Modificaciones hemodinámicas y metabólicas maternas secundarias al uso de betametasona para la maduración pulmonar fetal

Keibis Jiménez Castillejo; Yolima Ruiz Lopez; Eduardo Reyna Villasmil; Duly Torres Cepeda; Joel Santos Bolívar; Jhoan Aragón Charry; Jorly Mejia Montilla; Nadia Reyna Villasmil

Modificaciones hemodinámicas y metabólicas maternas secundarias al uso de betametasona para la maduración pulmonar fetal(Hemodynamical and metabolic modifications secondary tobetamethasone use for fetal lung maturity)Keibis Jiménez-Castillejo1, Yolima Ruiz-Lopez1, Eduardo Reyna-Villasmil1, Duly Torres-Cepeda1, Joel Santos-Bolívar1, Jhoan Aragón-Charris1, Jorly Mejia-Montilla1, Nadia Reyna-Villasmil2.1 Servicio de Obstetricia y Ginecología, Maternidad “Dr. Nerio Belloso”, Hospital “Dr. Urquinaona”, Maracaibo - Venezuela.2 Centro de Investigaciones Endocrino-Metabólicas “Dr. Félix Gómez”, Maracaibo – Venezuela. [ARTÍCULO ORIGINAL] Recibido: 31 de Diciembre de 2012. Aceptado: 05 de Abril de 2013.ResumenEl objetivo de la investigación fue determinar las modificaciones hemodinámicas y metabólicas maternas secundarias al uso de betametasona para la maduración pulmonar fetal. Se realizó una investigación de tipo explicativa, prospectiva y longitudinal con un diseño cuasi-experimental y una muestra no probabilística intencional de 106 pacientes que acudieron a la consulta pre-natal de alto riesgo del Hospital Central “Dr. Urquinaona". Una vez seleccionadas las pacientes se le administró inyecciones intramusculares de betametasona (12 mg) por dos días consecutivos. El valor de presión arterial sistólica presentó un leve aumento luego de la segunda medición y la tercera medición (p = ns). La presión arterial diastólica presentó aumento significativo durante la segunda medición y un nuevo aumento significativo en la tercera medición (p < 0,05). Se observaron aumentos significativos en el valor promedio de la frecuencia cardiaca luego de la segunda y tercera medición de betametasona (p < 0,05). No se encontraron modificaciones significativas en las concentraciones de glicemia, sodio y potasio entre las tres mediciones (p = ns). Se concluye que el uso de betametasona para inducir la maduración pulmonar fetal produce modificaciones hemodinámicas maternas acompañados de cambios metabólicos transitorios.Palabras claveBetametasona, Maduración Pulmonar fetal, Efectos maternos.AbstractThe objective of research was to determine maternal hemodynamic and metabolic modifications secondary to the use of betamethasone for fetal lung maturation. An explicative, prospective and longitudinal research was done with a quasi-experimental design and intentional non probabilistic sample of 106 patients who assisted to High Risk Antenatal Consult at Hospital Central “Dr. Urquinaona". Once patients were selected, two intramuscular injections of betamethasone (12 mg) were administered for two consecutive days. Systolic blood pressure presented a slight rise after second and third measurement (p = ns). Diastolic blood pressure presented a significant rise during second measurement and a new rise after third measurement (p < 0.05). There were observed significant rises in mean values of heart rates after second measurement and third measurements (p < 0.05). There were not found significant changes in glucose, sodium and potassium concentrations among three measurements (p = ns) It is concluded that the use of betamethasone for fetal lung maturation produced significantly in maternal hemodynamic changes and accompanied by transient metabolic changes.KeywordsBetametasone, Pulmonar maduration, Adverse effects.IntroducciónEl descubrimiento de Liggins y col. (1) que los esteroides tienen un papel importante en la maduración del feto durante el ultimo trimestre del embarazo ha llevado al uso rutinario del tratamiento con corticosteroides en el periodo prenatal, para tratar a las pacientes con amenaza de parto pretérmino. Diferentes estudios han descrito que el uso de corticosteroides en el periodo prenatal produjo una reducción significativa en la mortalidad neonatal, síndrome de dificultad respiratoria del recién nacido, hemorragia intraventricular y enterocolitis necrotizante asociadas al parto