. La patología causal más frecuente fue el sín-drome de obesidad-hipoventilación (65,9%) y la patología toracógena (17,1%). Se consiguie-ron mejorías gasométricas estadísticamente significativas entre el ingreso y alta (PaO2, PaCO2 y ph) y en el seguimiento (PaCO2), así como una reducción en el número de ingresos poste-riores. La media de horas de uso fue de 8,7 ± 3,2 horas/día, pero la tolerancia fue mala en el 50% de los casos. Al final del seguimiento (mediana 15 meses; rango: 3 - 135) la mortalidad fue del 70,7%. La supervivencia al año, 2º año y 3º año fue, respectivaente, del 63%, 56% y 44%. Fueron predictores independientes de supervivencia: la cumplimentación global, la patología toracógena como causa de indicación de VNID, un menor nivel de EPAP y el grado de disnea (mMRC) en el seguimiento.Conclusiones: Los resultados de la VNID en pacientes ancianos son satisfactorios, con-siguiendo mejorías mantenidas en el intercambio gaseoso, reingresos y supervivencias pro-longadas. La supervivencia fue superior en los pacientes cumplidores del tratamiento, con patología toracógena y con menor grado de disnea en el seguimiento.

Palabras clave: Ventilación no invasiva domiciliaria, fallo respiratorio, anciano, supervi-vencia.

J. Hernández Borge1, M.C. García García1, M.J. Antona Rodriguez1, A. Sanz Cabrera2, P. Pires Goncalves2, P. Cordero Montero2, A. M. Esquinas Rodríguez3.1Pulmonology Department. Complejo Hospitalario Universitario Infanta Cristina. Badajoz. 2Intensive Care Unit. Hospital Morales Meseguer. Murcia.

OUTCOME OF NON-INVASIVE DOMICILIARY VENTILATION IN THE ELDERLY


J. Hernández Borge et al. Home non-invasive ventilation in elderly patients

beginning NIV within the established period, ≥75 years old, regardless of the reason or condition at the start of treatment (acute respiratory failure, exacerbated chronic respiratory failure or stable chronic respiratory failure) or maintaining the condition after hospitalization. The diagnosis of obesity hypoventilation syndrome was established when BMI was >30 and daytime PaCO2 was >45, once other causes of hypercapnia were excluded. The study followed the ethics standards for our hospital and patients or their relatives signed an informed consent. Variables related to sociodemographic and clinical characteristics were collected (age, sex, environment of origin [rural/urban], presence and type of comorbidities [atrial fibrillation, presence of radiological or echocardiographic data showing pulmonary hypertension, history of neoplasm, previous diagnosis of sleep apnea syndrome, tuberculosis, hepatopathy, arterial hypertension, cardiopathy, obesity (BMI >30 kg/m2) and other comorbidities including history of depression], Charlson index, fundamental pathology leading to the start of home NIV, condition at the start of NIV [acute, exacerbated chronic or stable chronic respiratory failure], location where NIV was started, level of consciousness when NIV was started (Glasgow scale), baseline arterial blood gases at the start of hospitalization and before discharge, patient adaptation to NIV at the start of hospitalization and before discharge when treatment was started (subjectively collected based on comfort and the patient’s positive acceptance of treatment according to the judgment of the doctor responsible for the procedure), days of hospitalization, need for supplementary oxygen therapy, history of previous hospitalization before starting NIV, total number of previous hospitalizations and those in the year prior to beginning NIV and history of respiratory failure before beginning NIV, IPAP and EPAP pressure prescribed, type of interface (nasal/oronasal), Modified Medical Research Council (MMRC) degree of dyspnea before beginning NIV, FVC (in %), FEV1 (in %) and FEV1% before beginning NIV (recorded the year before and in stable condition) and the presence of chronic obstructive pulmonary disease [COPD])13.

Follow-up: all patients were prospectively monitored at a non-invasive ventilation specialized consultation unit every 3 months. During monitoring, the following variables were collected: baseline arterial blood gas under clinical stability, treatment tolerance according to judgment of

INTRODUCTION Home non-invasive ventilation (NIV) has been accepted as a treatment for chronic respiratory failure in patients with disorders of the thoracic cage and neuromuscular disease1-3. Additionally, in cases of acute respiratory failure, it has proven to be efficacious, reducing the need for endotracheal intubation and mortality. It is the treatment of choice in COPD exacerbations (AECOPD)4. In spite of this, its use in elderly patients has been less studied, questioning whether its efficacy is similar to that obtained in younger patients. There are studies that have found highly satisfactory results in elderly patients (>75 years), reducing the need for intubation in this population and showing that it can even be applied in patients with cognitive deterioration5-6. It has been suggested that the worse long-term tolerance along with the lower life expectancy in elderly patients could be limiting factors when indicating or maintaining NIV. There are very few studies available that evaluate the evolution and long-term survival of elderly patients treated with home NIV. Survival rates are found to be between 50 and 94%. The majority of these series include few patients, very diverse disease and, in general, short follow-ups7-12. The objective of our study has been to evaluate the evolution, both in the short and long term, in a cohort of elderly patients (>75 years) for whom home NIV was prescribed, placing particular emphasis on the indications and condition at the beginning of treatment, tolerance, compliance and long-term survival. In the same way, our aim is to understand what variables are related to long-term evolution in these patients.

MATERIAL AND METHODS

Study design: a prospective descriptive observational study was done in the Pulmonology Department at the Hospital Infanta Cristina, including all of the patients who began home NIV between 2002-2014. The procedure was primarily initiated during conventional hospitalization (95.1%), although two beds have been available since 2009 with continuous non-invasive monitoring, trained nursing staff and an on-duty pulmonologist to assure continuous care. All patients meeting the following inclusion criteria were selected:



