PERSISTENT PULMONARY HYPERTENSION OF THE

NEWBORN

HISTORICAL ASPECTS

Previously k/a Persistent fetal circulation (PFC)

First described as “unripe births of mankind” byWilliam Harvey in 1628 in Exercitatio AnatomicaDe Motu Cordis et Sanguinis in Animalibus .

Gersony et al in 1969 rediscovered this syndromeand labelled it as “persistent foetal circulation(PFC)”

However this term has now been abandoned (high-flow, low-resistance circuit through the placenta, ismissing)

OTHER NAMES

Persistent fetal circulation

Persistent pulmonary vascular obstruction

Pulmonary vasospasm

Neonatal pulmonary ischemia

Persistent transitional circulation

FETAL vs ADULT CIRCULATION

FETAL ADULTSGas exchange Placenta Lungs

RV,LV circuit Parallel Series

Pulmonary circulation Vasoconstricted Dilated

Stroke volume RV>LV(1.2:1 TO 1.5:1) RV= LV

Intracardiac & extracardiac shunts No shunts

LA LV AORTA DUCTUS ARTERIOSUS

FORAMEN OVALE

RV

IVC SVC UPPER BODYhepatic veins

55% THROUGH 45% TO LIVER

DUCTUS VENOSUS (PORTAL CIRCULATION)

UMBILICAL VEIN

Oxy.blood , nutrients

PLACENTA

• Upper part of fetal body (including coronary & cerebral arteries and those to upper extremities) is perfused exclusively from LV with blood that has a slightly higher PO2 , than the blood perfusing the lower part of the fetal body, which is derived mostly from RV

Only a small volume of blood from the ascending aorta (10% of fetal cardiac output) flows across the aortic isthmus to the descending aorta.

.

TRANSITIONAL CIRCULATION:

AT BIRTH • Expansion of the lungs to normal resting volume,

establishment of adequate alveolar ventilation andoxygenation, and successful clearance of fetal lung fluid

Rapid fall in PVR

• Removal of the placenta, the catecholamine surge a/w birth,relatively cold extrauterine environment

Increase in SVR

TRANSITIONAL CIRCULATION:

Right ventricle output now flows entirely into the pulmonary circulation.

Pulmonary vascular resistance becomes lower than systemic vascular resistance,

Shunt through ductus arteriosus reverses & becomes left to right.

TRANSITIONAL CIRCULATION:

High arterial PO2 (In several days)

Constriction of ductus arteriosus

It closes, becoming the ligamentum arteriosum.

TRANSITIONAL CIRCULATION

Increased volume of pulmonary blood flow

returning to left atrium

Increases left atrial volume and pressure

Closure of foramen ovale (functionally)

(Although the foramen may remain probe patent)

Becomes Fossa Ovalis

Removal of the placenta from the circulation

Also results in closure of the ductus venosus

The left ventricle is now coupled to the high-resistance systemic circulation its wall thickness and mass begin to increase.

In contrast, the right ventricle is now coupled to the low-resistance pulmonary circulation its wall thickness and mass decrease slightly.

If, for any reason, right-sided pressures remainhigh relative to those on the left side, fetalcirculation will most likely persist through one orboth of the fetal channels mentioned above.

PPHN is defined as postnatal persistence of rightto left ductal or atrial shunting, or both inpresence of elevated pulmonary pressures & inabsence of congenital heart disease

FACTORS AFFECTING PVRLower PVR:

oxygen, nitric oxide

prostacyclin, PG E1, D2

adenosine

magnesium

bradykinins

atrial natriuretic factor

alkalosis

histamine

acetylcholine

beta-adrenergic stimulation

potassium channel activation

Increase PVR:

hypoxia

acidosis

endothelin-1

leukotrienes, thromboxanes

platelet activating factors

prostaglandin F2- alpha

alpha-adrenergic stimulation

calcium channel activation

Factors contributing to high PVR in-utero:

Mechanical factors (compression of the smallpulmonary arterioles by the fluid-filled alveoli and alack of rhythmic distension)

Presence of low-resting alveolar and arteriolaroxygen tensions, and a relative lack ofvasodilators(NO, prostacyclins)

Elevated levels of vasoconstictors (endothelin-1,thromboxane,serotonin)

Normal Pulmonary Vascular Transition

The pulmonary vascular transition at birth is characterized by :

rapid increase in pulmonary blood flow

reduction in PVR

clearance of lung liquid.

