Persistent Pulmonary Hypertension of The Newborn - UpToDate

6/5/2019 Persistent pulmonary hypertension of the newborn - UpToDate
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Hipertensión pulmonar persistente del recién nacido.

Autores: Ann R Stark, MD, Eric C Eichenwald, MD
Editor de la sección: Joseph A Garcia-Prats, MD
Editor Adjunto: Melanie S Kim, MD
Todos los temas se actualizan a medida que se dispone de nueva evidencia y se completa nuestro proceso de
revisión por pares .
Revisión de literatura vigente hasta: abr 2019. | Este tema se actualizó por última vez: 03 de diciembre de
2018.
INTRODUCCIÓN
La hipertensión pulmonar persistente del recién nacido (PPHN, por sus siglas en inglés) ocurre
cuando la resistencia vascular pulmonar (RVP) permanece anormalmente elevada después del
nacimiento, lo que da como resultado una derivación de la sangre de derecha a izquierda a través
de las vías circulatorias fetales. Esto a su vez conduce a una hipoxemia grave que puede no
responder a la asistencia respiratoria convencional. La prevalencia de PPHN se ha estimado en
1.9 por 1000 nacidos vivos [ 1 ].
Aquí se analiza la fisiopatología, las manifestaciones clínicas, el diagnóstico y el tratamiento de la

HPPN.
FISIOLOGÍA
Circulación fetal y postnatal : en el feto, los circuitos pulmonar y sistémico funcionan en

paralelo. Tanto el ventrículo derecho como el izquierdo (VD / VI) expulsan sangre a la aorta con la
perfusión posterior de la placenta, el órgano fetal de la respiración ( figura 1 ). El VD es
dominante, y la sangre se desvía de derecha a izquierda a través del foramen oval y el conducto
arterioso, en su mayoría sin pasar por el pulmón, que no participa en el intercambio de gases.
Por el contrario, la circulación postnatal madura opera en serie. Todo retorno venoso pasa a
través del lado derecho del corazón hacia el pulmón, donde ocurre el intercambio de gases. La
sangre oxigenada regresa al lado izquierdo del corazón y se bombea a la circulación sistémica
https://www-uptodate-com.puce.idm.oclc.org/contents/persistent-pulmonary-hypertension-of-the-newborn/print?sectionName=DIAGNOSIS&sea… 1/28
para el suministro de oxígeno a los tejidos. No se produce mezcla entre los dos lados de la
circulación.
Circulación de transición : los ajustes circulatorios importantes se producen al nacer a medida

que el órgano de intercambio de gases cambia de la placenta al pulmón. En circunstancias
normales, una caída progresiva de la resistencia vascular pulmonar (RVP) acompaña al aumento
inmediato de la resistencia vascular sistémica (RVS) que se produce después del nacimiento.
Durante un corto período, existe un patrón circulatorio de transición que combina características
de los patrones circulatorios tanto fetal como adulto. La disminución de la relación PVR / SVR da
como resultado un aumento constante del flujo sanguíneo pulmonar y la captación de oxígeno en
el pulmón.
El proceso de transición depende de varios factores. Los factores que contribuyen al aumento
postnatal en la RVS incluyen la extirpación de la placenta, el aumento repentino de catecolamina
asociado al nacimiento y el ambiente extrauterino relativamente frío. Los factores que promueven
la disminución postnatal en la RVP incluyen la expansión del pulmón al volumen normal en
reposo, el establecimiento de una ventilación alveolar adecuada y la tensión de oxígeno, y la
eliminación exitosa del líquido pulmonar fetal.
Las condiciones que interfieren con el declive postnatal normal en la relación PVR / SVR hacen
que la circulación transitoria persista y resulte en PPHN.
PATOGÉNESIS
PPHN se presenta principalmente en término o prematuros tardíos niños ≥34 semanas de

gestación. Tres tipos de anomalías de la vasculatura pulmonar subyacen en el trastorno:
subdesarrollo, mal desarrollo y mala adaptación [ 2 - 5 ]. La evidencia experimental y clínica
sugiere que la lesión de la circulación pulmonar en desarrollo puede interrumpir la señalización
del factor de crecimiento endotelial vascular (VEGF) y contribuir a estas anomalías [ 6 ].
Subdesarrollo : en las anomalías del subdesarrollo, el área de la sección transversal de la

vasculatura pulmonar se reduce, lo que resulta en una elevación relativamente fija de la
resistencia vascular pulmonar (PVR). El subdesarrollo ocurre con hipoplasia pulmonar asociada
con una variedad de condiciones. Estos incluyen hernia diafragmática congénita (CDH),
malformación congénita pulmonar (adenomatoide quística), agenesia renal, oligohidramnios que
acompañan a la uropatía obstructiva y restricción del crecimiento fetal. Aunque puede ocurrir
cierto grado de vasodilatación pulmonar postnatal, este mecanismo de adaptación es limitado.
Como resultado, el riesgo de mortalidad es mayor en esta categoría de pacientes. (Ver "Hernia
diafragmática congénita en el neonato" y"Malformación congénita de las vías respiratorias
pulmonares (adenomatoides quísticos)" y "Agenesia renal: diagnóstico prenatal" y "Visión general
de las anomalías congénitas del riñón y del tracto urinario (CAKUT)" e "Hipodisplasia renal" y
"Lactantes con restricción del crecimiento fetal (intrauterino)" .)
Mal desarrollo : el mal desarrollo es una perturbación que ocurre en los pulmones que
normalmente se desarrollan, incluyendo la ramificación y la diferenciación alveolar, y tienen un
número normal de vasos pulmonares. Las características incluyen engrosamiento anormal de la
capa muscular de las arteriolas pulmonares y extensión de esta capa en pequeños vasos que
normalmente tienen paredes delgadas y no células musculares [ 4 ]. La matriz extracelular que
rodea los vasos pulmonares también es excesiva. En este trastorno, se piensa que la
remodelación del lecho vascular pulmonar ocurre durante los primeros 7 a 14 días después del
nacimiento, con una caída acompañante en la RVP.
Los mecanismos que estimulan el mal desarrollo de la vasculatura pulmonar son inciertos, pero
los mediadores vasculares parecen desempeñar un papel. En un informe, por ejemplo, los bebés
con PPHN grave tuvieron, en comparación con controles sanos, concentraciones plasmáticas
más elevadas del endotelina 1 vasoconstrictor y concentraciones más bajas de monofosfato de
guanosina cíclica (que representan la estimulación de la guanilato ciclasa por el óxido nítrico
[NO], un vasodilatador que no se puede medir fácilmente) [ 7 ].
La predisposición genética puede influir en la disponibilidad de precursores para la síntesis de NO

y afectar la adaptación cardiopulmonar al nacer. Esto se ilustró en un informe en el que los
lactantes con hipertensión pulmonar (HP) tenían concentraciones plasmáticas más bajas de
arginina, un precursor de NO y un ciclo intermedio de urea, y metabolitos de NO que los lactantes
de control con dificultad respiratoria [ 8 ]. Un polimorfismo funcional del gen que codifica la
carbamoilfosfato sintetasa, que controla la etapa limitante de la velocidad en el ciclo de la urea, se
produjo con mayor frecuencia en todos los lactantes con dificultad respiratoria, con o sin HP, que
en la población general.
Las afecciones asociadas con la PPHN causada por el mal desarrollo vascular incluyen la
administración postparto, la tinción con meconio y el síndrome de aspiración de meconio (MAS).
En estos trastornos, la vasculatura pulmonar responde pobremente a los estímulos que
normalmente producen una disminución de la RVP, como el aumento de la tensión alveolar de
oxígeno y el establecimiento de una ventilación efectiva. (Ver "Características clínicas y
diagnóstico del síndrome de aspiración de meconio" .)
Los trastornos que producen una perfusión excesiva del pulmón fetal también pueden
predisponer al mal desarrollo vascular. Incluyen el cierre prematuro del conducto arterioso (por
ejemplo, causado por los antiinflamatorios no esteroideos [AINE]) o foramen oval, alta resistencia
vascular placentaria y drenaje venoso pulmonar anómalo total. Se ha propuesto que el uso de
AINE en el embarazo está asociado con la PPHN debido a la constricción ductal en el feto [ 9 ].
Sin embargo, los datos posteriores están en conflicto sobre si existe una verdadera asociación
entre el uso materno de AINE y PPHN [ 10,11 ].
Mala adaptación : en la mala adaptación, el lecho vascular pulmonar se desarrolla normalmente.