RESULTS A total of 82 patients aged 75 or older (24.2% of the total number of patients [338] who began home NIV) were included. The main characteristics of these patients are found in Table 1. The majority were women (72%) with frequent comorbidities, especially of cardiological origin, and with a high prevalence of obesity (66%). A history of previous respiratory failure (65.9%) and previous hospitalizations (76.8%) were frequent. The diseases leading to starting home NIV are shown in Table 1. The main etiology was obesity hypoventilation syndrome (OHS) in 65.9% and thoracogenic disease. A significant percentage had poor adaptation to the initial NIV (42.7%) or NIV at discharge (31.7%); in spite of this, the doctor responsible chose to prescribe it. The length of hospitalization was an average of 10 days (interquartile range 25 - 75: 7 - 16). Statistically significant improvements were seen in gas status at discharge which continued to improve in outpatient tests in a state of maintained stability (Table 2). In the same way, the number of rehospitalizations and the level of dyspnea significantly decreased after starting home NIV. The median follow-up for the cohort was 15 months (interquartile range 25 - 75: 3 - 41.2). A significant percentage of patients (50%) showed poor treatment tolerance, in spite of the fact that the average number of hours of daily use was considered good in general. At the end of follow-up, mortality was 70.7% (Table 2). The mortality table method was used to estimate survival at one year, two years and three years as 63%, 56% and 44%, respectively. The median survival was 29.4 months. The survival function and mortality risk shown in the distribution of mortality throughout the follow-up period is included in Figure 1. Mortality was higher in cases of atrial fibrillation, a higher Charlson index, cases of previous respiratory failure (p = 0.07) and a higher number of hospitalizations prior to starting home NIV, as well as cases of poor adaptation to NIV upon hospitalization or at discharge (p = 0.07). During follow-up, mortality was higher in patients with rehospitalizations and a higher number of rehospitalizations after starting home NIV, with worse PaCO2 levels, a higher level of dyspnea in follow-up (p = 0.05) and, above all, those who had poor treatment tolerance and a poor quality of life (Ta-ble 3). The survival analysis with the Kaplan-Meier method (Figures 2,

the doctor responsible (considered poor if the number of hours of daily use was <5 hours/day and/or the patient or their caretaker referred to frequent problems with home NIV related to the subjective feeling of comfort during sleep and side effects related to the device or interface), number of hours of ventilation per day, including the number of daytime and nighttime ventilation hours using a personal interview with the patient and/or caretaker (these results were confirmed by reading the number of hours of use on the ventilator), additional hospitalizations and the date of the first rehospitalization after discharge, the number of rehospitalizations after discharge, the MMRC level of dyspnea after at least three months of home NIV, FVC (in %) and FEV1 (in %) and FEV1% at least three months after starting home NIV in stable condition. Finally, the patient’s quality of life was subjectively evaluated according to the judgment of the doctor responsible (good: the patient was completely autonomous at home and could leave without help or with minimal assistance from their caretaker, and bad: non-autonomous patient at home, unable to perform activities outside their home without significant help from their caretaker). Patients were monitored until June 2015, noting the date of death when applicable. Information was obtained for 100% of patients without registering losses other than death of a patient through the systematic review of the electronic clinical history or phone contact when necessary.

Statistical analysis: a descriptive analysis was done using the average, range, and standard deviation for the quantitative variables, as well as frequencies and percentages for the qualitative variables. The student’s t test for independent samples was used to measure the association between quantitative variables and the chi-squared test was used for qualitative variables. The student’s t test for related data was used to measure the association between quantitative variables throughout the follow-up period. The level of significance was set as p <0.05. Mortality tables, the Kaplan-Meier method and the Cox model were used for the univariate survival analysis. For this, the outcome event was defined as a combination of negative results including death, discontinuing home NIV or loss of the patient due to NIV stability. All of the variables that were found to be significant in the univariate analysis (p <0.1) were included in a Cox proportional hazards model to evaluate their contribution with regard to survival.



3 and 4) showed similar results with a higher mortality in cases with poor adaptation, poor tolerance, and worse quality of life. The type of disease was also associated with survival, as better survival was seen in thoracogenic patients (average survival 73 months; CI 95%; 62.7-83.2), followed by OHS (average survival 34 months; CI 95%: 22.9-45) and the worst was seen in neuromuscular disease (average survival 3 months; CI 95%: 2-5.1). In the multivariate analysis, survival was associated with good treatment tolerance, thoracogenic disease being the reason for starting home NIV, the need for a lower EPAP level and a lower level of dyspnea in follow-up (Table 4).

Table 1: Clinical characteristics and sociodemographics of the patients included in the study (n = 82)

Age* 79.9 ± 3.7Male/female (%) 28/72Rural/urban environment (%) 61/39Comorbidities (%):

Depression 36.6 Atrial fibrillation 37.8 Pulmonary hypertension 29.3 Neoplasm 15.9 Obstructive sleep apnea syndrome 39 Residual tuberculosis 4.9 Hepatopathy 3.7 Arterial hypertension 81.7 Cardiopathy 58.5 Obesity (BMI >30) 66 Other comorbidities 76.8 COPD 26.8 >3 comorbidities 67.1 Charlson index* 5.2 ± 1.3

Condition at the start of NIV (%): Acute respiratory failure 19.5 Exacerbated chronic respiratory failure 57.3 Stable chronic respiratory failure 23.2

Location NIV was started (%): Pulmonology ward 95.1 Elsewhere** 4.9

Level of consciousness at start of NIV (%): Glasgow <10 6.1 Glasgow 10-14 26.8 Glasgow >14 67.1

Primary disease leading to start of NIV (%): Neuromuscular disease*** 6.1 Thoracogenic disease**** 17.1 Obesity hypoventilation syndrome 65.9 COPD 11

Interface (%): Nasal 56.1 Oronasal 43.9

Previous respiratory failure (%) 65.9Previous hospitalizations (%) 76.8Total number of previous hospitalizations* 2.4 ± 2.6Number of hospitalizations in the last 12 months* 1.3 ± 1.5Poor initial adaptation to NIV (%) 42.7Poor adaptation to NIV at discharge (%) 31.7Need for supplementary oxygen therapy (%) 74.4IPAP level* 15 ± 2.1EPAP level* 4.4 ± 0.9 *Average±standard deviation. **Including ICU or the emergency department ***Including 5 cases of amyotrophic lateral sclerosis and 1 of polymyositis ****Including 9 cases of kyphoscoliosis, 4 of fibrothorax and 1 thoracoplasty. COPD: chronic obstructive pulmonary disease. BMI: body mass index. NIV: non-invasive ventilation IPAP (in cm of H2O): inspiratory positive airway pressure. EPAP: expira-tory positive airway pressure.