Central role in the pulmonary vascular transition

Pulmonary endothelial cells

NO

Arachidonic acid metabolites

Vascular endothelium releases several vasoactiveproducts that play a primary role in pulmonarytransition at birth.

Pulmonary endothelial NO production increasesmarkedly at the time of birth.

NO

Oxygen-important catalyst for increased NOproduction

Shear stress resulting from increased pulmonaryblood flow- induce endothelial nitric oxide synthase(eNOS) expression

Nitric oxide exerts its action through sGC and cGMP.

Increased cGMP concentrations producevasorelaxation via decreasing intracellular calciumconcentrations.

Pulmonary expression of both endothelial nitricoxide synthase (eNOS) and its downstreamtarget, soluble guanylate cyclase (sGC), increasesduring late gestation.

THE PROSTACYCLIN PATHWAY

Cyclooxygenase (COX)- rate-limiting enzyme thatgenerates prostacyclin from arachidonic acid.

COX-1 in particular is upregulated during lategestation

Increased O2 concentration also stimulates COX-1activity

- There is evidence that the increase in estrogenconcentrations in late gestation play a role inupregulating PGI synthesis.

- Prostacyclin interacts with adenylate cyclase toincrease intracellular cyclic adenosinemonophosphate levels, which leads tovasorelaxation.

- Inhibition of prostacyclin production by NSAIDsduring late pregnancy has been associated with PPHNalthough this association has been recently calledinto question

Oxygenation also causes pulmonary dilatationthrough the activation of K channels and inhibitionin Ca channels in pulmonary artery smooth muscles

Atrial natriuretic peptide (ANP), B-type natriureticpeptide (BNP) and C-type natriuretic peptide (CNP)dilate fetal pulmonary vasculature by increasingcGMP and may play a role in pulmonary vasculartransition at birth.

PPHN

Presence of elevated PVR and rightleft shuntthrough the ductus arteriosus and/or foramen ovale(in absence of congenital heart disease) , resulting inhypoxemia and labile oxygen saturations

Contrary to primary pulmonary hypertension inadults, the newborn syndrome is not defined by aspecific pressure of the pulmonary circulation

Occurs due to failure of the pulmonary circulationto undergo the normal transition after birth

Incidence and mortality

Affects mainly at-term or post-term newborns,although also present in premature infants

Reported incidence: 0.43-6.8 per thousandnewborns.

It is likely to be much more in developingcountries, where little data is available

North America- 1.9/1,000 in the population ofneonates born at term, with a mortality of 11%

UK- 0.4 to 0.68/1,000 live births

Brazil- 2 /1,000 live births, and mortality rates of11.6%.

PATHOGENIC MECHANISMS FOR PPHN

Pulmonary vascular underdevelopment (decreasedvascular growth)

Mal-development (abnormal vascular structure)

Mal-adaption (perinatal hypoxia-induced vascular spasm)

Functional obstruction to pulmonary blood flow due toincreased blood viscosity (polycythemia)

UNDERDEVELOPMENT

Reduced cross sectional area of pulmonaryvasculature resulting in a relatively fixed elevationof PVR

Occurs with pulmonary hypoplasia associatedwith a variety of conditions like:

congenital diaphragmatic hernia (CDH),

cystic adenomatoid malformation of the lung,

renal agenesis, oligohydramniosaccompanying obstructive uropathy

intrauterine growth restriction.

Although some degree of postnatal pulmonaryvasodilatation can occur, this adaptivemechanism is limited.

As a result, mortality risk is greatest in thiscategory of patients.

MALDEVELOPMENT

Lungs have normal branching and alveolardifferentiation, and have a normal number ofpulmonary vessels.