Sin embargo, las condiciones perinatales adversas causan una vasoconstricción activa e
interfieren con la caída postnatal normal en la RVP. Estas afecciones incluyen depresión perinatal,
enfermedades del parénquima pulmonar e infecciones bacterianas, especialmente las causadas
por el estreptococo del grupo B (SGB). El mecanismo del aumento de PVR con infección por GBS
es la activación de mediadores vasoactivos por componentes de fosfolípidos bacterianos. En un
estudio en corderos recién nacidos, se indujo PH por infusión de cardiolipina y fosfatidilglicerol,
fosfolípidos localizados principalmente en la pared celular de GBS [ 12 ]. (Consulte "Infección por
estreptococos del grupo B en recién nacidos y lactantes", sección "Neumonía" .)
EPIDEMIOLOGÍA
La incidencia de PPHN es aproximadamente del 0,2 por ciento, como lo demuestra un estudio
poblacional de bebés nacidos con ≥34 semanas de gestación sin cardiopatía congénita en
California [ 13 ]. En este informe basado en una base de datos estatal que vincula los egresos
hospitalarios maternos e infantiles, el análisis de regresión múltiple identificó los siguientes
factores de riesgo para la HPPN: edad gestacional 34 a <37 semanas (es decir, recién nacidos
prematuros), raza negra materna, lactantes que eran grandes o pequeños para la edad
gestacional, y madres con diabetes preexistente y gestacional, obesidad y edad avanzada. Los
factores asociados con un menor riesgo de PPHN incluyeron el sexo femenino, la etnicidad
hispana y la gestación múltiple.
MANIFESTACIONES CLÍNICAS La
PPHN suele aparecer en recién nacidos a término, aunque también puede presentarse en
lactantes prematuros tardíos o después del parto [ 1 ]. Aunque se ha pensado que el diagnóstico
es raro en los bebés con muy bajo peso al nacer (VLBW) (BW <1500 g) [ 14 ], los datos de un
estudio retrospectivo y multicéntrico sugieren que la prevalencia de PPHN ha aumentado en los
bebés extremadamente prematuros (edad gestacional [ GA] <28 semanas) y el riesgo aumenta
con la disminución de GA [ 15 ].
La PPHN se caracteriza por sus características tanto prenatales como neonatales, como se
ilustra en un estudio de 385 bebés con PPHN (media de GA de 39 semanas) atendidos en
centros participantes en la Red de Investigación Neonatal del Instituto Nacional de Salud Infantil y
Desarrollo Humano (NICHD) [ 1 ] .
Los factores prenatales - hallazgos prenatales asociados con hipertensión pulmonar

persistente se cree que son signos de asfixia intrauterina y perinatal. Estos incluyen anomalías de
la frecuencia cardíaca fetal (es decir, bradicardia y taquicardia) y líquido amniótico teñido de
meconio [ 1 ]. La exposición intrauterina de los inhibidores selectivos de la recaptación de
serotonina (ISRS) durante la segunda mitad del embarazo también se ha asociado con un riesgo
seis veces mayor de PPHN en comparación con los bebés no expuestos. (Consulte "Exposición
prenatal a los inhibidores selectivos de la recaptación de serotonina (ISRS) y los inhibidores de la
recaptación de serotonina-norepinefrina (IRSN): resultados neonatales", sección "Hipertensión
pulmonar persistente del recién nacido" .)
Aunque la PPHN es rara en los recién nacidos prematuros con VLBW, la ruptura prematura
prolongada de las membranas (PPROM) parece ser una característica común. En un estudio
prospectivo de 765 recién nacidos prematuros (AG ≤32 semanas), se observó PPROM en los 17
pacientes con evidencia ecocardiográfica de hipertensión pulmonar (HP) [ 14 ].
Hallazgos neonatales : la mayoría de los neonatos con PPHN se presentan dentro de las
primeras 24 horas de vida con signos de dificultad respiratoria (p. Ej., Taquipnea, retracciones y
gruñidos) y cianosis. En el estudio NICHD, más de la mitad de los lactantes tenían puntuaciones
de apgar bajas y casi todos los pacientes recibieron intervenciones en la sala de partos, incluida
la terapia con oxígeno, ventilación con bolsa y mascarilla e intubación endotraqueal [ 1 ].
Como se señaló anteriormente, el examen físico se caracteriza por cianosis y signos de dificultad
respiratoria. Además, puede haber tinción de meconio en la piel y las uñas, lo que puede ser
indicativo de estrés intrauterino. El examen cardíaco de niños con PPHN puede ser notable por
un impulso precordial prominente y un segundo sonido cardíaco estrecho y acentuado. En el
borde esternal inferior izquierdo a veces se escucha un soplo sistólico áspero consistente con
insuficiencia tricuspídea.
La mayoría de los bebés también tienen otros diagnósticos respiratorios asociados con la PPHN.
En la cohorte NICHD mencionada anteriormente, se observaron los siguientes trastornos
respiratorios primarios y sus frecuencias relativas [ 1 ]:
● Síndrome de aspiración de meconio (MAS, 41 por ciento) (ver "Características clínicas y

diagnóstico del síndrome de aspiración de meconio" )
● Neumonía (14 por ciento) (ver "Neumonía neonatal" )
● Síndrome de dificultad respiratoria (SDR, 13 por ciento) (consulte "Fisiopatología,
manifestaciones clínicas y diagnóstico del síndrome de dificultad respiratoria en el recién
nacido" )
● Neumonía y / o SDR, cuando no pudieron distinguirse (14 por ciento)
● Hernia diafragmática congénita (CDH, 10 por ciento) (ver "Hernia diafragmática congénita en
el neonato" )
● Hipoplasia pulmonar (4 por ciento)
● Idiopático (no se observa ninguna otra afección respiratoria, 17 por ciento)
En el estudio poblacional de California mencionado anteriormente, la infección fue la causa más

común de PPHN [ 13 ].
Pruebas de laboratorio iniciales : la mayoría de los pacientes se someterán a pruebas

iniciales que incluyen exámenes de oximetría de pulso, muestreo de gases en sangre arterial y
radiografía de tórax. Sin embargo, el diagnóstico se hace generalmente por ecocardiografía. (Vea
'Diagnóstico' a continuación.)
Evaluación de oximetría de pulso - valoración del pulso oximetría generalmente demuestra

una diferencia de más de 10 por ciento entre el pre y posductal (pulgar derecho y, o bien dedo
gordo del pie) la saturación de oxígeno. Este diferencial se debe a una derivación de derecha a
izquierda a través del ductus arterioso permeable (PDA). Sin embargo, es importante reconocer
que la ausencia de un gradiente pre- y postductal en la oxigenación no excluye el diagnóstico de
PPHN, ya que la derivación de derecha a izquierda puede ocurrir predominantemente a través del
foramen oval en lugar de la PDA.
Gasometría arterial : una muestra de gas en sangre arterial generalmente mostrará una baja
presión arterial parcial de oxígeno (PaO 2 por debajo de 100 mmHg en pacientes que reciben una
concentración de oxígeno inspirado al 100 por ciento), particularmente muestras que son
postductales. Sin embargo, a diferencia de los bebés con lesiones cianóticas, muchos bebés con
PPHN tienen al menos una medición de PaO 2 > 100 mmHg al principio del curso de su
enfermedad. La presión arterial parcial del dióxido de carbono (PaCO 2 ) es normal en niños sin
enfermedad pulmonar acompañante. La derivación de derecha a izquierda de la sangre a través
del PDA también se puede documentar en las diferencias en PaO 2entre las muestras obtenidas
de la arteria radial derecha (muestra preductal) y la arteria umbilical (muestra posductal).
(Consulte "Entrega de oxígeno y control de oxígeno en el recién nacido", sección "Recolección de
muestras" .)
Radiografía de tórax : la radiografía de tórax suele ser normal o muestra los hallazgos de
una afección pulmonar asociada (p. Ej., Enfermedad del parénquima, fuga de aire o CDH). El
tamaño del corazón suele ser normal o ligeramente agrandado. El flujo sanguíneo pulmonar
puede parecer normal o reducido.
DIAGNÓSTICO
El diagnóstico definitivo de PPHN se realiza mediante ecocardiografía. La ecocardiografía es una