Table 2. Developmental characteristics in the patients included in the study (n = 82)

Variable At start of NIV

At dischar-ge

In follow-up

PaO2** 59 ± 16.4 67.2 ± 12.3 65.7 ± 13*PaCO2** 68 ± 20.2 52.1 ± 9.4 48 ± 9.3*pH** 7.32 ± 0.09 7.42 ± 0.05 7.39 ± 0.05*No. of hospitalizations 2.43 ± 2.68 - 1.33 ± 1.98Dyspnea (MMRC)*** 3.8 ± 0.5 - 2.8 ± 0.7*FVC in % 58.3 ± 20.2 - 59.7 ± 19.2*FEV1 in % 52.9 ± 20.2 - 57.1 ± 19.4*FEV1% 73.2 ± 17.4 - 76 ± 12.3*Home NIV tolerance (%):

Good - - 50 Bad - - 50

No. of daily hours of NIV - - 8.7 ± 3.2*No. of daily hours of NIV daytime use - - 1.1 ± 2.3*Rehospitalizations for respiratory failure (%) - - 58.5Quality of life (%):

Good - - 62.2 Bad - - 37.8

Status at the end of monitoring (%): Stable in home NIV - - 29.3 Death - - 70.7

*Clinically stable after at least 3 months of home NIV**p <0.05 in comparisons between admission and discharge, and between discharge and follow-up (except PaO2 and pH)***p <0.05.

Table 3. Clinical and developmental characteristics of patients according to living situation at the end of follow-up

Variable Living (n = 24)

Dead (n = 58)

p

Age 79.1 ± 2.8 80.2 ± 4.1 nsMale/female (%) 37.5/62.5 24.1/75.9 nsComorbidities (%):

Depression 29.2 39.7 ns Atrial fibrillation 20.8 44.8 0.05 Pulmonary hypertension 29.3 29.2 ns Neoplasm 12.5 17.2 ns Obstructive sleep apnea syndrome 37.5 39.5 ns Residual tuberculosis 0 6.9% ns Hepatopathy 5.2 0 ns Arterial hypertension 87.5 79.3 ns Cardiopathy 50 62.1 ns Obesity (BMI >25) 79.2 58.6 ns Other comorbidities 66.7 81 ns COPD 27.6 ns >3 comorbidities 58.3 70.7 ns Charlson index* 5.4 ± 1.2 0.03

Primary disease leading to start of NIV (%): Neuromuscular disease 4.2 6.9 Thoracogenic disease 25 13.8 ns Obesity hypoventilation syndrome 62.5 67.2 COPD 8.3 12.1

Status at the start of NIV (%): Acute or exacerbated chronic respiratory failure 70.8 79.3 ns Stable chronic respiratory failure 29.2 20.7

Glasgow <14 at start of NIV (%): 33.4 32.8 ns

Oronasal interface (%): 54.2 39.7 ns



Previous hospitalizations (%) 70.8 79.3 nsPrevious respiratory failure (%) 50 72.4 0.07Total number of previous hospitalizations* 1.5 ± 1.7 2.81 ± 2.9 0.02Number of hospitalizations in the last 12 months* 0.92 ± 1.13 1.57 ± 1.7 0.04Poor initial adaptation to NIV (%) 25 50 0.05Poor adaptation to NIV at discharge (%) 16.7 37.9 0.07Need for supplementary oxygen therapy (%) 66.7 77.6 nsRehospitalization after starting home NIV 37.5 67.2 0.02Number of rehospitalizations after starting home NIV 0.67 ± 1.2 1.6 ± 2.1 0.01PaO2 during follow-up 68.8 ± 10.7 64.5 ± 14.5 nsPaCO2 during follow-up 45 ± 5.8 49.2 ± 10.2 0.03pH in follow-up 7.40 ± 0.03 7.39 ± 0.05 nsDyspnea prior to starting NIV (MMRC) 4 ± 0 3.7 ± 0.6 nsDyspnea in follow-up (MMRC) 2.6 ± 0.4 2.9 ± 0.8 0.05IPAP level 14.7 ± 1.5 15.1 ± 2.3 nsPoor home NIV tolerance in follow-up (%) 20.8 62.1 0.001No. of daily hours of NIV* 8.7 ± 2 8.6 ± 3.6 nsNo. of daily hours of NIV daytime use* 0.8 ± 1.4 1.2 ± 2.7 nsQuality of life (%):

Bad 12.5 48.3 0.003 Good 87.5 51.7*Average±standard deviation.

Table 4. Variables independently associated with mortality in elderly patients using home NIV*

Variable P OR CI 95% Good compliance with home NIV 0.02 0.46 0.24 - 0.87Thoracogenic disease 0.01 0.36 0.16 - 0.82EPAP level 0.01 1.60 1.11 - 2.31Developing dyspnea (MMRC) 0.008 2.12 1.22 - 3.69*Cox proportional hazards model (adjusted for age, Charlson index, EPAP level, number of previous hospitalizations, presence of depression, treatment compliance, initial and hospitalization adaptation, quality of life, presence of thoracogenic disease and level of MMRC dyspnea). Backward stepwise method.

Figure 1: Survival function and mortality risk function (deaths/patient/month) for patients >75 in home NIV (mortality table method).

Figure 2: Survival curves for the patients studied according to adaptation to NIV upon hospitalization and at discharge (Kaplan-Meier method). NIV: non-invasive ventilation *Log-rank test.



DISCUSSION The causes of respiratory failure (RF) in the elderly requiring the start of NIV are multifactorial14, 15, although the primary causes are COPD, heart failure, thoracogenic disease and OHS8. In our case, the main indications for home NIV were OHS (65.9%) and thoracogenic disease (17%), while COPD only represented 11%, although these discrepancies can be attributed to the fact that our study was based on patients included in a home NIV program and did not focus on NIV in acute patients10, 12. Many of the studies on NIV in these patients find that, along with age itself, comorbidities and the frequent presence of physical limitations prevent patients from being candidates for endobronchial intubation or ICU admission. In our case, the majority of patients began in a conventional pulmonology ward (95.1%), in spite of the fact that up to 76.8% were in a state of exacerbated RF and 35.9% had a deteriorated level of consciousness. We found a high frequency of comorbidities (>3 comorbidities: 67.1%, Charlson index: 5.2 ± 1.3), a fact which is often referred to in other work6,

8. More important than these facts were the number of patients who had had previous RF (65.9%) or a high number previous hospitalizations (2.4 ± 2.6), which leads us to think that, in many cases, the start of NIV in states of exacerbation is being delayed, estimating a high rate of early lethality. However, there are studies that have compared the efficacy and results of NIV in acute situations, without finding differences with respect to younger patients8. In this way, mortality upon discharge in different works has varied from 6% to 45%5-12, 16-18. The differences in the results are closely related to the type of study, number of patients, place and methodology used start NIV, RF etiology and the associated comorbidities. In general, many works support NIV indications in elderly patients with hypercapnic acute respiratory failure secondary to AECOPD, finding an increased efficacy compared to more aggressive measures. They even point out that NIV can be effective in highly incapacitated patients or those with forms of dementia and note that these problems can be controlled in units specifically dedicated to this type of patient (transitional care units or geriatric pulmonology departments) with high success rates and mortality rates comparable to younger subjects. Many of these studies only evaluated the effects of NIV during acute respiratory failure without posterior follow-up. However, the majority agree in affirming that it is a safe procedure with few complications and it improves the short-term evolution of elderly patients in

Figure 3: Survival curves for the patients studied according to the presence of depression and tolerance for NIV during follow-up (Kaplan-Meier method). NIV: non-invasive ventilation *Log-rank test.