Abnormal thickening of muscle layer of pulmonaryarterioles, and extension of this layer into smallvessels that normally have thin walls and no musclecells

Excessive extracellular matrix

Pulmonary vasculature responds poorly to stimulithat normally result in a decrease in PVR, such as↑ed O2 tension and the establishment of effectiveventilation

• Egs: Chronic intrauterine asphyxia, post-termdelivery, meconium staining

Remodeling of the pulmonary vascular bed isthought to occur during the first 7 to 14 days afterbirth, with an accompanying fall in PVR.

Disorders producing excessive perfusion of thefetal lung also may predispose to vascularmaldevelopment.

Egs: premature closure of the ductus arteriosus(eg, caused by nonsteroidal antiinflammatorydrugs) or foramen ovale, high placental vascularresistance, and total anomalous pulmonaryvenous drainage.

It is believed that in these cases, the maintenanceof pulmonary vasoconstriction with an increase inpulmonary artery pressure for a prolonged periodof time leads to vascular remodeling

Central role of vasoactive mediator imbalance(eg: ↑ed endothelin, ↓ed NO)

Genetic predisposition may influence theavailability of precursors for NO synthesis andaffect cardiopulmonary adaptation at birth.

This was illustrated in a report in which infantswith pulmonary hypertension had lower plasmaconcentrations of arginine (a precursor of NO anda urea cycle intermediate), and NO metabolitesthan control infants with respiratory distress

A functional polymorphism of the gene encodingcarbamoyl-phosphate synthetase, which controlsthe rate-limiting step in the urea cycle, has alsobeen implicated in genesis of pulmonaryhypertension

MALADAPTATION

Pulmonary vascular bed is normally developed

However, adverse perinatal conditions causeactive vasoconstriction and interfere with thenormal postnatal fall in PVR.

Conditions include perinatal depression,pulmonary parenchymal diseases, and bacterialinfections, especially those caused by group Bstreptococcus (GBS).

ETIOLOGY OF PPHN

IDIOPATHIC PPHN-: 10-20% cases

No obvious predisposing factors

Possible causes include hypoxia, acidosis,hypothermia, hypoglycemia, etc, and some ofthem may not have been documented.

SECONDARY PPHN

Most commonly seen in infants with lung diseases

Other causes

• Asphyxia

• Sepsis/infection

• Pneumonia (bacterial)

• Congenial Diaphragmatic Hernia

• Transient Tachypnea of the Newborn

• Respiratory Distress Syndrome (RDS/HMD)

most common cause being meconium aspiration

• Polycythemia/hyperviscosity

• Metabolic disturbances (hypoglycemia, hypocalcemia, hypomagnesemia)

• Hypothermia

• Systemic hypotension

Potential risk factors for the development of PPHN

Male gender

African or Asian maternal race

Pre-conception maternal overweight

Maternal diabetes, Maternal asthma

Late preterm and large for gestational age

Chorioamnionitis

Antenatal exposure to SSRIs, NSAIDs

Infection(mainly GroupB Streptococcus)

Hypothermia

Hypocalcemia

Polycythemia

CLINICAL MANIFESTATIONS

Usually occurs in term infants, although it mayalso present in late preterm or postterm infants

The diagnosis is rare in very low birth weight(VLBW) infants

PPHN is characterized by both prenatal andneonatal features

Prenatal factors - signs of intrauterine andperinatal asphyxia including fetal heartabnormalities (ie, bradycardia and tachycardia)and meconium-stained amniotic fluid

Neonatal findings

Most present within 1st 24 hours of life with signsof respiratory distress (eg, tachypnea, retractions,and grunting) and cyanosis, low apgar scores

Physical examination : cyanosis, signs of respiratorydistress; there may be meconium staining of skinand nails, which may be indicative of intrauterinestress.

Differential cyanosis may appear in severe cases(with a pink upper body and a cyanotic lower body)

Chest Examination-

A prominent RV impulse and a single and loud S2

Occasional gallop rhythm (from myocardialdysfunction) and a soft regurgitant systolicmurmur of TR may be audible.

Breath sounds may be normal (If pneumonia ormeconium staining exists, crackles or wheezesmay be present)

Severe cases of myocardial dysfunction maymanifest with systemic hypotension.