prueba esencial en cualquier infante con cianosis no explicada que no se explica por la
enfermedad pulmonar parenquimatosa, para excluir la enfermedad cardíaca estructural y
confirmar un diagnóstico de PPHN.
En la PPHN, la ecocardiografía muestra una anatomía cardíaca estructural normal con evidencia
de hipertensión pulmonar (HP) (p. Ej., Tabique ventricular aplanado o desplazado). Los estudios
Doppler muestran derivaciones de derecha a izquierda a través del conducto arterioso y / o
foramen oval permeables. La medición Doppler de onda continua de la velocidad de un chorro de
regurgitación tricuspídea (TR) (si está presente) mediante una ecuación de Bernoulli modificada
se puede usar para estimar la presión sistólica del ventrículo derecho (VD). En ausencia de
obstrucción del flujo de salida del VD, se puede calcular la presión sistólica de la arteria pulmonar
(diferencia de presión pico = 4 x [velocidad máxima de TR] 2 ), que está elevada en pacientes con
PPHN [ 5 ]. Además, se puede utilizar la ecocardiografía para evaluar Función ventricular, que
puede estar alterada.
Gravedad de la HP : la ecocardiografía también puede proporcionar una estimación de la

gravedad de la hipertensión pulmonar (HP).
estimación
● La de la presión del ventrículo derecho (RVp), mediante evaluaciones del chorro TR
y / o cambios en la posición septal, se compara con la presión arterial sistémica (PA) y se
determina el grado de derivación del conducto arterioso y / o auricular . Las estimaciones de
severidad son las siguientes:
• PPHN leve a moderada: la RVp estimada se encuentra entre la mitad a tres cuartos de la
PA sistémica
• PPHN de moderada a grave: la RVp estimada es mayor que tres cuartos de la PA

sistémica pero menor que la BP sistémica
• PPHN grave: RVp estimado mayor que la PA sistémica
evidencia
● La de disfunción del VD sugiere una HP grave
evidencia
● La de disfunción biventricular puede representar un insulto global (por ejemplo,
depresión perinatal)
DIAGNÓSTICO DIFERENCIAL
El diagnóstico diferencial de PPHN incluye:
● Cardiopatía congénita cianótica (CHD), que se distingue de la PPHN por ecocardiografía.

(Consulte "Causas cardíacas de la cianosis en el recién nacido" y "Diagnóstico y tratamiento
inicial de la cardiopatía cianótica en el recién nacido" .)
● Enfermedad pulmonar parenquimatosa primaria aislada, como neumonía neonatal, taquipnea

transitoria del recién nacido (TTN) y síndrome de dificultad respiratoria (SDR). Estos
trastornos generalmente se diferencian de la PPHN por el entorno clínico y la radiografía de
tórax. Sin embargo, como se señaló anteriormente, la mayoría de los pacientes con PPHN
también tendrán un trastorno pulmonar asociado. En estos pacientes, la ecocardiografía
confirma el diagnóstico de PPHN. (Consulte "Descripción general de la dificultad respiratoria
neonatal: trastornos de la transición", sección "Características clínicas" y "Descripción
general de la dificultad respiratoria neonatal: trastornos de la transición", sección "Radiografía

de tórax" .)
● La sepsis se distingue por el entorno clínico, los hemocultivos positivos y la ecocardiografía.

Sin embargo, la PPHN puede aparecer como un componente de la sepsis en un neonato.
(Consulte "Características clínicas, evaluación y diagnóstico de la sepsis en recién nacidos
prematuros a término y prematuros", sección "Manifestaciones clínicas" ).
● La displasia capilar alveolar con desalineación de las venas pulmonares (ACD-MPV, por sus
siglas en inglés) es un trastorno raro que puede tener una presentación similar a la PPHN
severa de hipoxia severa que es refractaria a la atención de apoyo general. Sin embargo, los
bebés con ACD-MPV típicamente tienen un período inicial de estabilidad y desarrollan una
hipoxemia grave más tarde que la PPHN después de las primeras horas o días de vida. Si se
sospecha un diagnóstico de ACD-MPV, se necesita una evaluación adicional que incluya
cateterización y biopsia de pulmón para confirmar el diagnóstico. (Ver "Clasificación de la
enfermedad pulmonar difusa (enfermedad pulmonar intersticial) en lactantes y niños",
sección sobre 'Displasia alveolar capilar con desalineación de las venas pulmonares'
y"Enfoque para el lactante y el niño con enfermedad pulmonar difusa (enfermedad pulmonar
intersticial)", sección "Enfoque diagnóstico" .
GESTIÓN
La gestión de PPHN consiste en lo siguiente:
● Atención cardiorrespiratoria de apoyo general.
● En casos graves, o en aquellos que no responden a las medidas de apoyo, otras

intervenciones incluyen el uso de agentes vasodilatadores (por ejemplo, óxido nítrico
inhalado [iNO]) que reducen la proporción de resistencia vascular pulmonar a sistémica
(PVR / SVR). o la oxigenación por membrana extracorpórea (ECMO) que proporciona una
oxigenación adecuada del tejido hasta que la PVR cae.
● Tratamiento específico para cualquier enfermedad pulmonar parenquimatosa asociada (p.

Ej., Tratamiento con antibióticos para la neumonía o surfactante para el síndrome de
dificultad respiratoria neonatal [SDR]). (Consulte "Neumonía neonatal", sección sobre
"Tratamiento" y "Prevención y tratamiento del síndrome de dificultad respiratoria en recién
nacidos prematuros" .)
Evaluación de la gravedad utilizando el índice de oxigenación - El índice de oxigenación

(OI) se utiliza para evaluar la gravedad de la hipoxemia en PPHN y para guiar el momento de las
intervenciones, tales como la administración de iNO o soporte ECMO. La OI se calcula de la
siguiente manera:
OI = [presión media de la vía aérea x FiO 2 ÷ PaO 2 ] x 100
En la mayoría de los casos, cuando se usa la OI, el bebé recibe una fracción de oxígeno
inspirado (FiO 2 ) de 1 y se lo ventila mecánicamente. Por lo tanto, la OI puede calcularse
fácilmente a partir de la presión media de la vía aérea (MAP) que se muestra en el ventilador y la
presión arterial parcial de oxígeno (PaO 2 ).
Una OI alta indica insuficiencia respiratoria hipoxémica grave. Un recién nacido a término o
prematuro tardío con una OI ≥25 debe recibir atención en un centro donde la ventilación
oscilatoria de alta frecuencia (HFOV), iNO y ECMO están disponibles además de la atención de
apoyo general [ 16 ].
En pacientes con OI <25, la atención de apoyo general suele ser adecuada y generalmente no se
requiere ninguna intervención invasiva.
Medidas de soporte - El enfoque general para el cuidado es similar para todos los lactantes y
comienza con la identificación de factores de riesgo y la anticipación de posibles enfermedades.
Los bebés deprimidos al nacer deben ser resucitados rápidamente y monitoreados de cerca para
asegurar una adecuada oxigenación y ventilación. Debido a que la sepsis puede estar asociada
con la PPHN, se deben obtener hemocultivos y se debe iniciar una terapia antimicrobiana
empírica. Todos los recién nacidos con mala apariencia deben ser atendidos en un ambiente
térmico neutral para minimizar el consumo de oxígeno. (Ver "Descripción de la dificultad
respiratoria neonatal: trastornos de la transición" .)
Las medidas cardiorrespiratorias generales pueden revertir o prevenir un mayor aumento de la

vasoconstricción pulmonar e incluyen lo siguiente:
● oxígeno suplementario
● ventilación mecánica
● Fluidoterapia y agentes inotrópicos para el soporte circulatorio.
● Corrección de acidosis.
Oxygen — Oxygen is a pulmonary vasodilator and it should be initially administered in a

concentration of 100 percent to infants with PPHN in an attempt to reverse pulmonary
vasoconstriction. However, because the administration of high oxygen concentrations, even for a
short time period, may cause lung injury and there is no advantage to maintaining an elevated
PaO2, oxygen concentration should be adjusted to maintain preductal oxygen saturation target of
90 to 95 percent. Although uncommon in PPHN, persistent hyperoxemia should be avoided.
If the oxygen saturation cannot be maintained above 90 percent, other interventions to preserve
adequate tissue oxygenation include maintenance of a hemoglobin concentration between 15 and
16 g/dL and optimizing circulatory function. If these measures do not result in adequate
oxygenation (assessed by calculating the oxygenation index), more directed/invasive measures