Figure 4. Survival curves for the patients studied according to quality of life and the pathology leading to starting NIV (Kaplan-Meier method). NIV: non-invasive ventilation *Log-rank test.



rate, such as Schortgen et al.11 (mortality at 6 months: 51%) and Scarpazza et al.9 (mortality at 3 years: 31% in ventilated patients vs 65.2% in patients with home oxygen therapy). In our case, mortality at one year was 47% and 56% at three years, with an average survival rate of 31.8 months. We found different variables related to mortality at the end of follow-up, noticing that patients with a higher Charlson index, a higher number of previous hospitalizations or history of RF, without thoracogenic disease, with poor NIV adaptation, with rehospitalizations, with a higher level of dyspnea during follow-up, with poor tolerance and a poor quality of life died more frequently and earlier than the other patients. Early and correct indication could avoid starting home NIV in more advanced stages of the disease, when its effects may not be as satisfactory. On the other hand, the problem with adaptation and tolerability in these patients must be taken into account, both in the initial phase and during home control, optimizing the means of outpatient support as a way of obtaining long-term satisfactory results. In this sense, the companies supplying home respiratory therapies must play an essential role in the long-term adaptation by coordinating with the medical service prescribing the treatment. In our case, good treatment tolerance was related to a higher survival rate in patients and was one of the variables independently related to this. Finally, it is necessary to establish some treatment limits in these patients. In this sense, it is necessary to take their quality of life into account, not only as an indicator for long-term vital prognosis, but also as an estimation of the benefits home NIV is providing. Perhaps we should reconsider maintaining NIV over the long term in patients with very advanced disease, poor quality of life and in whom home NIV does not manage to improve certain aspects of their condition (dyspnea, sleep, comfort). The main limitations of the study stem from the number of patients included, the type of disease in which home NIV was used and including the course of action for a single hospital center. As we have mentioned, the studies available on this type of patient are scarce and, in general, are also monocentric. Other limitations stem from the methodology used in applying NIV. Some works have suggested the vulnerability and frequent complications associated with NIV use in the elderly, recommending administration in departments specifically dedicated to this procedure where there are higher possibilities of success5, 6, 8, 9, 11. In spite of this, our results support the use of home NIV in elderly

comparison to the guidelines for conventional treatment5-12. NIV in these patients comes with significant problems with adaptation and tolerability. Our results indicate this as up to 31.7% of patients were considered to have poorly adapted at discharge according to the doctor responsible. In other studies, the presence of complete intolerance during hospitalization varies between 6 and 10%5, 6 and there are no studies that prospectively evaluate this concept in patients over the long term. We found clear improvements at discharge in gasometric parameters, which were maintained during follow-up, as well as the level of dyspnea and number of hospitalizations after starting home NIV. We concur with other authors8, 10,

12 in stressing the convenience of maximally optimizing home NIV in order to avoid rehospitalizations that can substantially influence the long-term prognosis of these patients. In follow-up we saw that the tolerance for home NIV was poor in half of the patients in spite of the fact the average number of hours of daily use was good in general (8.7 ± 3.2 hours/day). Along with the number of hours used, the definition of poor tolerance included aspects related to patient satisfaction, the appearance of side effects related to the interface or discomfort caused by the ventilator and according to the opinion of the patient’s caretaker. In the work by Farrero et al.10, the initial level of tolerance was good, although 11% ended up discontinuing home NIV. This author notes that this percentage is significantly higher than that observed in young patients (4%), but similar to that seen in other studies on patients of any age19. One of the facts that can influence these results is the type of disease in which home NIV is indicated, with higher rates of discontinuation in COPD patients for whom there is controversy as to whether to use the treatment during periods of clinical stability. In any case, poor tolerance and discontinuation of home NIV are not identical concepts, although in our opinion the former may be a predictor for the latter. Some 58.5% of patients were rehospitalized for RF and 37.8% were con-sidered to have a poor quality of life, thus the final mortality in the study was high (70.7%). Works following this patient group are scarce7-12, 18 and many of them focus on the start of NIV, retrospectively registering the evolution and generally short follow-ups, with a mortality rate ranging from 6 to 51%. Farrero et al.10 monitored 43 patients for an average of 36 ± 24 months, with a mortality rate of 50%. Other studies followed patients among whom a high percentage do not continue home NIV and found a much higher mortality



14. Aminzadeh F, Dalziel WB. Older adults in the emergency department: a systematic review of patterns of use, adverse outcomes, and effectiveness of interventions. Ann Emerg Med. 2002; 39: 238–47.

15. Ray P, Birolleau S, Lefort Y. Acute respiratory failure in the elderly: etiology, emergency diagnosis and prognosis. Crit Care. 2006; 10: R82.

16. Vargas N, Vargas M, Gallucio V et al. F. Non-invasive ventilation for very old patients with limitations to respiratory care in half-opne geriatric ward: experience on a consecutive co-hort of patients. Aging Clin Exp Res 2014. DOI 10.1007/s40520-014-0223-1.

17. Laudisio A, Scarlata S, Pedone C et al. RA. Noninvasive ventilation in older adults admitted to a pneumogeriatric unit .JAGS 2014; 62: 1195-1197.

18. Nava S, Grassi M, Fanfulla F et al. Non-invasive ventilation in elderly patients with acute hypercapnic respiratory failure: a randomized controlled trial. Age and Ageing 2011; 40: 444-50.

19. Rey L, Echave-Sustaeta J, Pérez V et al. Interrupción de la ventilación mecánica domicilia-ria. Arch Bronconeumol 2002; 38 (Suppl 2): 52 [abstract].

patients, obtaining sustained improvements in gas exchange, level of dyspnea, rehospitalization and prolonged survival. We would like to highlight that the frequent problems with adaptation and tolerance over the long term must be monitored and corrected as a way of improving treatment results. Finally, we believe it is necessary to evaluate the quality of life in this group of patients, which could be a clear predictor of mortality and, in many cases, a determining factor in prescribing home NIV over the long term.

