Joshua E PetrikinJune 26th, 2015

ObjectivesDescribe the fetal circulation and the

normal transitional circulatory changes that occur at birth

Describe the problems that arise when there is maladaptive cardio-respiratory transition at birth

Discuss the pathogenesis of persistent pulmonary hypertension

Discuss the neonatal conditions that predispose to persistent pulmonary hypertension

Describe the management of persistent pulmonary hypertension

ContentsIntroductionFetal and transitional neonatal circulationPathophysiology of PPHNConditions associated with PPHNClinical Presentation & DiagnosisManagement of PPHNPrognosis & Follow-up

IntroductionFetal adaptation to postnatal conditions

requires the transition of the pulmonary circulation from a high resistance state in-utero to a low resistance state

results in a nearly 10 fold increase in pulmonary blood flow (PBF)

Pulmonary Vascular Resistance (PVR) continues to decline after birthnormally reaches 80% of total decrease by 24-

48 hoursreaches nearly adult values around 6 weeks of

life

IntroductionPersistent pulmonary hypertension of the newborn

(PPHN)the failure to achieve or sustain the normal decrease in

PVR at birtha clinical syndrome that can occur in association with

diverse cardio-respiratory disorders

These conditions share common pathophysiologic features, includinghigh pulmonary vascular resistanceextra-pulmonary shunting (right to left) of blood flow

across the ductus arteriosus or foramen ovalemarked hypoxemia

Fetal Circulation

Transitional Circulation- NewbornInflation of the lungs

↓ the resistance to pulmonary blood flow results in ↑ blood flow to the lungs ↓ blood flows through the foramen ovale to the LA

Increased volume of blood returns from the lungs ↑ pressure in the LA

The ↑ LA pressure & ↓ RA pressure (due to ↓ PVR) closes foramen ovale

The ductus arteriosus, closes off shortly after birth replaced by connective tissue

The increased PBF flow distends the vasculature causing a “structural reorganization” of

the vascular wall

Local vasoregulatory mediators play an important role in this transition

Pathophysiology of PPHNHallmarks of PPHN include

sustained elevation of PVRabnormal vasoreactivitystructural remodeling of the pulmonary

vascular bed

Mechanisms leading to failure of postnatal adaptation are poorly understood

Vasoregulation of the Normal Fetal Pulmonary CirculationDue to the high PVR in the normal fetus, the

pulmonary circulation receives ~ 10% of combined ventricular output

Factors that contribute to high basal PVR include: low O2 low basal production of vasodilator products ( PGI2 & NO

Adenosine) increased production of vasoconstrictors (ET1, LT, TBX, PAF ) altered smooth muscle cell reactivity

NO-cGMP cascade important role in vasoregulation of the fetal pulmonary circulation: Modulating basal PVR in the fetus Mediating vasodilator response to physiologic & pharmacologic stimuli Opposing the strong myogenic tone in the normal fetal lung

L-arginine L-citrullineNOS

Endogenous Nitric Oxide (NO) Effects

↑cGMP NO

+cGMP kinase

↓IC Calcium

+sGC

Vasodilation5’GMP

Phosphodiesterase

Developing Lung Circulation

Intrauterine InjuryHemodynamic StressChronic StressInflammationOther (genetic)

Vascular Growth

Abnormal Vascular Reactivity

Altered Vascular Structure

↓ Angiogenesis↓ Alveolarization ?

↓ Vasodilators (NO, PGI2, Adenosine)↑ Vasoconstrictors (ET1, LT, TBX, PAF)Enhanced Myogenic Tone

↑ SMC ProliferationAltered Extracellular MatrixAdventitial thickening

Pathogenesis of PPHN

Pulmonary hypoplasiaCDH

RDS, MAS, GBS

Chronic IU hypoxiaIdiopathic PPHN

Clinical Presentation & Diagnosis- PPHN

Dx considered when hypoxemia is out of proportion to the degree of parenchymal disease severity on the CXR (idiopathic), a positive perinatal hx may be helpful

Physical examinationrespiratory distressCyanosisTachycardiaHypotensionO2 sat differencesingle/loud S2systolic murmur of TRdifference between preductal & postductal

oxygenation

Clinical Presentation & Diagnosis of PPHN

Lability of Oxygenation : wide swings in PaO22DTTEcho

level & direction of shuntPAP estimated (Bernoulli equation)abnormal septal motionflat septum, increase RA