(eg, iNO or ECMO) are required.
Assisted ventilation — Because hypercarbia and acidosis increase PVR, we initially attempt
to establish and maintain normal ventilation (arterial partial pressure of carbon dioxide [PaCO2] 40
to 45 mmHg). As the infant's oxygenation and ventilatory status become more stable, we maintain
PaCO2 in the range of 40 to 50 mmHg to minimize lung injury associated with high tidal volumes.
The strategy of ventilator support depends upon the presence or absence of pulmonary
parenchymal disease, and the infant's response to treatment.
● In infants with no associated lung disease, hypoxemia is caused by right-to-left shunting

rather than ventilation-perfusion imbalance. As a result, hypoxemia may not respond to
conventional ventilator maneuvers. In this circumstance, strategies that elevate MAP may
actually impede cardiac output and increase PVR. Thus, we minimize MAP by using low
inspiratory pressures and short inspiratory times or volume targeted ventilation. However, it is
essential to maintain adequate lung recruitment with modest levels of positive end-expiratory
pressure (PEEP).
● When PPHN is associated with lung disease, atelectasis and the resulting maldistribution of
ventilation may exacerbate high PVR. Assisted ventilation with PEEP is used to recruit
atelectatic segments, maintain adequate resting lung volume, and ensure appropriate
oxygenation and ventilation. When lung disease is severe, or ventilator peak pressures reach
28 to 30 cm H2O, we usually use HFOV. In a randomized trial of HFOV and iNO in patients
with severe PPHN, combined therapy with HFOV and iNO was more effective than treatment
with HFOV or iNO only, with a lower rate of death or ECMO treatment [17]. (See "Mechanical
ventilation in neonates", section on 'High-frequency ventilation'.)
Infants with PPHN may breathe out of synchrony with the ventilator which may cause worsening
hypoxemia. A patient-triggered ventilator mode may improve synchrony. If asynchrony persists, we
add an opioid analgesic, (See 'Sedation' below.)
Sedation — Pain and agitation cause catecholamine release, resulting in increased PVR and
increased right-to-left shunting. In addition, agitation may result in ventilator asynchrony which can
worsen hypoxemia. In patients with agitation and asynchrony that persists on a patient-triggered
ventilator mode, we add an opioid analgesic. Therapeutic choices include intravenous (IV)
morphine sulfate (loading dose of 100 to 150 mcg/kg over one hour followed by a continuous
infusion of 10 to 20 mcg/kg per hour) or fentanyl (1 to 5 mcg/kg per hour). (See "Prevention and
treatment of neonatal pain", section on 'Opioid therapy'.)
If dyssynchronous breathing and severe hypoxemia persist and a specific cause cannot be
identified (eg, airway obstruction or air leak), we may use neuromuscular blockade. However, we
avoid this intervention if at all possible because of potential adverse effects [1,18].
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Circulatory support — In patients with PPHN, right-to-left shunting increases as cardiac

output and systemic blood pressure (BP) decrease. Thus, maintaining optimal cardiac output and
systemic BP is important to reduce the right-to-left shunting and to maintain adequate tissue
oxygenation. Systemic BP targets are set at the upper limits of normal (mean BP 45 to 55 mmHg;
systolic BP 50 to 70 mmHg) because the pulmonary arterial pressure in patients with PPHN is at
or near normal systemic levels. This is accomplished by:
● Adequate vascular volume should be maintained with IV fluids. Transfusion of packed red
blood cells usually is required to replace blood lost from sampling and to optimize tissue
oxygen delivery, especially in patients with marginal oxygenation. In general, we maintain
hemoglobin concentration above 15 g (hematocrit above 40 to 45 percent).
● Vasopressor support usually is needed in patients with PPHN [19]. Dopamine has been the
most commonly used medication in neonates requiring pharmacologic inotropic support. In
our centers, we begin with IV infusion of dopamine at a starting dose of 2.5 mcg/kg per
minute and titrate the infusion rate (usually to a maximum dose of 20 mcg/kg per minute) to
maintain the mean arterial BP at a targeted level that minimizes right-to-left shunting. Little
evidence exists comparing the effects of dopamine with other alternative inotropic agents in
PPHN. Dobutamine may improve cardiac output if ventricular dysfunction is present, but does
not reliably increase BP in neonates. Epinephrine can increase both systemic BP and left
ventricular (LV) output [20] but increased LV afterload due to increased PVR may exacerbate
right ventricle (RV) afterload.
● If the echocardiography demonstrates RV or LV dysfunction, IV milrinone in conjunction with

iNO may facilitate reduction in PVR while enhancing myocardial performance and forward
flow of blood [21]. However, evidence of safety or efficacy of milrinone is lacking in neonates
with PPHN and it is unclear whether this agent should be used in treating PPHN. Of note,
hypotension is a contraindication for use. (See 'Severity of PH' above.)
Correction of acidosis — Acidosis increases PVR and attempts should be made to maintain
partial pressure of carbon dioxide (PCO2) values between 40 and 50 mmHg and improve
metabolic acidosis by cautious correction of a severe base deficit, if present. Sodium acetate may
be added to infused IV fluids at a dose of 2 to 3 mEq/kg per day. Rapid infusion of sodium
bicarbonate in face of impaired ventilation may worsen intracellular acidosis and is not
recommended [22,23]. (See "Approach to the child with metabolic acidosis", section on
'Neonates'.)
Evidence of benefit of alkali therapy in neonatal respiratory disease remains lacking [24,25].
Hyperventilation and/or IV administration of high doses of alkali therapy (eg, sodium bicarbonate)
to maintain "controlled" alkalosis is not recommended, as persistent alkalosis may be associated
with reduced cerebral blood flow and impaired release of oxygen from hemoglobin.
Surfactant — Surfactant therapy does not appear to be effective when PPHN is the primary
diagnosis [26]. However, it should be considered in patients with associated parenchymal lung
disease, in whom there is either a suspected surfactant deficiency (eg, neonatal RDS) or
impairment (meconium aspiration syndrome [MAS]) [26,27]. (See "Prevention and treatment of
respiratory distress syndrome in preterm infants", section on 'Surfactant therapy' and "Prevention
and management of meconium aspiration syndrome", section on 'Surfactant'.)
Interventions for severe cases — In severe cases, general supportive care is often insufficient to
maintain adequate oxygenation. Infants with OI greater than 25 despite the use of HFOV are
candidates for iNO therapy or other vasodilatory agents that decrease PVR. Patients who fail to
respond to these agents may require ECMO. (See 'Assessment of severity using oxygenation
index' above.)
Inhaled nitric oxide
Efficacy — Inhaled nitric oxide (iNO) improves oxygenation and reduces the need for
ECMO in term and late preterm infants with severe PPHN (defined as an OI ≥25) as illustrated by
the following clinical trials [17,28-33].
● In a NICHD Neonatal Research Network trial of 235 infants with gestational age (GA) ≥34
weeks who had severe hypoxic respiratory failure (OI ≥25) and did not have congenital
diaphragmatic hernia (CDH), infants randomly assigned to iNO (initial dose 20 ppm) had a
reduction in the composite primary endpoint of death within 120 days or need for ECMO
therapy compared with controls who received 100 percent oxygen (46 versus 64 percent;
relative risk [RR] 0.72, 95% CI 0.57-0.91) [28]. This difference was entirely due to a
decreased requirement for ECMO (39 versus 54 percent), as there was no difference in
mortality between groups.
● In another trial of 248 neonates (GA >34 weeks) with severe respiratory failure (OI >25), the
use of ECMO was lower in patients who received iNO compared with controls (38 versus 64
percent). The 30-day mortality rate was similar for both groups.
Additional evidence of the benefit of iNO was provided by a systematic review of the literature that
showed the beneficial effect of iNO therapy compared with placebo in near-term and term infants
with respiratory failure [33]. One limitation of this review regarding its application to PPHN is that it
included all trials for infants with respiratory failure, and echocardiographic evidence of PPHN was
not always available. Nevertheless, the authors concluded that the following results were not
affected by whether there was or was not clear echocardiographic evidence of PPHN.
● There was a reduction in the combined outcome of death or need for ECMO. However, this
reduction was due to a reduction in use of ECMO and there was no difference in mortality
between the two groups.
● Oxygenation improved in 50 percent of infants who received iNO. The OI decreased by a