BIBLIOGRAPHY1. Leger P, Muir JF. Selection of patients for long-term nasal intermittent positive pressure

ventilation: practical issues. Eur Respir Mon 1998; 8: 328–47.2. Domenech-Clar R, Nauffal-Manzur D, Perpiña-Tordera M et al. Home mechanical ventila-

tion for restrictive thoracic diseases: effects on patient quality-of-life and hospitalizations. Resp Med 2003; 97 (12): 1320–7.

3. Simonds AK, Muntoni F, Heather S, et al. S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998; 53: 949–52.

4. British Thoracic Society Standards of Care Committee. Noninvasive ventilation in acute respiratory failure. Thorax 2002; 57: 192–211.

5. Balami JS, Packham SM, Gosney MA. Non-invasive ventilation (NIV) for respiratory failu-re due to acute exacerbations of chronic obstructive pulmonary disease (COPD) in older patients. Age Ageing 2006; 35: 75-8.

6. Rozzini R, Sabatini T, Trabucchi M. Non-invasive ventilation for respiratory failure in el-derly patients. Age Ageing 2006; 35: 546-547.

7. Corral Gudino L, Jorge Sanchez RJ, García Aparicio J et al. Use of noninvasive ventilation on internal wards for elderly patients with lmitations to respiratory care: a cohort study. Eur J Clin Invest 2011; 41 (1): 59-69.

8. Segrelles G, Zamora E, Girón R et al. Ventilación mecánica no invasiva en una población anciana que ingresa en una unidad de monitorización respiratoria: causas, complicaciones y evolución al año de seguimiento. Arch Bronconeumol 2012; 48 (10): 349-354.

9. Scarpazza P, Incorvaia C, Amboni P et al. W. Long term survival in elderly patients with a do not intubate order treated with nonivasive mechanical ventilation. Int J Chron Obstruct Pulmon Dis 2011; 6: 253-257.

10. Farrero E, Prats E, Manresa F et al. Outcome of noninvasive domiciliary ventilation in elderly patients. Repir Med 2007; 101: 1068-1073.

11. Schortgen F, Follin A, Piccari L et al. Results of noninvasive ventilation in very old patients. Ann Intensive Care 2012; 2: 5.

12. Comer DM, Oakes A, Mukherjee R. Domiciliary non-invasive ventilation in the Elderly. Effective, tolerated and justified. Ulster Med J 2015; 84 (1): 22-25.

13. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. (Updated 2014). http://www.goldcopd.org.

247

CLINICAL NOTE


Abstract: A case is presented of a patient with a history of low-intensity smoking, with an accumulated tobacco index of less than 5 packs-year and without other personal history of interest. She went to the emergency room several times over 2 months, complaining of a diffuse, oppres-sive and intermittent headache and diplopia accompanied by occasional blurred vision, being diagnosed with ischemic paralysis of the fourth cranial nerve of the left eye and initiating treatment with antiplatelets. Despite treatment, she returned to the emergency room within a week, as she had been suffering from progressive dizziness, instability when walking, loss of vision mainly in the left eye and a greater feeling of weakness in the upper limbs. Fina-lly, admission to Neurology was decided upon with the suspicion of subacute tuberculous meningoencephalitis. However, after various diagnostic tests, it was concluded that it was a pulmonary adenocarcinoma, which began as meningeal carcinomatosis without presenting associated respiratory symptoms.

Key words: Lung cancer, meningeal carcinomatosis, lung adenocarcinoma.

Received: January 2, 2017. Accepted: November 29, 2017.

María Pérez [email protected]

CARCINOMATOSIS MENÍNGEA: FORMA INUSUAL DE PRESENTACIÓN DEL ADENOCARCINOMA DE PULMÓN

ResumenSe presenta el caso de una paciente con antecedentes de ser fumadora de baja intensidad, con índice acumulado de tabaco menor de 5 paquetes/año y sin otros antecedentes personales de interés. Acudió en diversas ocasiones durante 2 meses a urgencias, refiriendo cefalea difusa, opresiva e intermitente y diplopía acompañada de visión borrosa ocasional, siendo diagnos-ticada de parálisis isquémica del IV par craneal del ojo izquierdo e iniciando tratamiento con antiagregante. A pesar del tratamiento, a la semana acudió de nuevo a urgencias, ya que progresivamente había ido presentado mareos, inestabilidad en la marcha, pérdida de visión con predominio en ojo izquierdo y mayor sensación de debilidad en miembros superiores, Finalmente, se decidió ingreso en Neurología ante la sospecha de meningoencefalitis suba-guda tuberculosa, pero tras diversas pruebas diagnósticas se llegó a la conclusión de que se trataba de un adenocarcinoma pulmonar, que debutó en forma de carcinomatosis meníngea sin haber presentado sintomatología respiratoria asociada.

Palabras clave: cáncer de pulmón, carcinomatosis leptomeningea, Adenocarcinoma pul-monar.

M. Pérez Morales, G. Jiménez Gálvez, C. España Domínguez, L.C. Márquez Lagos.

Pulmonology, Allergy and Thoracic Surgery Clinical Management Unit. Hospital Universitario Puerta del Mar. Cádiz.First clinical case awarded at the 2017 Congress

MENINGEAL CARCINOMATOSIS: UNUSUAL PRESENTATION OF ADENOCARCINOMA OF THE LUNG

INTRODUCTION Lung cancer (LC) is the most common tumor and the one which caus-es the highest mortality rate in the developed world1, with 1,800,000 new cases per year and 1,600,000 deaths in 2012. In Spain3, there were 33,370 new cases diagnosed in 2015, making it the third most prevalent tumor in our country. The incidence rate is variable according to sex, in such a way that in 2015, 22,430 men were diagnosed compared to 5,917 women. It is the most common malignant tumor in men, and ranks third place in women3. Additionally, during the next decade, incidences are expected to

continue increasing for both sexes. The mortality rate for both woman and men hasn’t stopped rising in our country since 1980 and is currently the type of tumor that causes the highest number of deaths in the general population, both in Spain and on a global level4. Of the new cases at the time of diagnosis, only 20% are found in early stages (Stage I-II of the TNM classification) and up to 40% of cases already have distant metas-tasis. The survival rate of patients with lung cancer is very low and it’s because of this that the proportion of mortality to incidence maintains a