Disease severity suggested by oxygenation indexOI = 100 X (MAP)(FiO2) / PaO2 OI > 25 receive care at ECMO centerOI >40- ECMO

Differential DiagnosisCongenital Heart Disease

PAPVR */ TAPVRPA with intact ventricular septumTransposition of Great Arteries (TGA)Tricuspid Atresia

Pulmonary Alveolar Capillary Dysplasiafailed formation & growth of alveolar capillaries and

medial musculature hypertrophy

Conditions Associated with PPHNMAS( 41%)Idiopathic (17%)RDS (13%)Sepsis/Pneumonia (14%)CDH (10%)Pulmonary Hypoplasia (4%)

Meconium Aspiration Syndrome (MAS)Most severe condition associated with

meconium passage in utero

MAS occurs in 2-5% of infants with meconium stained amniotic fluid (MSAF) Meconium in utero may be a response to stress

chronic hypoxia, acidemia or infection Most infants with MSAF are asymptomaticMSAF rarely occurs before 38 weeks gestation

incidence increases with longer gestations 30% of newborns born at 42 weeks have MSAF

Diagnosis based on clinical history of MSAFmeconium aspirated from below the vocal cordsan infant with respiratory distresscoarse opacification seen on CXR

Meconium Aspiration SyndromeMechanism of respiratory distress leading to

PPHN includeblockage of the airwayinactivation of surfactantdirect damage to the lung parenchymaatelectasis & V-Q mismatch

Infants usually present with mild to moderate respiratory distress, but rapidly progress to respiratory failure with cyanosis & PPHN

These infants are prone to air leaks- pneumothorax

Meconium Aspiration SyndromeCXR shows

coarse infiltrateswidespread consolidationhyperinflationpneumothoraxpneumomediastinum

Treatment includessupplemental O2ventilatory strategies to prevent air-

trappingtherapy for PPHN- iNO & ECMO

Meconium Aspiration Syndrome

bilateral patch opacity with hyperinflation & air leak

Meconium Aspiration Syndrome

Rt pneumothorax

Idiopathic Persistent Pulmonary Hypertension (“black lung”)

Profound hypoxemia & hyperlucent lung fields

Constriction of ductus in-utero > exposure to NSAID

Exposure to SSRIDown SyndromeUnknown factors-

genetic or biologic susceptibility

Congenital Diaphragmatic Hernia (CDH)Developmental defect in the diaphragm

allows abdominal viscera (liver, spleen, stomach, intestine) to herniate into the thoracic cavity

secondary to persistence of the pleuroperitoneal canal in the posterolateral portion of the diaphragm

90% on left through foramen of Bochdalek10% on right through foramen of Morgagni

1: 2200 live birthsPulmonary hypoplasia and abnormal

vascular development withDecreased bronchial and pulmonary arterial

branchingPulmonary arterial muscle hyperplasia leading to

PPHN

Congenital Diaphragmatic Hernia (CDH) Affected neonates present in first a few

hours of life with respiratory distress CXR- postnatally is diagnosticMay be asymptomatic in newborn periodDefinitive treatment – surgical

not emergentelective repair when hemodynamically stable &

PPHN resolved/under control

With advent of antenatal Dx & improvement in neonatal care, survival has improved, but remains significant risk of death (population-based studies no improvement in survival)

Congenital Diaphragmatic Hernia (CDH)

Congenital Diaphragmatic Hernia (CDH)

pattern of bowel in the left hemithorax.  There is mediastinal shift to the right. 

Congenital Diaphragmatic Hernia (CDH)

Congenital Diaphragmatic Hernia (CDH) Prenatal Dx, monitoring, labor induced in

controlled setting at 38-39weeksAt delivery, minimize bag-mask ventilation and

intubateInsert NG tube for gastric decompression

Maintain adequate systemic blood pressureAvoid barotrauma to the hypoplastic lungs

Contributes to CDH mortalityAttempt to ventilate with low peak pressure

(<25cmH2O) to minimize/ prevent lung injury Sedation as needediNO and surfactant of unproven benefitiNO frequently used as a bridge to ECMO

Pulmonary HypoplasiaCan occur in association with

Oligo/anhydramniosbilateral dysplastic kidneyssevere PUVCDH Other congenital abnomalities