weighted mean value of 15.1 within 30 to 60 minutes after commencing iNO therapy, and
there was also a mean increase in arterial partial pressure of oxygen (PaO2) of 53 mmHg.
● iNO therapy did not appear to be beneficial in patients with CDH.
However, iNO may not be effective in patients with milder PPHN. In a randomized trial, early
initiation of iNO in infants with mild to moderate respiratory impairment with OI between 15 and 25
compared with routine initiation at OI >25 did not reduce the incidence of mortality or the need for
ECMO therapy [34]. It also did not affect the outcomes of neurodevelopment and hearing of
surviving infants evaluated at 18 to 24 months of age [35]. As a result, iNO is not recommended
for infants with moderate respiratory distress and should be reserved for infants with severe
respiratory failure with an OI >25.
Mode of action — Endogenous NO regulates vascular tone by causing relaxation of

vascular smooth muscle. Exogenous iNO is a selective pulmonary vasodilator that acts by
decreasing the pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio [36].
Oxygenation improves as vessels are dilated in well-ventilated parts of the lung, thereby
redistributing blood flow from regions with decreased ventilation and reducing intrapulmonary
shunting. In the circulation, NO combines with hemoglobin and is rapidly converted to
methemoglobin and nitrate. As a result, there is little effect on SVR and systemic blood pressure.
Potential toxicity — Potential toxicity of iNO includes methemoglobinemia secondary to

excess iNO concentrations or impaired metabolism, pulmonary injury related to increased levels of
nitrogen dioxide during administration, and contamination of ambient air. However, iNO appears to
be safe when administered in the established therapeutic dosing range for PPHN and with
appropriate monitoring [33,37]. Bleeding times are prolonged in newborns treated with iNO
because of inhibition of platelet function, although clinically significant bleeding has not been
observed in term or late preterm infants [38]. (See 'Our approach' below.)
Congenital diaphragmatic hernia — iNO does not appear to be of long-term benefit in

infants with CDH and it use in neonates with CDH is discussed separately. (See "Congenital
diaphragmatic hernia in the neonate", section on 'Postnatal management'.)
Preterm infants — Routine use of iNO for respiratory failure in preterm infants <34 weeks
gestation is not recommended [39,40]. Respiratory failure in most such infants is a result of
primary lung disease with ventilation/perfusion mismatch due to surfactant deficiency. However,
because pulmonary hypertension does occur in a small proportion of very low birth weight (VLBW)
infants (BW <1500 g), it has been thought that select VLBW infants with hypoxic respiratory failure
(OI >25) with echocardiographic evidence of PPHN, who are unresponsive to surfactant therapy
and conventional respiratory care, may benefit from iNO therapy [14,32]. But iNO was not found to
be beneficial in a retrospective large case control study of mechanically ventilated preterm infants
born at 22 to 29 weeks gestation [40]. In this study that matched infants based on propensity
score to patients who did not received iNO, there was no difference in mortality. A subanalysis of
patients with PPHN showed no effect of iNO on mortality. Of note, iNO exposure was associated
with higher mortality for patients with RDS alone. (See "Prevention and treatment of respiratory
distress syndrome in preterm infants", section on 'Inhaled nitric oxide'.)
As a result, until there is further information that identifies a subset of preterm infants for whom
iNO is beneficial, iNO is not recommended for preterm infants as it remains an unproven and
expensive intervention.
Our approach — We begin iNO therapy in term or late preterm infants (GA ≥34 weeks) with
severe hypoxemic respiratory failure, defined as an OI ≥25 with maximum respiratory support
using conventional mechanical ventilation or HFOV. Prior to initiating treatment, we perform
echocardiography to confirm the diagnosis of PPHN and exclude congenital heart disease (CHD).
(See 'Diagnosis' above.)
We recommend an initial iNO dose of 20 ppm [28,29,41]. We do not recommend doses above this
level because higher doses have not been accompanied by improved response, but have been
associated with elevated methemoglobin and nitrogen dioxide levels. In infants who respond, an
improvement of approximately 20 percent in PaO2 or arterial oxygen saturation (SaO2) levels
typically occurs within 15 to 20 minutes. The iNO concentration is decreased slowly as
oxygenation improves [42]. In general, we initially wean supplemental oxygen concentration,
maintaining SaO2 greater than 90 percent; when supplemental oxygen concentration is at or less
than 60 percent, we begin to wean iNO concentration. Patients who respond to iNO typically
require treatment for three to four days, although some require longer courses.
Our centers also follow the recommendations published by the American Academy of Pediatrics
(AAP) for the use of iNO in infants with severe hypoxemic respiratory failure [16]:
● Care of patients in centers with personnel experienced with multiple modes of respiratory
support, rescue therapies, and use of iNO.
● Availability of ECMO at the center, or an established mechanism for timely transfer of infants
to an ECMO center.
● Performance of an echocardiogram to exclude the diagnosis of CHD.
● Use of iNO according to the indications, dosing, administration, and monitoring guidelines on
the product label.
Although some centers measure methemoglobin levels, we routinely do not measure

methemoglobin, as the risk of toxicity is low when using a maximum iNO concentration of 20 ppm.
Extracorporeal membrane oxygenation — Approximately 40 percent of infants with severe

PPHN remain hypoxemic on maximal ventilatory support despite administration of iNO [28]. In
these patients who fail to respond to iNO, ECMO therapy should be considered. The goal of this
treatment is to maintain adequate tissue oxygen delivery and avoid irreversible lung injury from
mechanical ventilation while PVR decreases and pulmonary hypertension resolves.
Criteria for institution of ECMO include an elevated OI that is consistently ≥40. However, because
MAPs are higher on HFOV than conventional ventilation, some clinicians wait until OI is ≥60 when
HFOV is used.
Most patients with PPHN are weaned from ECMO within seven days [43]. However, two or more
weeks occasionally may be necessary for adequate remodeling of the pulmonary circulation in
severe cases. Patients who fail to improve may have an irreversible condition, such as alveolar
capillary dysplasia (ACD) [44] or severe pulmonary hypoplasia.
In one large series from a single institution from 2000 to 2010, the survival rate following ECMO
support was 81 percent [43].
Other vasodilatory agents — Although iNO and ECMO have improved outcome for many
infants with PPHN, there still remain those who do not respond to these interventions. In addition,
these modalities are expensive and unavailable in many regions of the world.
Sildenafil — Sildenafil, a phosphodiesterase inhibitor type 5, is an agent that has been

shown to selectively reduce pulmonary vascular resistance in both animal models and adult
humans. It has also been reported to be successful in the treatment of infants with PPHN [45-49].
In a systematic review, meta-analysis of three studies that included 77 patients showed enteral
sildenafil therapy compared with placebo was associated with a reduction in mortality (RR 0.20,
95% CI 0.07-0.57) and improved oxygen levels [50]. These three studies were performed in
resource-limited settings, in which iNO and high frequency ventilation were not available.
An open-label dose-escalation trial of a continuous IV infusion of sildenafil was conducted in 36

neonates between 48 hours and 7 days of age with PPHN and an OI >15 [51]. In patients who
received higher doses of sildenafil, OI improved from 28.7 to 19.3 after four hours of continuous
infusion. There was one death (which was not considered related to sildenafil), and one patient
required ECMO. Six of seven infants given sildenafil prior to treatment with iNO survived to
discharge with no need for iNO or ECMO. Six treatment-related adverse events were reported in
five patients, including five hypotensive episodes (three of which required discontinuation of
therapy) and the development of patent ductus arteriosus with left-to-right shunting in one patient.
In 2012, the US Food and Drug Administration (FDA) issued a warning that sildenafil not be
prescribed to children with pulmonary arterial hypertension (PAH) because of reports of associated
mortality with administration of high doses of sildenafil in children between 1 and 17 years of age,
and that low doses of this drug were not effective in improving the exercise ability in these children
[52].
However, guidelines from the American Heart Association/American Thoracic Society (AHA/ATS)
concluded that sildenafil may be a reasonable adjunctive therapy for infants with PPHN who are
refractory to iNO [21].
Because data regarding efficacy and safety are insufficient, we do not recommend enteral
sildenafil as initial therapy if iNO is available. It may be considered in a resource-limited setting.
Agents not recommended — The following agents have been used in the management of
PPHN, but are not recommended for routine use because of the lack of data regarding efficacy
and safety.
● Prostacyclin – Inhaled or IV prostacyclin is a potential intervention in patients who fail NO