M. Pérez Morales et al. Meningeal carcinomatosis: Unusual presentation of adenocarcinoma of the lung

stable relationship which is close to the same in our country and the rest of the world (0.86)5. Tobacco smoke is the most important risk factor for the development of LC, with smokers being approximately 20 times more at risk of developing the disease than non-smokers. In the same way, the passive inhaling of tobacco smoke increases the risk of develop-ing LC between 20% and 30% compared to the non-exposed population. Adenocarcinoma is the most common histological type, constituting 38% of the cases of LC diagnosed at present, also being the lineage that is least related to the consumption of tobacco in comparison with squamous cell carcinoma or with small cell carcinoma. The first symptoms are often extrathoracic, given its propensity to develop early metastases, and it is not uncommon for it to start with neurological symptoms due to brain metastasis, with a range of occurrence of these symptoms between 3-21%6, 7. Paraneoplastic syndromes appear in less than 1% of patients with cancer and the majority of them present with carcinoma of the lung (generally small cell), breast or ovary. They are not limited to the nervous system, but they affect it frequently. The effects at the central nervous system (CNS) level include progressive dementia, behavior alterations, convulsions and, on a lesser scale, focal motor or sensory signs. The main outlying effects are muscular weakness and peripheral neu-ropathy. The diagnosis is usually by exclusion, unless autoantibodies are detected in the patient’s serum or cerebrospinal fluid (CSF). The differ-ential diagnosis includes metabolite disorders, meningeal carcinomato-sis and progressive multifocal leukoencephalopathy. There is no specific treatment, although patients can occasionally improve with treatment of the primary neoplasm8, 9. Nowadays, the anatomopathological diagnosis of lung cancer is a multi-step process, beginning with the morphological diagnosis to deter-mine the histological type and then refining with immunohistochemistry, which is required to perform an appropriate characterization of the tu-mor. This increasingly complex diagnosis algorithm poses many changes for the management of patients with lung cancer. Nowadays, we know that a significant proportion of patients with lung cancer suffer from tumors with molecular characteristics (mutations, gene fusions, etc.) which allow us to establish a therapeutic target. Currently,

the vast majority of those molecular abnormalities that are susceptible to specific therapeutic processes are presented, for the most part, in adenocarcinoma of the lung. Laboratory studies based on predictive biomarkers, which identify said abnormalities to be able to respond with targeted therapies, represent an example of change in lung cancer diagnosis and have become an important evolution in this pathology. Active mutations in the growth factor receptor gene (EGFR) tyrosine kinase appear in 10-16% of cases of adenocarcinoma in European patients10. However, in squamous cell carcinoma, these mutations very scarcely appear in a reliable form. The cause of the EGFR mutation is unknown, but it’s not related to tobacco. Thus, these mutations are more common, although not exclusive, in non-smokers or long-time former smokers and in young women. Independent of this data, recent evidence indicates that patients with any type of lung cancer, including small cell, that have a minimal or remote history of smoking should be considered for said gene test10. Studies in phase III which include patients from Asia, Europe and America with metastatic disease, whose tumors have the mutated EGFR, have demonstrated higher response ratios (approximately 70%) and a higher survival rate, without significant progression in patients initially treated with EGFR tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, afatinib), compared to those who received chemotherapy11-13. The use of EGFR TKIs is currently well established in clinical practice, requiring routine tests in appropriate cases.

CLINICAL CASE A female, 55-year-old patient, allergic to acetylsalicylic acid, pyrazolones, non-steroidal anti-inflammatories, penicillin and derivatives, cephalosporin, gentamicin and fosfomycin. Very sporadic smoker. She did not refer to any other personal history of interest nor active treatment. She visited the emergency room several times over two months, suffering from a diffuse, oppressive and intermittent headache and diplopia accompanied by occasional blurred vision. She was initially diagnosed with ischemic paralysis of the fourth cranial nerve of the left eye after performing a nuclear magnetic resonance (MRI) scan. Treatment began with clopidogrel. Despite this, she returned to the emergency room a



vasculitis associated with meningitis (Figure 1). The electroencephalogram showed signs of mild generalized cerebral electrical involvement, predominantly in anterior areas of both hemispheres and a certain right predominance. A second lumbar puncture was carried out that showed findings similar to the previous one, with high cellularity of mononuclear, hyperproteinorrachy and hypoglycorrhachia predominance and with higher red blood cell content (leukocytes: 10 leu/dL [95% mononuclear], red blood cells: 100 hem/dL, proteins: 220 mg/dL and glucose: 16 mg/dL). Additionally, a rise in adenosine deaminase (ADA) with a value of 9.2 (normally 0-7) was found. The determination of microbacteria through the polymerase chain reaction (PCR) in CSF was negative, as were the stains and microbacteria, bacteria and fungus cultures. The cytology of the CSF was positive, compatible with meningeal carcinomatosis of adenocarcinoma. The chest CT scan showed a 3.3 x 2.7 x 4.5 cm mass in the right upper lobe (RUL), which comes into contact with the mediastinal pleura on an approximate surface of 2 cm. Furthermore, a dense lesion with sclerotic appearance was described on the posterosuperior side of the D1 vertebral body and a discrete pseudonodular thickening of the left adrenal gland with undetermined characteristics was observed. If it was a neoplasm, it would be stage IB (T2a, N0, Mx). The positron emission tomography (PET)-CT showed a metabolically positive pulmonary mass in the CSF with ipsilateral mediastinal lymphatic and osseous involvement (vertebra D1, L5 and right iliac bone), suggestive of malignancy. There was pseudonodular thickening without significant uptake in the left adrenal gland, indicating a low probability of malignancy (Figure 2). Finally, a CT-guided biopsy of the pulmonary mass was carried out, with cytology compatible with adenocarcinoma of pulmonary origin, with mutation of the positive endothelial growth factor receptor (EGFR). The definitive diagnosis was stage IV (T2a, N2, M1b) adenocarcinoma of the lung, with osseous metastasis (D1, L5 and right iliac bone) and carcinomatous meningoencephalitis. Once the diagnosis was decided, treatment began with the instillation of intrathecal dexamethasone and erlotinib. Levetiracetam was also added after the patient presented an absence seizure on one occasion during