DIAGNOSIS

Consider PPHN when hypoxemia is out of proportion to the degree of parenchymallung disease and there is no e/o cyanotic CHD.

Laboratory Studies

Pulse oximetry -Hypoxia is universal,labile and isunresponsive to 100% oxygen given by hood, butmay respond transiently to hyperoxichyperventilation(by bag and mask or afterintubation)

A difference >10% between the pre- andpostductal (right thumb and either great toe)oxygen saturation (d/t RL shunt through PDA)

However, absence of a pre- and postductalgradient in oxygenation does not exclude thediagnosis of PPHN, since right-to-left shunting canoccur predominantly through the foramen ovalerather than the PDA.

Arterial blood gas- PaO2 gradient of > 20 mmHgbetween pre-ductal (upper extremity or head)and post-ductal (lower extremity or abdomen)ABGs

In contrast to infants with cyanotic lesions, manyinfants with PPHN have at least onemeasurement of PaO2 >100 mmHg early in thecourse of their illness

Hyperoxia test

To distinguish PPHN & CHD from parenchymallung disease

Give 100% O2 x 10-15 min.PPHN or CHD = PaO2 < 100 mmHgParenchymal = PaO2 >100 mmHg

If PaO2 > 100 mm of Hg , CHD more or less ruledout

Hyperoxia - hyperventilation test

To distinguish PPHN from CHDAdminister 100% O2Hyperventilate (face mask or ET tube) to

"critical“ PaCO2 level(20-25 mm Hg)PPHN = PaO2 > 100 mmHgCHD = PaO2 little change (< 100 mmHg

Caution: Should be performed by skilledpersonnel only

Response to iNO may help to differentiate PPHNfrom cyanotic CHD

Most neonates with PPHN respond rapidly toiNO, with an increase in PaO2 and oxygensaturations.

Some neonates who have severe PPHN andinfants who have cyanotic CHD may experience asmall or no increase in oxygenation with iNO

CHEST RADIOGRAPH

Usually normal or demonstrates the findings of anassociated pulmonary condition (eg, parenchymaldisease, air leak, or congenital diaphragmatichernia).

The heart size typically is normal or slightlyenlarged.

Pulmonary blood flow may appear normal orreduced.

ELECTROCARDIOGRAM

Right ventricular predominance, which is normalfor age.

Signs of myocardial ischemia, such as ST segmentelevation, may be present in infants withperinatal depression

ECHOCARDIOGRAPHY

Gold standard for diagnosing PPHN

Normal structural cardiac anatomy with evidenceof pulmonary hypertension (eg, flattened ordisplaced ventricular septum).

Right-to-left or bidirectional shunting of blood atthe foramen ovale and/or the ductus arteriosus

High pulmonary arterial/right ventricular systolicpressure estimated by Doppler velocitymeasurement of TR jet

In addition, echocardiography may be used toassess ventricular function, which may beimpaired.

Cardiac catheterization

Needed rarely when echo is not definitive

A vasodilator trial using hyperoxia or short-actingagents such as inhaled NO, at the time of thecatheterization, may be useful to identify thoselikely to have a favorable long-term response topulmonary vasodilators.

DIFFERENTIAL DIAGNOSIS

Congenital heart disease, including transposition of thegreat arteries, total and partial anomalous pulmonaryvenous connection, tricuspid atresia, and pulmonaryatresia with intact ventricular septum

Primary parenchymal lung disease such asbronchopulmonary dysplasia (BPD), neonatalpneumonia, respiratory distress syndrome, pulmonarysequestration, and pulmonary hypoplasia

SepsisAlveolar capillary dysplasiaSurfactant protein B deficiency

MANAGEMENT

General supportive cardiorespiratory care.

In severe/ non-responsive cases- use of vasodilatoryagents (eg, inhaled nitric oxid [iNO]), orextracorporeal membrane oxygenation (ECMO)

Specific treatment for any associated parenchymallung disease (eg, antibiotic therapy for pneumonia, orsurfactant for neonatal respiratory distresssyndrome).

Assessment of severity using oxygenation index(OI)

OI - used to assess the severity of hypoxemia inPPHN and to guide the timing of interventionssuch as iNO administration or ECMO support.