pretérmino (2,3).Estudios realizados en animales, por ejemplo, en ovejas cercanas al termino del embarazo se reportó que los corticosteroides producen una reducción significativa del flujo cerebral fetal (4), elevación sostenida de la presión arterial, aumentos de los valores basales de cortisol (5), aumento de la resistencia vascular y periférica (4,5), y alteración de la sensibilidad vascular a los factores derivados del endotelio (6). En el embarazo tardío en ratas, la dexametasona produce alteraciones de la inervación cardiaca y de la función beta-adrenérgica (7). Más aún, hallazgos experimentales demuestra que existe una alteración de la respuesta perinatal a la hipoxia la cual puede alterar la adaptación al trabajo de parto (8).El uso de algunos tipos de corticosteroides en el periodo prenatal ha demostrado que produce una considerable reducción en la frecuencia cardiaca y los movimientos corporales fetales después de la primera dosis (9). En algunos casos, las marcadas alteraciones de la frecuencia cardiaca fetal que se observan han sido mal interpretadas como sufrimiento fetal. Estos cambios temporales no parecen ser debidos a la hipoxemia inducida por los corticosteroides debido a que no se han encontrado cambio en los índices de flujo Doppler de los diferentes vasos fetales ni alteraciones en la frecuencia cardiaca fetal (10).En la actualidad solo existen datos clínicos limitados y conflictivos sobre la influencia del uso de corticosteroides en la función cardiovascular de la embarazada que los recibe. En los adultos se ha reportado que la dexametasona tiene una amplia variedad de efectos adversos sobre las funciones cardiovascular, metabólica y endocrina (11).La administración materna de dexametasona al final del embarazo induce solo efectos hemodinámicos transitorios, mientras que dosis bajas en ovejas embarazadas no producen efectos sobre la presión arterial. En contraste, la betametasona en monos causa una elevación aguda de la presión arterial por al menos 24 horas (12), aunque los efectos posteriores son desconocidos. Todo esto ha llevado a considerar los posibles efectos adversos maternos de la potencia excesiva de los esquemas actuales de dosificación de los corticoides sintéticos en la práctica clínica actual (13).El objetivo de la investigación fue determinar las modificaciones hemodinámicas y metabólicas maternas secundarias al uso de betametasona para la maduración pulmonar fetal.MetodologíaLa investigación de este estudio fue explicativa, prospectiva y longitudinal con un diseño cuasi-experimental y una muestra no probabilística intencional de 106 pacientes que acudieron a la consulta pre-natal de alto riesgo del Hospital Central “Dr. Urquinaona". El Comité de Ética del hospital aprobó la investigación y se obtuvo el consentimiento informado de todas las pacientes.Se incluyeron embarazadas entre 18 y 40 años de edad, con embarazos de 24 a 34 semanas de gestación, y embarazos de alto riesgo (por ejemplo, cirugías uterinas previas, tumoraciones uterinas) que ameritaron la administración de betametasona para la inducción de la maduración pulmonar fetal.Se excluyeron las pacientes con embarazadas con polihidramnios, hemorragia del tercer trimestre, sospecha de restricción del crecimiento intrauterino del feto (circunferencia cefálica, circunferencia abdominal y longitud del fémur menor del percentil 10 de referencia), síndrome de HELLP, alteraciones de la frecuencia cardiaca fetal, gestaciones múltiples, presencia de infección intrauterina o materna activa, enfermedad hipertensiva crónica o gestacional, enfermedad cardiaca, hepática, renal o sistémica crónica, diabetes mellitus pre o gestacional y hábito tabáquico. También se excluyeron a las pacientes que se negaron a participar en la investigación.115Una vez seleccionadas las pacientes se les administraron inyecciones intramusculares de betametasona (12 mg) por dos días consecutivos. Las mediciones de presión arterial y frecuencia cardiaca se realizaron en tres ocasiones: La primera medición, antes de la administración de la primera dosis de betametasona; la segunda medición, 24 horas después de la segunda y última inyección; y la tercera medición, siete días luego de la administración