week later, as the signs had progressively worsened. She presented further dizziness, instability when walking, loss of vision mainly in the left eye and a greater feeling of weakness in the upper limbs, therefore a spinal tap was performed in the emergency room, obtaining cerebrospinal fluid (CSF) with predominantly mononuclear cellularity. With the suspicion of tuberculous meningitis, admission to the Neurology department was decided and empirical antituberculous treatment was initiated. At first, the signs of the physical and neurological examination were normal, but the day of admission for physical examination she displayed hypo-reactive pupils, especially the left, which appears to be Marcus Gunn pupil. It’s difficult to explore the extrinsic ocular motility due to loss of visual acuity. Furthermore, it is accompanied by facial paresis of the upper and lower right bundle branch, together with weakness of the soft palate and a certain nasalization of the voice. She also presents weakness in neck flexion, absence of peripheral motor reflexes in extremities and cutaneous extensor plantar reflexes. Once she was admitted, the following set of diagnostic tests was carried out. No alterations in the hemogram nor the biochemistry were found. The acetylcholine antireceptor antibody was negative. An anterior-posterior chest and left anterior oblique x-ray showed a consolidation-mass located in the right upper lobe (RUL) of approximately 4 cm in maximum diameter. A chest CT scan was carried out. A cranial CT scan was carried out, without observing pathological findings. A Doppler ultrasound of supra-aortic trunks was performed, with no alterations in either carotids or vertebral arteries. In the transcranial Doppler ultrasound, there were also no alterations in the examination of the cerebral arteries. An initial lumbar puncture was carried out, which showed high cel-lularity with mononuclear, hyperproteinorrachy and hypoglycorrhachia predominance, with leukocytes: 15 leu/dL (polymorphonuclear 13%, mononuclear 87%), red blood cells: 0 hem/dL, proteins: 64.2 mg/dL and glucose: 31 mg/dL. The fundus of the eye didn’t show any evidence of papilledema or other alterations. In the cranial MRI with contrast, pachy and leptomeninges involvement was observed that posed as the differential diagnosis between infectious meningitis and granulomatous processes such as sarcoidosis and carcinomatosis. Furthermore, an early subacute ischemic lesion was evident on the left side of the protuberance, compatible with probable



hospitalization. The patient evolved, developing a new absence seizure after a month as she had decreased the dose of antiepileptic medication without medi-cal supervision. Two months after discharge, she was diagnosed with left iliofemoral deep vein thrombosis, requiring admission to start anticoag-ulation, being stable from the neurological and pulmonological point of view. Three months after starting treatment, a control chest CT scan was carried out, evidencing signs of partial response, with shrinking of the CSF tumor mass to diameters of 21 x 17 mm (33 x 27 mm in previous study). No radiologically significant lymphadenopathies appeared in the study. Bone lesions had increased their degree of sclerosis, a modification which could be in relation to internal reparative changes. Furthermore, the study showed signs of pulmonary thromboembolism in some segmental arteries, with partial occupation of the lumen of the vessels, without appreciable parenchymal repercussions or signs of right cardiac overload. A control cranial NMR was also performed, in which the disappearance of the hyper-uptake and leptomeningeal thickening seen in the previous study can be noted at the cranial level. This highlights the presence of signs of subcortical atrophy and increased small vessel ischemic leukoencephalopathy in the cerebral study. Also highlighted was the relative increase of the ventricular system, uniformly and globally, compared to the previous study. In the final progressive test, the patient continued the treatment with erlotinib, presenting grade 3 cutaneous toxicity of the scalp and grade 2 paronychia , therefore the dose was reduced as the patient was neurologically stable and showed asymptomatic breathing.

Figure 1. Cranial NMR, which highlights a diffuse and linear enhancement of the dura mater, as well as diffuse leptomeningeal enhancement with a linear predominance that adopts a pseudonodular pattern at the level of the folia of the cerebellum.



into account, within the differential diagnoses of the pathology that simulates symptoms of intracranial neoplasia. Furthermore, MC in non-small cell carcinoma of the lung (NSCCL) is a difficult illness to treat and is a very serious entity in the course of these tumors. The survival rate of these patients is approximately 3 months, which is shorter than that of patients with meningeal involvement in other illnesses like breast cancer or malignant hematological illnesses15. These patients are frequently treated with holo-cranial radiotherapy, intrathecal chemotherapy with methotrexate, cytarabine or thiotepa (or both), although this is less common. The survival rate remains poor, independent of the use of treatments or not. Thus, although holo-cranial radiotherapy may play an important role in terms of symptom control, there is little evidence to support its survival benefit16. There is also no clear evidence of the advantages of intrathecal chemotherapy in terms of the survival of these patients17. However, there are studies, reports and case series whose data suggests that patients with meningeal carcinomatosis with the EGFR mutation, treated with EGFR TKIs like erlotinib or gefitinib, had a higher average survival rate (3 months)18-21.

DISCUSSION Meningeal carcinomatosis (MC) is more commonly present in patients with disseminated neoplastic disease (70%), but it can occur after a disease-free interval (20%) and even be the first sign of cancer (5-10%)14. Similarly, several autopsy studies indicate that up to 19% of patients with cancer associated with neurological signs and symptoms have evidence of meningeal involvement due to MC. Furthermore, the incidence of MC in patients with cancer ranges from 5% to 8%. The first tumors that usually indicate MC in the adult population are breast (30-50%) and lung (15-25%), mainly small cell carcinoma and adenocarcinoma, followed by melanoma (11%) and gastric cancer (0.16-0.69%)14. It is especially interesting to note how the patient’s initial clinical symptoms focused the pathology towards the central nervous system, at first suspecting a possible intracranial expansive lesion, which was ruled out after the complementary examinations. It is worth noting that the patient was completely exempt from respiratory symptoms, which made the initial diagnosis difficult and, therefore, delayed an adequate therapeutic approach. This case is interesting because it can help us to take meningeal carcinomatosis

Figure 2. A) PA chest x-ray with image of an approximately 4-cm consolidation-mass located at right upper lobe level. B) Chest CAT scan with 3.3 x 2.7 x 4.5 cm mass in right upper lobe. C) Pulmonary section of PET-CT, with image of metabolic hyper-uptake in CSF.



lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13: 239–246.

12. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label randomized phase 3 study. Lancet Oncol 2011; 12: 735–742.

13. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pe-metrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–3334.

14. LeRhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal me-tastases in solid tumors. Surg Neurol Int. 2013; 4 Suppl 4: S265–88.

15. Hyeon GY, Hye JK, Yu JK et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung can-cer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer 2009; 65: 80–84.

