Persistent Pulmonary Persistent Pulmonary Hypertension (PPHN)Hypertension (PPHN)

F. Hazel R. Villa, MDF. Hazel R. Villa, MD

PL1PL1

ObjectivesObjectives

to review the fetal,transitional and postnatal to review the fetal,transitional and postnatal circulation in relation to PPHNcirculation in relation to PPHN

To understand the pathophysiology of PPHN To understand the pathophysiology of PPHN as it applies to clinical manifestations and as it applies to clinical manifestations and managementmanagement

Pulmonary vesselsPulmonary vessels

VASOCONSTRICTORSVASOCONSTRICTORS

(Maintain high fetal PVR)(Maintain high fetal PVR)

NorepinephrineNorepinephrine

A-adrenergic stimulationA-adrenergic stimulation

HypoxiaHypoxia

EndothelinEndothelin

ThromboxanesThromboxanes

LeukotrienesLeukotrienes

Platelet activating factorPlatelet activating factor

PGF2aPGF2a

VASODILATORSVASODILATORS(Decrease PVR during (Decrease PVR during

transition)transition)

PGI2PGI2, PGD2, PGE2, PGD2, PGE2

Nitric oxideNitric oxide

Cyclic GMPCyclic GMP

Cyclic AMPCyclic AMP

OxygenOxygen

AdenosineAdenosine

BradykininBradykinin

Fetal circulation

Fetal circulationFetal circulation

pO2, PGI2, NOpO2, PGI2, NO ADMA -- competes with arginineADMA -- competes with arginine

inhibit NOSinhibit NOS

VasoconstrictionVasoconstriction

Postnatal circulation

Transitional circulation

Transitional to postnatalTransitional to postnatal

At birth At birth increase in NO, NOS-increase in NO, NOS- cGMP cGMP

increase guanylate cyclase-increase guanylate cyclase- cGMP cGMP

increase in PGI2 (effect of estrogen)increase in PGI2 (effect of estrogen) cAMP cAMP

DDAH metabolizes ADMADDAH metabolizes ADMA

VasodilatationVasodilatation

Transitional to postnatalTransitional to postnatal

At birthAt birth

ventilationventilation

increase pulmonary blood flowincrease pulmonary blood flow

OxygenationOxygenation

Transitional to postnatalTransitional to postnatal

Oxygen- stimulates NOS, COX1Oxygen- stimulates NOS, COX1 Pulmonary blood flow- release of NO, PGI2Pulmonary blood flow- release of NO, PGI2

Evidence: NO-cGMP pathway is a more Evidence: NO-cGMP pathway is a more potent modulator of pulmonary vascular tonepotent modulator of pulmonary vascular tone

Increase in SVRIncrease in SVR

Removal of the placentaRemoval of the placenta

Catecholamine associated with birth Catecholamine associated with birth

Cold environmentCold environment

Postnatal decrease in PVRPostnatal decrease in PVR

Expansion of the lungExpansion of the lung

Adequate ventilation, oxygenationAdequate ventilation, oxygenation

Clearance of fetal lung fluidClearance of fetal lung fluid

3 types of abnormalities3 types of abnormalities

MaladaptationMaladaptation

MaldevelopmentMaldevelopment

UnderdevelopmentUnderdevelopment

MaladaptationMaladaptation

Prototype: Meconium aspiration pneumoniaPrototype: Meconium aspiration pneumonia Pneumonia, RDSPneumonia, RDS

Obstruction of the airwaysObstruction of the airways Chemical pneumonitisChemical pneumonitis Release of endothelin,thromboxaneRelease of endothelin,thromboxane

vasoconstrictorsvasoconstrictors

MaldevelopmentMaldevelopment

Prototype: Idiopathic PPHN Prototype: Idiopathic PPHN (“black lung” PPHN)(“black lung” PPHN) Vessel wall thickeningVessel wall thickening Smooth muscle hyperplasiaSmooth muscle hyperplasia Cause – intrauterine exposure to NSAIDCause – intrauterine exposure to NSAID constriction of ductus arteriosus constriction of ductus arteriosus geneticgenetic

Disruption of NO-cGMP pathwayDisruption of NO-cGMP pathway Disruption of PGI2-cAMP pathwayDisruption of PGI2-cAMP pathway Guanylate cyclase is less activeGuanylate cyclase is less active Increased ROS (reactive oxygen species)Increased ROS (reactive oxygen species)

vasoconstrictorvasoconstrictor Increased thromboxane, endothelinIncreased thromboxane, endothelin