OI = [mean airway pressure x FiO2 ÷ PaO2] x 100

A high OI indicates severe hypoxemic respiratoryfailure.

Patients with OI ≥25 should receive care in acenter where high-frequency oscillatoryventilation (HFOV), iNO, and ECMO are readilyavailable

In patients with OI <25, general supportive care istypically adequate and no further invasiveintervention is usually required

General supportive therapy

Avoid hypothermia, hypoglycemia, hypovolaemia,hypocalcaemia, anaemia, polycythemia

Correct metabolic acidosis

Treat underlying cause (e.g. sepsis)

Maintain systemic blood pressure (adequatevolume replacement, inotropes)

Hyperventilation & alkali infusions to maintain analkaline pH- strategies previously in use, nowconsidered outdated.

Lack of conclusive benefit & concerns ofneurological injury & sensorineural deafness withrespiratory alkalosis

Oxygen and optimal oxygen saturations

Providing adequate oxygenation forms the mainstayof PPHN therapy.

However, there are currently no randomized studiescomparing different PaO2 levels in the managementof PPHN in a term infant

Hypoxia increases PVR and contributes to thepathophysiology of PPHN, although hyperoxia doesnot further decrease PVR and instead results in freeradical injury

It has been shown that brief exposure to 100%oxygen in newborn lambs results in increasedcontractility of pulmonary arteries and reducesresponse to iNO

Maintaining preductal oxygen saturations of 90-95% with PaO2 levels b/w 55-80 mmHg isrecommended

Intubation and mechanical ventilation

Indication

• Persistent hypoxaemia despite maximaladministration of supplemental oxygen

Ventilatory strategies include conventional positivepressure ventilation with initial rates of 60–80/minute, an I:E ratio of 1:1.2, a PEEP of 3 cm H2O,and sufficient peak pressure to achieve a PaCO2 ofnot greater than 35–45 mmHg with the pH between7.35 and 7.45.

PaO2 should be maintained at 60–90 mmHg

If high frequency oscillatory ventilation (HFOV) isavailable it can be advantageously used in infantswith pulmonary parenchymal disease and thoseawaiting inhaled nitric oxide therapy.

However a recent meta analysis has failed to show aclear benefit of HFOV over conventional ventilationas an elective or as a rescue mode of ventilation interm or preterm infants with PPHN

Sedation to minimize agitation (which ↑PVR)-fentanyl(1 to 5 mcg/kg per hour), or morphinesulphate(loading dose of 100 to 150 mcg/kg overone hour followed by a continuous infusion of 10to 20 mcg/kg per hour)

Surfactant

Does not appear to be effective when PPHN is theprimary diagnosis

Should be considered in patients with associatedparenchymal lung disease, in whom there iseither a suspected surfactant deficiency (eg,neonatal respiratory distress syndrome) orimpairment (meconium aspiration syndrome)

Interventions for severe cases

Infants with OI>25 despite the use of HFOV arecandidates for iNO therapy or other vasodilatoryagents that decrease PVR.

Patients who fail to respond to these agents mayrequire ECMO

Nitric Oxide

FDA approved in 1999

Mainstay of PPHN treatment

Achieves potent and selective pulmonaryvasodilation without ↓ing SVR

In intravascular space combines with hemoglobinto form methemoglobin, which prevents systemicvasodilation (selective effect).

iNO reduces V/Q mismatch by entering onlyventilated alveoli and redirecting pulmonaryblood by dilating adjacent pulmonary arterioles

Large multi-center trials- demonstrated that iNOreduces the need for ECMO by 40%.

A meta-analysis of 7 RCTs- revealed that 58% ofhypoxic near-term and term infants responded toiNO within 30 to 60 minutes

While use of iNO did not reduce mortality in anystudy analyzed, but the need for rescue ECMOtherapy was significantly↓ed

Indicated for patients with OI ≥25

Earlier initiation (for an OI of 15-25) does notdecrease the incidence of ECMO use and/ordeath or improve other patient outcomes

Currently, the initial recommended concentrationof iNO is 20 ppm.