16. Chuang TY, Yu CJ, Shih JY et al. Cytologically proven meningeal carcinomatosis in patients with lung cancer: clinical observation of 34 cases. J Formos Med Assoc 2008; 107: 851–856

17. Kim DY, Lee KW, Yun T et al. Comparison of intrathecal chemotherapy for leptomenin-geal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combina-tion with cytosine arabinoside and hydrocortisone. Jpn J Clin Oncol 2003; 33 (12): 608–12

18. Katayama T, Shimizu J, Suda K et al. Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol 2009; 4:1415– 1419.

19. Masuda T, Hattori N, Hamada A et al. Erlotinib efficacy and cerebrospinal fluid concen-tration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. Cancer Chemother Pharmacol 2011; 67: 1465–1469.

20. Wagner M, Besse B, Balleyguier C et al. Leptomeningeal and medullary response to second-line erlotinib in lung adenocarcinoma. J Thorac Oncol 2008; 3: 677–679.

21. Morris PG, Reiner AS, Rosenvald O et al. Leptomeningeal Metastasis from Non-Small Cell Lung Cancer. Survival and the Impact of Whole Brain Radiotherapy. Journal of Thoracic Oncology 2012; 7: 2.

W e specifically mention a study with 11 patients with meningeal carcinomatosis in the context of NSCCL which was treated with erlotinib or high doses of gefitinib. The results of the study show, among other things, that the survival rate of 8 of the patients was more than 6 months and, additionally, another 2 patients survived +2.5 and +4.4 months. Clinical improvement was documented in 9 of the patients. Thus, the results suggest that treatment with erlotinib or an increased dose of gefitinib is an effective therapeutic option for selected patients with this pathology15. In this way, taking the clinical evidence into account, since the positive result for the EGFR mutation was obtained in our patient, treatment with erlotinib was started. Subsequent tests showed a good response to the therapy, with improvement both in the pulmonary and metastatic lesions and, for the time being, with an above-average survival rate compared with patients who can’t be treated with this therapy due to absence of the EGFR mutation.

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rary and future challenges worldwide. Ann Transl Med 2016;4(8):150 3. Sociedad española de oncología médica. Las cifras del cáncer en España, 2017. https://

www.seom.org/en/prensa/el-cancer-en-espanyacom/105941-las-cifras-del-cancer-en-es-pana-2017.

4. Leiro-Fernández V, Mouronte-Roibás C, Ramos-Hernández C Et al. Cambios en el estadio y presentación clínica del cáncer de pulmón a lo largo de dos décadas. Arch Bronconeumol 2014; 50 (10):417–421.

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6. Beckles MA, Spiro SG, Colice GL. Initial evaluation of the patient with lung cancer. Symp-toms, signs, laboratory tests and paraneoplastic syndromes. Chest 2003;123 (1): 97-104.

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11. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell

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Received: February 28, 2017. Accepted: July 7, 2017.

Graciela López Muñ[email protected]

G. López Muñiz, C. López Represa, T. Ruiz Albi.

Pulmonology Department. Hospital Universitario Rio Hortega. Valladolid.

ENDOBRONCHIAL LESION IN A FEMALE SMOKER

where said mass was found; excrescent, pedunculated, with a mamelonated appearance and attached to the wall of the bronchus, highly vascularized, which makes it friable with the passage of the bronchoscope and causes partial obstruction (approximately 30%) of the bronchial lumen (Image 1c). Samples of said lesion were taken, both by a biopsy with alligator clamps and a telescoped brushing. The anatomopathological result was compatible with a predominantly glandular endobronchial papilloma, compared with the initial suspicion of bronchogenic carcinoma. The patient was referred to thoracic surgery for endoscopic treatment, proceeding to the excision of the lesion with laser surgery. Currently, radiological monitoring finds the patient asymptomatic and without new lesions.

Papillomas are rare, benign tumors, which hardly represent 0.38% of all pulmonary tumors1. They are divided into three categories: squamous, which predominates and is related to tobacco use, having a greater tendency to become malignant; glandular and mixed, which are more frequent in elderly women2. As for the forms of presentation, patients can remain asymptomatic,

CASE DESCRIPTION Female patient, 53 years old, smoker from a young age, with an accumulated rate of 28 packs-year, without relevant medical history. She is referred to our office for evaluation after having presented an episode of hemoptysis, evolving over two days, which was self-limited. In the medical history, the patient reports having presented similar signs a year ago, although to a lesser extent and duration, which was attributed to an infection, without carrying out additional tests. From the respiratory point of view, she was found to be asymptomatic, with the hemoptysis having ceased and with no accompanying respiratory symptoms. Furthermore, both the physical examination and chest x-ray were normal.

As she is a smoker with hemoptysis, a computerized axial tomography (CAT) of the chest was requested, within the CB Process protocol, in which a 1 x 1.5 cm solid mass was observed at the endobronchial level, located in the right bronchus intermedius. The images were highly suggestive of malignancy (image 1A and 1B with arrows). Given the high suspicion of a neoformative process, a diagnostic videobronchoscopy was performed to take samples


G. López Muñiz et al. Endobronchial lesion in a female smoker

BIBLIOGRAPHY1.- Ashmore PG. Papilloma of the bronchus: case report. J Thorac Surg 1954; 27: 293-294.2.- Allan JS: Rare solitary benign tumors of the lung. Semin Thorac Cardiovasc Surg 2003, 15:

315-322.3.- Flieder DB, Koss MN, Nicholson A et al.: Solitary Pulmonary Papillomas in Adults: A

Clinicopathologic and In Situ Hybridization Study of 14 Cases Combined With 27 Cases in the Literature. American Journal of Surgical Pathology 1998, 22: 1328-1342.

4.- Fabrice Paganin, Martine Prevot, Jean Baptiste Noel et al. A solitary bronchial papilloma with unusual endoscopic presentation: case study and literature review. BMC Pulmonary Medicine 2009, 9: 40 doi: 10.1186/1471-2466-9-40.

have a cough, radiological alterations and hemoptysis (4/13 in the Fielder et al. study3), as was the case with our patient. Given that bronchogenic carcinoma is the first differential diagnosis considered, bronchoscopy is carried out on practically all patients. They are usually polypoid, friable lesions, between 0.2 and 2.5 cm3 in size and located in the most proximal region of the airway. Endoscopic treatment is acceptable, given their small size. The YAG laser is the most commonly used, as with our patient, although an electrocautery scalpel can also be used for its resection.

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.

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Originals Image - Neumosur · 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 00.000 intervenciones,