MaldevelopmentMaldevelopment

UnderdevelopmentUnderdevelopment

Prototype: Congenital diaphragmatic herniaPrototype: Congenital diaphragmatic hernia Pulmonary hypoplasiaPulmonary hypoplasia

Decreased cross sectional area of pulmonary Decreased cross sectional area of pulmonary vasculaturevasculature

Decreased pulmonary blood flowDecreased pulmonary blood flow Abnormal muscular hypertrophy of the pulm Abnormal muscular hypertrophy of the pulm

arteriolesarterioles

Clinical signs and symptomsClinical signs and symptoms

PE:PE: meconium stainingmeconium staining Prominent precordial impulseProminent precordial impulse Narrow split accentuated P2Narrow split accentuated P2 Systolic murmur LLSBSystolic murmur LLSB

LabsLabs

CXR: CDH, decreased vascular markings, CXR: CDH, decreased vascular markings, parenchymal diseaseparenchymal disease

ECG: RV predominance, ST elevationECG: RV predominance, ST elevation ABG: hyperoxic test (pO2 < 100 at 100% O2)ABG: hyperoxic test (pO2 < 100 at 100% O2) Pre and postductal ABG (R radial artery: Pre and postductal ABG (R radial artery:

umbilical artery/lower extremity) umbilical artery/lower extremity) 10-15% saturation and or 10-15mmHg pO210-15% saturation and or 10-15mmHg pO2

LabsLabs

EchocardiographyEchocardiography Structural heart disease is determinedStructural heart disease is determined R-L shunting (Ductus or FO)R-L shunting (Ductus or FO) Pulmonary arterial pressure is measuredPulmonary arterial pressure is measured

ManagementManagement

Oxygen 100% pO2 should be kept between Oxygen 100% pO2 should be kept between 50-90mmHg (O2 saturation >90%)50-90mmHg (O2 saturation >90%)

Correct factors promoting vasoconstriction: Correct factors promoting vasoconstriction: hypoglycemia, hypocalcemia, anemia, hypovolemiahypoglycemia, hypocalcemia, anemia, hypovolemia

Optimize cardiac function Optimize cardiac function (inotropic agents, volume (inotropic agents, volume expansion expansion

Mechanical ventilationMechanical ventilation SurfactantSurfactant

Inhaled Nitric oxide- an ideal selective Inhaled Nitric oxide- an ideal selective pulmonary vasodilatorpulmonary vasodilator OI of >25 OI of >25 OI=(MAP x FiO2)/pO2 x 100OI=(MAP x FiO2)/pO2 x 100 Contraindications: CHD which are PDA dependentContraindications: CHD which are PDA dependent

(aortic stenosis, interrupted aortic arch, hypolastic heart (aortic stenosis, interrupted aortic arch, hypolastic heart syndrome)syndrome)

May worsen pulmonary edema in obstructed TAPVRMay worsen pulmonary edema in obstructed TAPVR

ManagementManagement

Used to transport patient for ECMO

ECMO ECMO Goal of this treatment: Goal of this treatment: maintain adequate tissue oxygenation and maintain adequate tissue oxygenation and avoid irreversible lung injury, while PVR avoid irreversible lung injury, while PVR

decreases and correcting pulm HTNdecreases and correcting pulm HTN ECMO if OI is >40ECMO if OI is >40

ManagementManagement

Other Pulmonary VasodilatorsOther Pulmonary Vasodilators

Sildenafil- PDE5 inhibitorSildenafil- PDE5 inhibitor increased cGMP increased cGMP Milrinone- PDE3 inhibitorMilrinone- PDE3 inhibitor increased cAMP increased cAMP Inhaled PGI2Inhaled PGI2 Superoxide dismutase-superoxide scavengerSuperoxide dismutase-superoxide scavenger

Dilates pulm vessels, and increase endogenous NODilates pulm vessels, and increase endogenous NO

ReferencesReferences

http://neoreviews.aappublications.org/cgi/content/full/8/1/e14http://neoreviews.aappublications.org/cgi/content/full/8/1/e14 http://www.utdol.com/utd/content/topic.do?http://www.utdol.com/utd/content/topic.do?

topicKey=neonatol/1427&view=printtopicKey=neonatol/1427&view=print www.emedicine.com/ped/topic2530.htmwww.emedicine.com/ped/topic2530.htm www.emedicine.com/PED/topic2530.htmwww.emedicine.com/PED/topic2530.htm phassociation.org/medical/phassociation.org/medical/....../Summer_2006//Summer_2006/

persistent_ph_newborn.pdfpersistent_ph_newborn.pdf

Thank you!