Higher concentrations are not more effective andare associated with a higher incidence ofmethemoglobinemia and formation of nitrogendioxide

In infants who respond, an improvement inoxygenation is evident within few minutes.

Once initiated, iNO should be gradually weaned toprevent rebound vasoconstriction.

Use of iNO has not been demonstrated to reduce theneed for ECMO in newborns with congenitaldiaphragmatic hernia.

In these newborns, iNO should be used in non-ECMOcenters to allow for acute stabilization, followed byimmediate transfer to a center that can provideECMO.

Contraindications to iNO include congenital heartdisease characterized by left ventricular outflowtract obstruction (eg, interrupted aortic arch,critical aortic stenosis, hypoplastic left heartsyndrome) and severe left ventriculardysfunction.

Extracorporeal membrane oxygenation

About 40% of infants with severe PPHN remainhypoxemic on maximal ventilatory support despiteadministration of iNO

In these patients ECMO therapy should beconsidered.

Goal- maintain adequate tissue oxygen deliveryand avoid irreversible lung injury from mechanicalventilation while PVR decreases & pulmonaryhypertension resolves.

Cochrane review of 4 trials of ECMO showed a strong benefit in terms of survival, without evidence of increased risk of severe disability

Criteria for institution- elevated OI that is consistently ≥40.

However, because mean airway pressures are higher on HFOV than conventional ventilation, some clinicians wait until OI is ≥60 when HFOV is used

Most patients weaned from ECMO within 7 days

However, occasionally ≥2 weeks may benecessary for adequate remodeling of thepulmonary circulation in severe cases.

Who fail to improve may have an irreversiblecondition, such as alveolar capillary dysplasia orsevere pulmonary hypoplasia.

In one large series from a single institution from2000 to 2010, the survival rate following ECMOsupport was 81%

Other vasodilatory agents

SILDENAFIL, a PDE5 inhibitor- ↓ PVR in both animalmodels and adult humans.

Reported to be successful in the treatment of infantswith PPHN in many small studies

In a Cochrane meta-analysis with 37 newborns fromcenters that did not have access to NO and HFV,significant improvement in oxygenation was observedin the group receiving sildenafil. This study noted thatsildenafil may be a treatment option for PPHN.

Starting doses of 0.25–0.5 mg/kg/dose upto a maximum of 2 mg/kg/dose; every 6-8 hourly

In 2012, the US FDA issued a warning thatsildenafil not be prescribed to children withpulmonary arterial hypertension (PAH) because ofreports of associated mortality withadministration of high doses of sildenafil inchildren between 1 and 17 years of age

Indicates the need for further assessment of theefficacy and safety of sildenafil, especially withlong-term treatment

Inhaled or intravenous prostacyclin

Potential intervention in patients who fail NOtherapy

RCTs in adults and animal models have shown itsefficacy; however in neonates only case reportsare available

No longer commonly used (short t1/2 requiringpermanent vascular access, many adverse effects,rebound fatal pulmonary hypertension in case ofdrug interruption)

Bosentan

Endothelin-1 receptor antagonist, was reported tobe effective and safe in short-term treatment ofpatients with PPHN in a single trial in 47 neonates

Potential for serious hepatic injury

Larger studies needed

Milrinone

Phosphodiesterase III inhibitor, has improvedoxygenation in infants refractory to iNO in smallcase series

However, one of these series reportedintraventricular hemorrhage in three of fourtreated infants

RCTs needed to evaluate efficacy and safety

Magnesium sulfate

Promotes vasodilatation by antagonizing entry ofcalcium ions into smooth muscle cells

Small case series reporting its use

One RCT(2010) of iNO versus Mg in treatment of PPHN in babies receiving HFOV, found better outcomes with iNO

Pre-term neonates are at high risk for respiratory depression due to magnesium sulfate

OUTCOMES & PROGNOSIS

With availability of both iNO and ECMO, mortalityin PPHN has reduced from 25–50% to 10–15%

Survivors- at ↑ed risk of adverse sequelaeincluding chronic pulmonary disease and long-term development of neuro-developmentaldisabilities, hearing impairment, and brain injuryand therefore need to be on long term follow-up.