therapy, but is no longer commonly used with the exception of infants who fail to respond to
iNO [53-55].
● Bosentan – The scant data available on bosentan, an endothelin-1 receptor antagonist, are
conflicting regarding efficacy.
• A single trial of 47 neonates with PPHN in a setting where iNO and ECMO are
unavailable showed bosentan (1 mg/kg given through orogastric tube twice a day) was
more effective than placebo in improving OI and oxygen saturation, and in decreasing the
time of mechanical ventilation [56].
• In contrast, a small trial of 21 infants with PPHN reported no improvement in oxygenation

or other outcomes in the group treated with enteral bosentan compared with those who
received placebo [57]. This trial was terminated early because of slow recruitment.
However, the small number of subjects and significant differences in study design between
the two reports make it difficult to ascertain whether or not there is a role for bosentan,
particularly in centers in which iNO and ECMO are not available.
● Milrinone – There are no published clinical trials using milrinone, a selective inhibitor of type
III cyclic adenosine monophosphate (cAMP) phosphodiesterase isoenzyme in cardiac and
vascular muscle with both positive inotrope and vasodilator effects, in the treatment of PPHN
[58]. Two small case series from a single tertiary center suggest that milrinone improved
oxygenation without compromise of systemic blood pressure [59,60]. As a result, the efficacy
and safety of milrinone in the treatment of PPHN are not known. We do not recommend the
routine use of milrinone for infants with PPHN.
OUTCOME
The incidence in developed countries ranges from 1 to 2 per 1000 live births with an estimated
mortality rate of 10 percent [1,61].
Survivors of severe PPHN and/or extracorporeal membrane oxygenation (ECMO) treatment are at
increased risk of developmental delay, motor disability, and hearing deficits [62-68]. In one study,
survivors of PPHN compared with a matched control group were more likely to have sensorineural
hearing loss (SNHL) based upon audiologic evaluation and chronic health problems (eg, cerebral
palsy [CP], developmental delay, the use of bronchodilator therapy, and remedial education) by
parental report at 5 to 11 years of age [68].
Inhaled nitric oxide — Inhaled nitric oxide (iNO) does not appear to increase the risk of adverse
outcomes:
● In one report, 87 percent of surviving infants enrolled in the National Institute of Child Health
and Human Development (NICHD) Neonatal Research Network trial of iNO were evaluated at
18 to 24 months of age [62]. Approximately one-third of the infants had at least one disability.
Abnormal outcomes included SNHL (14 percent) and moderate to severe CP (7.5 percent),
but were not different between iNO and control groups. Mental and psychomotor
developmental scores also were not different.
● In a report from a single tertiary center, 109 of 187 children who were term infants treated for
PPHN were evaluated at school age (mean age 7.1 years) [69]. Overall, 9 percent of the
cohort had an intelligence quotient (IQ) score less than 70, and 7 percent had an IQ score
between 70 and 84. There was no difference in the medical and neurodevelopmental
outcome between the 77 children who had received iNO, of whom 12 were also treated by
ECMO, and those who did not receive iNO.
● The previously mentioned systematic review of infants with respiratory failure also reported no
additional adverse effect on neurodevelopmental outcome with the use of iNO [33].
● Treatment with iNO does not appear to alter lung function in later infancy, as illustrated in a
study in which 22 infants who had severe PPHN (15 treated with iNO) and 18 healthy controls
were evaluated 4 to 12 months after discharge from the neonatal intensive care unit (NICU)
[70]. No differences between groups were detected in functional residual capacity or
respiratory system compliance.
FOLLOW-UP
All infants with severe PPHN who have been treated with inhaled nitric oxide (iNO) and/or
extracorporeal membrane oxygenation (ECMO) should have neurodevelopmental follow-up [16].
Assessment should be performed through infancy at 6- to 12-month intervals, and longer if
abnormalities are present. Hearing should be tested prior to hospital discharge and at 18 to 24
months corrected age.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Pulmonary hypertension
in children".)
INFORMATION FOR PATIENTS
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The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
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Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Persistent pulmonary hypertension in a newborn (The
Basics)")
SUMMARY AND RECOMMENDATIONS
Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular
resistance (PVR) remains elevated after birth, resulting in right-to-left shunting of blood through
fetal circulatory pathways (figure 1) that leads to hypoxemia, which in some cases may be severe
and not responsive to conventional respiratory support.
● PPHN occurs primarily in term or late preterm infants (gestational age [GA] ≥34 weeks). It is
caused by abnormalities of the pulmonary vasculature that include underdevelopment,
maldevelopment (ie, abnormally thick pulmonary arteriolar musculature), and maladaption
(abnormal vasoconstriction that interferes with the normal postnatal fall in PVR). (See
'Pathogenesis' above.)
● Infants with PPHN generally present with cyanosis and respiratory distress (eg, tachypnea).
PPHN is associated with prenatal risk factors (fetal heart rate abnormalities and meconium-
stained amniotic fluid), and a variety of primary respiratory disorders, such as meconium
aspiration syndrome (MAS), pneumonia, respiratory distress syndrome (RDS), congenital
diaphragmatic hernia (CDH), and pulmonary hypoplasia. (See 'Clinical manifestations'
above.)
● Initial testing includes pulse oximetry assessment, which may demonstrate a significant
difference (>10 percent) between pre- and postductal oxygen saturation, chest radiograph,
which is typically normal in patients without another pulmonary condition, and an
echocardiogram. (See 'Initial laboratory tests' above.)
● The diagnosis of PPHN should be considered in any neonate, especially term infants, with
severe cyanosis, and is confirmed by echocardiography. In PPHN, the echocardiogram
demonstrates normal structural cardiac anatomy and evidence of pulmonary hypertension (ie,
flattened or displaced ventricular septum, or evidence of elevated pulmonary arterial
pressure). (See 'Diagnosis' above.)
● The differential diagnosis of PPHN includes cyanotic congenital heart disease (CHD), primary
pulmonary disorders, and sepsis. (See 'Differential diagnosis' above.)
● The management of PPHN consists of general supportive cardiorespiratory care, therapy

directed towards associated pulmonary conditions, and in patients with severe PPHN,
pulmonary vasodilatory agents (eg, inhaled nitric oxide [iNO]) and extracorporeal membrane
oxygenation (ECMO).
● Our approach to treating infants with PPHN includes the following:
• Because oxygen is a pulmonary vasodilator, we recommend that supplemental oxygen

should be initially administered in a concentration of 100 percent to infants with PPHN in
an attempt to reverse pulmonary vasoconstriction (Grade 1A). PaO2 should be
maintained subsequently in the range of 50 to 90 mmHg (preductal oxygen saturation 90
to 95 percent) to minimize lung toxicity. The oxygenation index (OI) is used to assess the
severity of hypoxemia in PPHN and is used to determine whether additional interventions
(eg, iNO and ECMO) are warranted. (See 'Oxygen' above.)
• Mechanical ventilation to initially maintain PaCO2 between 40 and 50 mmHg, as

hypercarbia and acidosis increase PVR. (See 'Assisted ventilation' above.)
• Maintenance of adequate systemic blood pressure by providing sufficient vascular