de la última dosis de betametasona para la maduración pulmonar fetal. La presión sanguínea y la frecuencia cardiaca se midieron en posición sentada después de 15 minutos de descanso.Figura 1. Valores promedio de presión arterial diastólica antes y después del uso de betametasona.Las muestras de sangre para la determinación de glucosa, sodio y potasio se recolectaron en todas las pacientes en las mismas tres ocasiones que se realizaron las mediciones hemodinámicas. Se tomaron las muestras (10 ml) de la vena antecubital y se dejaron coagular a temperatura ambiente, posteriormente fueron centrifugadas y almacenadas a -80ºC. Todas las mediciones fueron hechas por duplicado y el promedio de las dos mediciones fue el resultado final. La glucosa sérica se cuantificó por el método de la glucosa oxidasa. Las concentraciones séricas de sodio y potasio se determinaron utilizando colorimetría.Los resultados se presentan en tablas. Se utilizaron medidas absolutas y relativas. Una vez que se utilizó la prueba de Kolmogorov-Smirnov para evaluar el tipo de distribución de los datos, se confirmó que la distribución de estos era igual a la normal (p = ns). La comparación de las variables cuantitativas se realizó utilizando la prueba de ANOVA utilizando la post-prueba de Dunnett utilizando como control los valores de la primera medición (antes del uso de la betametasona). Se consideró p < 0,05 como estadísticamente significativa.ResultadosFigura 2. Valores promedio de frecuencia cardíaca antes y después del uso de betametasona.Se seleccionaron 106 pacientes que fueron sometidas a inyecciones de betametasona para inducir la maduración pulmonar fetal. La edad promedio de las pacientes fue de 22,6±5,1 años y la edad gestacional al momento del tratamiento fue de 31,8±3,0 semanas. 116En la tabla 1 se muestran las modificaciones hemodinámicas posteriores a las inyecciones de betametasona. El valor de presión arterial sistólica en la primera medición fue de 108,8±10,6 mmHg, observándose un leve aumento luego de la segunda medición (112,8±6,4 mmHg) y la tercera medición (113,7±4,3 mmHg), pero estas diferencias no se consideraron estadísticamente significativas (p = ns); ver figura 1. En cuanto a la presión arterial diastólica el valor de la primera medición fue de 64,9±7,3 mmHg, el cual presentó un aumento significativo luego de la segunda medición para alcanzar valores de 71,8±6,9 mmHg y un nuevo aumento significativo posterior a la tercera medición, siendo el valor promedio de 74,2±5,1 mmHg (p < 0,05). De igual forma, el valor promedio de la primera medición frecuencia cardiaca fue de 83,3±5,9 latidos por minuto, y luego de la segunda y tercera medición de betametasona se observaron aumentos significativos de los valores que alcanzaron 89,2±7,0 y 87,2±6,7 latidos por minutos, respectivamente (p < 0,05); ver figura 2.Con respecto a las modificaciones metabólicas (tabla 2), se observó que las inyecciones con betametasona producían aumentos de las concentraciones de glicemia en ayunas, ya que el valor de la primera medición fue de 78,1±10,6 mg/dL, las concentraciones aumentaron a 94,2±13,4 mg/dl durante la segunda medición y a 86,5±7,3 mg/dL luego de la tercera medición, pero esta variación no fue significativa (p = ns); ver figura 3. No se encontraron modificaciones significativas en las concentraciones de sodio y potasio entre los dos periodos de estudio y los valores iniciales (p = ns).Discusión117Clínicamente, tanto la betametasona como la dexametasona disminuyen significativamente la morbilidad y mortalidad neonatal. Además, el tratamiento con betametasona ha demostrado producir una mayor reducción en el síndrome de dificultad respiratoria, sepsis y mejores resultados de desarrollo neurológico en la infancia (14). La betametasona parece ser el corticosteroide óptimo para el uso en mujeres con amenaza de parto pretérmino, aún cuando sus efectos maternos sean marcados durante el uso de un esquema de dosis múltiple.Figura 3. Valores promedio de glicemia en ayunas antes y después del uso de betametasona.Tabla 1. Modificaciones hemodinámicas maternas de las inyecciones de betametasona.n=106PrimeraMedición(Antes de la primera dosis)SegundaMedición(24 horas después de la