Arrest of lung development & differentiation

Potters Syndrome: bilateral renal agenesis & pulmonary hypoplasia

Term gestation, posterior urethral valves

Post ECMO , Post Dialysis

Respiratory Distress Syndrome (RDS)Terminology

RDS: a clinical diagnosis Hyaline Membrane Disease (HMD) a pathological

diagnosis Surfactant Deficiency: describing the typical

appearances on CXR

Most common respiratory disorder observed in premature infantsAlso occurs in near term & term infants

A leading cause of morbidity & mortality in newborn period

Respiratory Distress Syndrome (RDS)

Caused by relative or total lack of surfactant

Deficiency of surfactant ---> ↓ FRC---> atelectasis & V-Q mismatch

ABG: low PaO2, high PaCO2 & acidosis

Clinical Risk Associated with RDSPrematurity (term & near- term))Gender

male > femalesandrogen- delayed surfactant maturation

Race- Black infants lower incidenceCesarean section- before onset of laborBirth depressionUncontrolled maternal diabetes- delayed

surfactant maturationGenetic- SP B deficiency/ more likely in

siblingsTwins- 2nd twin more likelyHypothermia- surfactant function impaired in

cold

Respiratory Distress Syndrome (RDS)

Diffuse reticulogranular pattern, air bronchograms & atelectasis

Management of PPHN: Investigations

CBC with manual diffABGBMP,Glucose, Ca2+, Mg, LFTBlood Culture, viral studiesCoagulation profileCXREchoHUSRenal US

Management of PPHN: ObjectivesCorrect the underlying cause of PPHN (if

known)

Maintain adequate systemic BP

Decrease pulmonary vascular resistanceOxygenAlkalosis (at least avoid acidosis)iNO

Maintain optimal oxygen delivery to tissues

Minimize ventilator-induced lung injury

Management- PPHN

Proven therapy Unproven therapy

HyperventilationGentle ventilationAlkali infusionIV VasodilatorsHFVSurfactant*INOECMO

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Therapeutic options for PPHN are varied with wide range of variations in their use

INO TherapyIndications PPHN or hypoxemic respiratory failureOI 15, reversible pulmonary disorderECHO -no evidence of CHDDosage : > 20ppm no additional benefit (optimal

lung inflation & adequate CO)Treatment Failure : OI >25 transfer, OI > 40

ECMODiscontinuation : OI < 10 , 2-6 days of iNOContraindications (No benefit in CDH)

Management of PPHN ECMO : Baseline ECMO criteria

≥ 34 weeksWt > 2000g (‘cannulas fit’)no major ICH on HUS (no > Gr II)reversible lung diseaseNo evidence of lethal congenital anomalies or

inoperable cardiac disease

UK trial impact of ECMO : survival ECMO group 68% compared to 41% in the control group

PPHN: Management SummaryConfirm Diagnosis

Echo helpful to rule out congenital heart disease, assess cardiac function

Maintain systemic BP and assist cardiac function as neededDopamineMilrinone

Oxygen & a conservative ventilation strategyaim for PaO2 60-90 mmHg

Modest hyperventilationpH 7.35-7.50, PaCO2 40-50mmHgAvoid acidosis

Sedatives as neededPhosphodiesterase inhibitorsSurfactant: consider in individual patientInhaled nitric oxideECMO for iNO non-respondersAlkali infusion & paralysis no longer first line

strategies

Post Recovery Issues & CareFeeding Problems

BPD

Withdrawal - narcotic

Neurological evaluation

Hearing exam

PROGNOSIS & FOLLOW-UPNINOS : INO not associated with an increase

in neurodevelopmental, behavioral or medical abnormalities at 2 yrs of age

Conservative Mx without induced alkalosis & paralysis : no hearing loss and good outcome (Marron et al)

PROGNOSIS & FOLLOW-UPMortality varies by diagnosisWith all available therapies MR < 20-25%MAS survival close to 100%CDH- survival variable

Morbidities linked to severity of clinical course, diagnosis and complicationsAt risk for neuro-developmental abnormalitiesHearing Loss: high risk of late onset sensorineural

hearing lossPulmonary recovery typically excellent if MASHigh risk for late pulmonary hypertension if CDH

REFERENCES

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