volume and the use of inotropic agents. (See 'Circulatory support' above.)
• In term and preterm infants with a gestational age greater than 34 weeks and who have
severe PPHN, defined as an OI ≥25, we recommend that iNO be administered at a dose
of 20 ppm (Grade 1B). (See 'Inhaled nitric oxide' above.)
• Because data regarding efficacy and safety are insufficient, we do not recommend
enteral sildenafil as initial therapy if iNO is available (Grade 1C). It may be considered in
a resource-limited setting. (See 'Sildenafil' above.)
• In patients who have an OI ≥40 despite the use of iNO and high ventilatory support, we
recommend ECMO (Grade 1C). (See 'Extracorporeal membrane oxygenation' above.)
• We recommend that blood cultures should be obtained and empiric antimicrobial therapy
initiated (Grade 1C). (See 'General supportive care' above and "Clinical features,
evaluation, and diagnosis of sepsis in term and late preterm infants", section on
'Evaluation and initial management'.)
● Survivors of severe PPHN and/or ECMO treatment are at increased risk of developmental
delay, motor disability, and hearing deficits. (See 'Outcome' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge James Adams, Jr., MD, who contributed
to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the
newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;
105:14.
2. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided
diaphragmatic hernia. J Pediatr 1978; 92:805.
3. Geggel RL, Murphy JD, Langleben D, et al. Congenital diaphragmatic hernia: arterial
structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr
1985; 107:457.
4. Murphy JD, Rabinovitch M, Goldstein JD, Reid LM. The structural basis of persistent
pulmonary hypertension of the newborn infant. J Pediatr 1981; 98:962.
5. Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal
Neonatal Ed 2012; 97:F223.
6. Abman SH. Impaired vascular endothelial growth factor signaling in the pathogenesis of
neonatal pulmonary vascular disease. Adv Exp Med Biol 2010; 661:323.
7. Christou H, Adatia I, Van Marter LJ, et al. Effect of inhaled nitric oxide on endothelin-1 and
cyclic guanosine 5'-monophosphate plasma concentrations in newborn infants with
persistent pulmonary hypertension. J Pediatr 1997; 130:603.
8. Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension--urea-cycle

intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl
J Med 2001; 344:1832.
9. Van Marter LJ, Leviton A, Allred EN, et al. Persistent pulmonary hypertension of the newborn
and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during
pregnancy. Pediatrics 1996; 97:658.
10. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal
antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of
the newborn. Pediatrics 2001; 107:519.
11. Van Marter LJ, Hernandez-Diaz S, Werler MM, et al. Nonsteroidal antiinflammatory drugs in
late pregnancy and persistent pulmonary hypertension of the newborn. Pediatrics 2013;
131:79.
12. Curtis J, Kim G, Wehr NB, Levine RL. Group B streptococcal phospholipid causes
pulmonary hypertension. Proc Natl Acad Sci U S A 2003; 100:5087.
13. Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, et al. Persistent Pulmonary Hypertension of the
Newborn in Late Preterm and Term Infants in California. Pediatrics 2017; 139.
14. Aikio O, Metsola J, Vuolteenaho R, et al. Transient defect in nitric oxide generation after
rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants
with hypoxic respiratory failure. J Pediatr 2012; 161:397.
15. Nakanishi H, Suenaga H, Uchiyama A, et al. Persistent pulmonary hypertension of the

newborn in extremely preterm infants: a Japanese cohort study. Arch Dis Child Fetal
Neonatal Ed 2018; 103:F554.
16. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric
oxide. Pediatrics 2000; 106:344.
17. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial of inhaled nitric oxide
and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the
newborn. J Pediatr 1997; 131:55.
18. Bhutani VK, Abbasi S, Sivieri EM. Continuous skeletal muscle paralysis: effect on neonatal
pulmonary mechanics. Pediatrics 1988; 81:419.
19. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol 2001; 6:85.
20. Dempsey EM, Barrington KJ. Treating hypotension in the preterm infant: when and with
what: a critical and systematic review. J Perinatol 2007; 27:469.
21. Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines
From the American Heart Association and American Thoracic Society. Circulation 2015;
132:2037.
22. Ostrea EM Jr, Odell GB. The influence of bicarbonate administration on blood pH in a
"closed system": clinical implications. J Pediatr 1972; 80:671.
23. Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy. Pediatrics 2008;
122:831.
24. Corbet AJ, Adams JM, Kenny JD, et al. Controlled trial of bicarbonate therapy in high-risk
premature newborn infants. J Pediatr 1977; 91:771.
25. Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing morbidity
and mortality in preterm infants with metabolic acidosis. Cochrane Database Syst Rev 2005;
:CD003215.
26. Lotze A, Mitchell BR, Bulas DI, et al. Multicenter study of surfactant (beractant) use in the
treatment of term infants with severe respiratory failure. Survanta in Term Infants Study
Group. J Pediatr 1998; 132:40.
27. Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium
aspiration syndrome. Pediatrics 1996; 97:48.
28. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-
term infants with hypoxic respiratory failure. N Engl J Med 1997; 336:597.
29. Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of
persistent pulmonary hypertension of the term newborn: a randomized, double-masked,
placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group.
Pediatrics 1998; 101:325.
30. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent
pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N
Engl J Med 2000; 342:469.
31. Roberts JD Jr, Fineman JR, Morin FC 3rd, et al. Inhaled nitric oxide and persistent
pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J
Med 1997; 336:605.
32. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the Use of Inhaled
Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. J
Pediatr 2016; 170:312.
33. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born
at or near term. Cochrane Database Syst Rev 2017; 1:CD000399.
34. Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard
inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory
failure. Pediatrics 2004; 113:559.
35. Konduri GG, Vohr B, Robertson C, et al. Early inhaled nitric oxide therapy for term and near-
term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J
Pediatr 2007; 150:235.
36. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent
pulmonary hypertension. Lancet 2001; 357:118.
37. Hamon I, Gauthier-Moulinier H, Grelet-Dessioux E, et al. Methaemoglobinaemia risk factors

with inhaled nitric oxide therapy in newborn infants. Acta Paediatr 2010; 99:1467.
38. George TN, Johnson KJ, Bates JN, Segar JL. The effect of inhaled nitric oxide therapy on
bleeding time and platelet aggregation in neonates. J Pediatr 1998; 132:731.
39. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement:
inhaled nitric-oxide therapy for premature infants. Pediatrics 2011; 127:363.
40. Carey WA, Weaver AL, Mara KC, Clark RH. Inhaled Nitric Oxide in Extremely Premature
Neonates With Respiratory Distress Syndrome. Pediatrics 2018; 141.
41. FDA prescibing information for iNO for hypoxic respiratory faliure. http://www.accessdata.fd
a.gov/drugsatfda_docs/label/2013/020845s014lbl.pdf (Accessed on April 24, 2013).
42. Davidson D, Barefield ES, Kattwinkel J, et al. Safety of withdrawing inhaled nitric oxide
therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999; 104:231.
43. Lazar DA, Cass DL, Olutoye OO, et al. The use of ECMO for persistent pulmonary
hypertension of the newborn: a decade of experience. J Surg Res 2012; 177:263.
44. Somaschini M, Bellan C, Chinaglia D, et al. Congenital misalignment of pulmonary vessels

and alveolar capillary dysplasia: how to manage a neonatal irreversible lung disease? J
Perinatol 2000; 20:189.
45. García Martínez E, Ibarra de la Rosa I, Pérez Navero JL, et al. [Sildenafil in the treatment of
pulmonary hypertension]. An Pediatr (Barc) 2003; 59:110.
46. Karatza AA, Narang I, Rosenthal M, et al. Treatment of primary pulmonary hypertension with
oral sildenafil. Respiration 2004; 71:192.
47. Keller RL, Hamrick SE, Kitterman JA, et al. Treatment of rebound and chronic pulmonary
hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Pediatr
Crit Care Med 2004; 5:184.
48. Baquero H, Soliz A, Neira F, et al. Oral sildenafil in infants with persistent pulmonary
hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117:1077.
49. Ahsman MJ, Witjes BC, Wildschut ED, et al. Sildenafil exposure in neonates with pulmonary
hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed
2010; 95:F109.
50. Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane
Database Syst Rev 2017; 8:CD005494.
51. Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates
with persistent pulmonary hypertension. J Pediatr 2009; 155:841.
52. FDA Drug Safety Communication: FDA recommends against use of Revatio in children with
pulmonary hypertension. http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm (Accessed o
n August 31, 2012).
53. Kelly LK, Porta NF, Goodman DM, et al. Inhaled prostacyclin for term infants with persistent
pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002; 141:830.
54. Golzand E, Bar-Oz B, Arad I. Intravenous prostacyclin in the treatment of persistent