segunda dosis)TerceraMedición(7 días despuésde la segunda dosis)Presión arterial sistólica, mmHg87,5±8,384,7±9,885,4±10,6Presión arterial diastólica, mmHg135,1±12,7137,2±18,9142,9±19,9*Frecuencia cardiaca, latidos por minutos23,1±6,014,8±7,0*20,0±9,7* * p < 0,05 comparado con los valores iniciales.Un hallazgo clave de la investigación es que los cambios hemodinámicos después de la inyección de la betametasona son significativos más no dramáticos (un aumento máximo de aproximadamente 9% para la presión arterial diastólica y 5% de la frecuencia cardiaca). Aunque se observó un aumento significativo en los valores promedios de presión arterial diastólica pero no en la presión arterial sistólica, esta última presentó un aumento que, aunque no fue estadísticamente significativo, tienen una importancia clínica manifiesta, ya que se debe tener en cuenta al momento de la evaluación de la paciente para evitar la confusión con otras patologías comunes del embarazo. Los resultados de la presente investigación son similares a reportes previos que reportan un incremento sostenido de la presión y resistencia vascular que se observa por lo menos en las 48 horas siguientes después de la administración de pequeñas dosis endovenosas de corticosteroides en ovejas (5). Los datos de esta investigación son consistentes con los efectos del tratamiento a largo plazo observados con diferentes dosis en ovejas después de la segunda mitad de la gestación (15).Varios estudios han demostrado que el tratamiento materno con corticosteroides en el periodo prenatal eleva la presión arterial en neonatos, ratas adultas, y en fetos de ovejas y ovejas adultas (16). En el feto de ovejas, la administración de corticosteroides sintéticos incrementa la presión arterial, si se administra directamente tanto al feto o como a la madre (17). La betametasona puede inducir vasoconstricción en los lechos placentarios periféricos y umbilicales y se ha postulado al incremento en la resistencia vascular como el mecanismo responsable del incremento la presión arterial posterior a la inyección de betametasona (16). El incremento en la resistencia vascular parece no estar relacionado con los cambios en las catecolaminas circulantes, pero puede ocurrir, en parte, por la inhibición de vasodilatadores como la prostaciclina y el óxido nítrico, lo cual puede llevar a un exceso de liberación o sensibilidad a vasoconstrictores como la endotelina 1 (18). Se ha reportado un incremento en la circulación de angiotensina II y un incremento de la sensibilidad vascular a la angiotensina II en respuesta al cortisol, a la betametasona y a la dexametasona (19).En forma particular, la administración de glucocorticoides eleva la concentraciones de adrenalina y neuropéptido Y (NPY), tanto durante como después de la administración, al igual que eleva el número de receptores de endotelina subtipo A (6). Más aún, el incremento de la presión arterial puede también estar relacionado parcialmente con un incremento en la actividad del eje hipotálamo-hipófisis-suprarrenal, con un aumento sostenido en las concentraciones basales de cortisol en las 48 horas siguientes a la administración de la betametasona, pero con concentraciones normales de ACTH (5) por la hipercortisolema (19). Consistente con esa hipótesis, es conocido que la exposición a corticosteroides in utero (en ovejas al principio del embarazo) produce hipertensión que puede estar relacionada con los cambios en el sistema renina angiotensina (20).118Tabla 2. Modificaciones metabólicas maternas de las inyecciones de betametasona.n=106PrimeraMedición(Antes de la primera dosis)SegundaMedición(24 horas después de la segunda dosis)TerceraMedición(7 días despuésde la segunda dosis)Glicemia en ayunas, mg/dL78,1±10,294,2±13,486,5±7,3Sodio, mEq/L138,1±4,0139,5±4,9138,8±4,1Potasio, mEq/L4,2±0,54,5±0,64,5±0,5 El NPY también puede contribuir a acentuar la vasoconstricción en las pacientes que reciben corticosteroides por mecanismos endocrinos y neuro-moduladores. En animales adultos, el NPY ejerce una vasoconstricción potente y duradera por la acción directa sobre los receptores NPY-Y1 en la vasculatura periférica y/o potenciando los efectos de las sustancias vasoconstrictoras circulantes como las catecolaminas (21). Los corticosteroides no parecen estimular la liberación de catecolaminas sistémicas (16), pero se conoce que el incremento de las concentraciones locales en los tejidos, incluyendo el cerebro y el corazón (22). La exposición a los esteroides incrementa la sensibilidad vascular a las catecolaminas, tanto in vitro como in vivo, y la administración de corticosteroides sintéticos, como la dexametasona, ha probado aumentar la respuesta simpática (23, 24). Es posible que el aumento de la frecuencia cardiaca pueda estar relacionado con el incremento transitorio de las concentraciones de catecolaminas o existe un incremento de la sensibilidad a las concentraciones circulantes de catecolaminas.Es un hecho comprobado que la infusión de glucosa aumenta la frecuencia cardiaca, probablemente en respuesta al incremento de la tasa metabólica basal. Como se observó en la presente investigación mientras las concentraciones de glucosa se mantuvieron elevadas, la frecuencia cardiaca también se mantuvo elevada. Además, es conocido que los corticosteroides tienen un efecto cronotrópico directo, mediado por un aumento de la unión de los beta-adrenoreceptores (23). Padbury y col. (25) demostraron que los recién nacidos que recibieron corticosteroides en el periodo prenatal tuvieron un aumento significativo de la presión arterial, gasto y contractilidad cardiaca, a pesar de tener pre-cargas similares. En parte, eso puede ser debido a un incremento significativo en la generación de monofosfato de adenosina cíclico dependiente del receptor beta-adrenérgico.Estudios previos han demostrado que la aplicación de ciclos cortos de corticosteroides exógenos se asocia con un incremento de la glucemia y con resultados anormales en la prueba de tolerancia glucosada en las mujeres embarazadas sanas (26). Estos efectos son generalmente transitorios y son más evidentes si las pruebas se realizan en las siguientes 24 horas al suministro del fármaco (26). Sin embargo, Los resultados de esta investigación confirman que las concentraciones de glucosa alcanzan valores a las 24 horas después de la segunda dosis de betametasona que podrían llevar a un error diagnóstico de diabetes gestacional. Sin embargo, estos valores disminuyen en la mayoría de las ocasiones, aunque pueden observarse concentraciones elevadas hasta 7 días después de esta medición comparado con los valores inicialesLos esteroides reducen la sensibilidad a la insulina tanto en la administración aguda como crónica produciendo un incremento en las concentraciones de insulina. Estudios previos han demostrado que la administración de dexametasona en embarazadas no afecta las concentraciones circulantes de insulina y glucosa. Sin embargo, solo 1 mg de dexametasona fue administrado por vía oral cuatro veces al día por un promedio de 7,8 días (27), lo cual es substancialmente diferente al esquema propuesto internacionalmente y el utilizado en esta investigación. Datos de otra investigación demostraron que el régimen de uso actual de betametasona y dexametasona induce un incremento transitorio y no significativo en las concentraciones de glucosa e insulina 24 horas después de completar el tratamiento (24). Aunque el feto también es expuesto a altas concentraciones de glucosa y probablemente también de insulina, la naturaleza transitoria de estos cambios puede significar que no son importantes.Sin embargo, aún los incrementos transitorios de las concentraciones de glucosa e insulina pueden ser suficientes para alterar en forma permanente la homeostasis de la glucosa si ocurre en un momento crítico del desarrollo fetal. Tal coincidencia es más probable que ocurra con la administración de dosis repetidas de corticosteroides (y en especial de betametasona) en mujeres con riesgo continuo de parto pretérmino. Este efecto no se observa si los corticosteroides son administrados en la primera o segunda semana del embarazo en ratas. 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El Milagro.Maracaibo, Estado Zulia. VENEZUELA.Teléfono: 584162605233. Correo electronico sippenbauch@gmail.comModificaciones hemodinámicas y metabólicas maternas con betametasona. 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