pulmonary hypertension of the newborn refractory to inhaled nitric oxide. Isr Med Assoc J
2005; 7:408.
55. Ahmad KA, Banales J, Henderson CL, et al. Intravenous epoprostenol improves oxygenation
index in patients with persistent pulmonary hypertension of the newborn refractory to nitric
oxide. J Perinatol 2018; 38:1212.
56. Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective study

of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J
Perinatol 2012; 32:608.
57. Steinhorn RH, Fineman J, Kusic-Pajic A, et al. Bosentan as Adjunctive Therapy for
Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter
Placebo-Controlled Exploratory Trial. J Pediatr 2016; 177:90.
58. Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary

hypertension of the newborn. Cochrane Database Syst Rev 2010; :CD007802.
59. McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in
neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 2006;
21:217.
60. McNamara PJ, Shivananda SP, Sahni M, et al. Pharmacology of milrinone in neonates with
persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric
oxide. Pediatr Crit Care Med 2013; 14:74.
61. Lipkin PH, Davidson D, Spivak L, et al. Neurodevelopmental and medical outcomes of
persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002;
140:306.
62. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the
neonatal inhaled nitric oxide study group (NINOS). J Pediatr 2000; 136:611.
63. Ellington M Jr, O'Reilly D, Allred EN, et al. Child health status, neurodevelopmental outcome,
and parental satisfaction in a randomized, controlled trial of nitric oxide for persistent
pulmonary hypertension of the newborn. Pediatrics 2001; 107:1351.
64. Rosenberg AA, Kennaugh JM, Moreland SG, et al. Longitudinal follow-up of a cohort of
newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J
Pediatr 1997; 131:70.
65. Robertson CM, Finer NN, Sauve RS, et al. Neurodevelopmental outcome after neonatal
extracorporeal membrane oxygenation. CMAJ 1995; 152:1981.
66. Cohen DA, Nsuami M, Etame RB, et al. A school-based Chlamydia control program using
DNA amplification technology. Pediatrics 1998; 101:E1.
67. Fligor BJ, Neault MW, Mullen CH, et al. Factors associated with sensorineural hearing loss
among survivors of extracorporeal membrane oxygenation therapy. Pediatrics 2005;
115:1519.
68. Eriksen V, Nielsen LH, Klokker M, Greisen G. Follow-up of 5- to 11-year-old children treated
for persistent pulmonary hypertension of the newborn. Acta Paediatr 2009; 98:304.
69. Rosenberg AA, Lee NR, Vaver KN, et al. School-age outcomes of newborns treated for
persistent pulmonary hypertension. J Perinatol 2010; 30:127.
70. Dobyns EL, Griebel J, Kinsella JP, et al. Infant lung function after inhaled nitric oxide therapy
for persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 1999; 28:24.
Topic 5045 Version 32.0
GRAPHICS
Fetal circulation
El grado de saturación de oxígeno se indica mediante el sombreado, como se explica en

la clave de la figura.
Gráfico 66765 versión 4.0
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Ann R Stark, MD Nada que divulgar Eric C Eichenwald, MD Nada que divulgar Joseph A Garcia-
Prats, MD Nada que divulgar Melanie S Kim, MD Nada que divulgar
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Cuando se encuentran, estos se abordan examinando un proceso de revisión multinivel y los requisitos para
que se proporcionen referencias que respalden el contenido. El contenido referenciado adecuadamente es
requerido por todos los autores y debe cumplir con los estándares de evidencia UpToDate.
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6/5/2019 Persistent pulmonary hypertension of the newborn - UpToDate

Reimpresión oficial de UpToDate ®

Hipertensión pulmonar persistente del recién nacido.

Aquí se analiza la fisiopatología, las manifestaciones clínicas, el diagnóstico y el tratamiento de la

Circulación fetal y postnatal : en el feto, los circuitos pulmonar y sistémico funcionan en

Circulación de transición : los ajustes circulatorios importantes se producen al nacer a medida

PPHN se presenta principalmente en término o prematuros tardíos niños ≥34 semanas de

Subdesarrollo : en las anomalías del subdesarrollo, el área de la sección transversal de la

La predisposición genética puede influir en la disponibilidad de precursores para la síntesis de NO

Mala adaptación : en la mala adaptación, el lecho vascular pulmonar se desarrolla normalmente.

Los factores prenatales - hallazgos prenatales asociados con hipertensión pulmonar

● Síndrome de aspiración de meconio (MAS, 41 por ciento) (ver "Características clínicas y

En el estudio poblacional de California mencionado anteriormente, la infección fue la causa más

Pruebas de laboratorio iniciales : la mayoría de los pacientes se someterán a pruebas

Evaluación de oximetría de pulso - valoración del pulso oximetría generalmente demuestra

El diagnóstico definitivo de PPHN se realiza mediante ecocardiografía. La ecocardiografía es una

Gravedad de la HP : la ecocardiografía también puede proporcionar una estimación de la

• PPHN de moderada a grave: la RVp estimada es mayor que tres cuartos de la PA

• PPHN grave: RVp estimado mayor que la PA sistémica

El diagnóstico diferencial de PPHN incluye:

● Cardiopatía congénita cianótica (CHD), que se distingue de la PPHN por ecocardiografía.

● Enfermedad pulmonar parenquimatosa primaria aislada, como neumonía neonatal, taquipnea

general de la dificultad respiratoria neonatal: trastornos de la transición", sección "Radiografía

● La sepsis se distingue por el entorno clínico, los hemocultivos positivos y la ecocardiografía.

La gestión de PPHN consiste en lo siguiente:

● Atención cardiorrespiratoria de apoyo general.

● En casos graves, o en aquellos que no responden a las medidas de apoyo, otras

● Tratamiento específico para cualquier enfermedad pulmonar parenquimatosa asociada (p.

Evaluación de la gravedad utilizando el índice de oxigenación - El índice de oxigenación

OI = [presión media de la vía aérea x FiO 2 ÷ PaO 2 ] x 100

Las medidas cardiorrespiratorias generales pueden revertir o prevenir un mayor aumento de la

Oxygen — Oxygen is a pulmonary vasodilator and it should be initially administered in a

oxygenation (assessed by calculating the oxygenation index), more directed/invasive measures

● In infants with no associated lung disease, hypoxemia is caused by right-to-left shunting

Circulatory support — In patients with PPHN, right-to-left shunting increases as cardiac

● If the echocardiography demonstrates RV or LV dysfunction, IV milrinone in conjunction with

Inhaled nitric oxide

● Oxygenation improved in 50 percent of infants who received iNO. The OI decreased by a

● iNO therapy did not appear to be beneficial in patients with CDH.

Mode of action — Endogenous NO regulates vascular tone by causing relaxation of

Potential toxicity — Potential toxicity of iNO includes methemoglobinemia secondary to

Congenital diaphragmatic hernia — iNO does not appear to be of long-term benefit in

● Performance of an echocardiogram to exclude the diagnosis of CHD.

Although some centers measure methemoglobin levels, we routinely do not measure

Extracorporeal membrane oxygenation — Approximately 40 percent of infants with severe

Sildenafil — Sildenafil, a phosphodiesterase inhibitor type 5, is an agent that has been

An open-label dose-escalation trial of a continuous IV infusion of sildenafil was conducted in 36

● Prostacyclin – Inhaled or IV prostacyclin is a potential intervention in patients who fail NO

• In contrast, a small trial of 21 infants with PPHN reported no improvement in oxygenation

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● The management of PPHN consists of general supportive cardiorespiratory care, therapy

● Our approach to treating infants with PPHN includes the following:

• Because oxygen is a pulmonary vasodilator, we recommend that supplemental oxygen

• Mechanical ventilation to initially maintain PaCO2 between 40 and 50 mmHg, as

• Maintenance of adequate systemic blood pressure by providing sufficient vascular

of 20 ppm (Grade 1B). (See 'Inhaled nitric oxide' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

8. Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension--urea-cycle

15. Nakanishi H, Suenaga H, Uchiyama A, et al. Persistent pulmonary hypertension of the

37. Hamon I, Gauthier-Moulinier H, Grelet-Dessioux E, et al. Methaemoglobinaemia risk factors

44. Somaschini M, Bellan C, Chinaglia D, et al. Congenital misalignment of pulmonary vessels