Persistent Pulmonary Hypertension of

Newborn-PPHN

Etiopathogenesis and Clinical features

Fetal,Transitional and Neonatal circulation:

• The placenta provides for gas and meatboliteexchange.

• Rt and Lt ventricle exist in parallel circuit.

• Three structures maintaining parallel circln.

1. Ductus venosus

2. Foramen ovale

3. Ductus arteriosus

• Pulmonary vasculature are constricted diverting blood away from pul.circulation

Pulmonary vascular resistance decreases due to mechanical expansion of lungs and increase in arterial Po2

Systemic vascular resistance increases due to removal of low resistance placental circulation.shunt through ductus arteriosusbecomes L to R.

High Po2 eventually closes ductus arteriosus over days and becomes ligamentum arteriosum.

Increase in volume of Lt atrium closes flap of foramen ovalefunctionally.

Removal of the placenta from the circulation also in results in closure of ductus venosus

Over few weeks pumonary vascular resistance further decreases secondary to remodelling of pulmonary vasculature i.e thinning of vascular smooth muscle and recruitment of new vessels.

Pulmonary Blood flow and PVR:

• Most fundamental and critical transition necessary for postnatal life is the establishment of breathing, accompanied by a fall in PVR.

• At midgestation, PVR is tenfold higher , last trimester, PVR seven- to eightfold greater than it is 24 hours after delivery .

• PVR reduction results from the physical growth of the pulmonary vasculature that increases the cross-sectional area.

• Mechanical and biochemical factors lead to the abrupt fall in PVR at delivery.

1. Aeration of the previously fluid-filled lungs removes the external compressive force on the pulmonary vasculature.

2. Responding to the sudden rise in oxygen tension, the endothelium secretes potent vasodilators, nitric oxide and prostacyclin.

3. Luminal diameter increases as endothelial and smooth muscle cells become thinner.

4. The increase in blood flow further recruits small lumen vessels- increase in the cross-sectional area of the pulmonary vascular bed.

• This first, rapid phase of pulmonary vasodilation is followed by a period of remodeling that lasts for months.

• PVR approximates adult values by about 2 months of age, and the remodeling process is usually complete by 6 months of age.

PFC/PPHN/Hypoxemic respiratory failure

• PPHN reflects disruption of the normal perinatal fetal to neonatal circulatory transition

-characterized by sustained elevation in pulmonary vascular resistance (PVR) rather than the decrease in PVR that normally occurs at birth, resulting in right-to-left shunting of blood through fetal circulatory pathways

Epidemology:

Population based study 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.

• 1 -2/1,000 live births and is most common among full-term and post-term infants.

• Risk factors for PPHN:

- Gestational age 34 to <37 weeks (ie, late preterm infants)

- Black maternal race,

-Large or small for gestational age.

-Mothers with pre-existing and gestational diabetes, obesity, and advanced age.

• Factors associated with a lower risk of PPHN included female sex, Hispanic ethnicity, and multiple gestation.

Pathogenesis:

Three types of abnormalities of the pulmonary vasculature underlie the disorder:

1. Underdevelopment

2. Maldevelopment

3. Maladaptation

Underdevelopment:

• Cross sectional area of the pulmonary vasculature is reduced.

• Resulting in a relatively fixed elevation of pulmonary vascular resistance (PVR).

• Occurs with pulmonary hypoplasia . Congenital diaphragmatic hernia (CDH), Congenital pulmonary (cystic adenomatoid) malformation, Renal agenesis Oligohydramnios accompanying obstructive uropathy.

&Fetal growth restriction. • Postnatal pulmonary vasodilatation is limited. • Mortality risk is greatest in this category of patients.

Maldevelopment:

• Lungs that are normally developed and have a normal number of pulmonary vessels

• Abnormal thickening of the muscle layer of the pulmonary arterioles, and extension of this layer into small vessels that normally have thin walls and no muscle cells .

• The extracellular matrix that surrounds the pulmonary vessels also is excessive.

• Pulmonary vasculature responds poorly to stimuli that normally result in a decrease in PVR.

• Vascular mediators appear to play a role-endothelin-1 , cGMP, arginine.

Maldevelopment:• Conditions associated with PPHN caused by

vascular maldevelopment include Post term delivery. Meconium staining & meconium aspiration

syndrome (MAS) IU exposure to SSRI.• Excessive perfusion of the fetal lung also may

predispose to vascular maldevelopment.Premature closure of the ductus arteriosus

[NSAIDs] High placental vascular resistance TAPVC

Maladaptation :

• The pulmonary vascular bed is normally developed. • Adverse perinatal conditions cause active

vasoconstriction and interfere with the normal postnatal fall in PVR.

• These conditions include -Perinatal depression-Pulmonary parenchymal diseases-Bacterial infections-GBS. • GBS &PPHN - activation of vasoactive mediators by

bacterial phospholipid components- cardiolipin and phosphatidylglycerol.

Idiopathic Pulmonary HTN(Black lung)

• No asssociated respiratory condition.

• Pathogenesis –maldevelopment-smooth muscle hyperplasia.

• Chronic IU hypoxia,exposure to NSAIDS and SSRI have been implicated,unknown genetic factors.

• Chest X ray-hyperlucent lung fields(Black lung)

Secondary PPHN:

• Respiratory diagnoses associated with PPHN

MAS, 41 %

Pneumonia 14%

RDS, 13 %

Pneumonia and/or RDS, when they could not be distinguished (14%)

CDH, 10 %

Pulmonary hypoplasia (4 %)

Clinical features:

• Prenatal findings in PPHN - signs of intrauterine and perinatal asphyxia-fetal heart rate abnormalities (ie, bradycardia and tachycardia) and MSAF.

• PPHN is rare in VLBW preterm infants, PPROM appears to be a common feature.

Clinical features:

• Most PPHN present within the first 24 hours of life with signs of respiratory distress and cyanosis.

• More than 50% have low apgar scores and received delivery room interventions .

• Physical examination is cyanosis and signs of respiratory distress.

• Meconium staining of skin and nails, which may be indicative of intrauterine stress.

• The cardiac examination.- Prominent precordial impulse, - Narrowly split and accentuated second heart sound. - Harsh systolic murmur consistent with tricuspid

insufficiency lower left sternal border.

Initial laboratory tests

Pulse oximetry assessment:• Labile O2 saturation• Demonstrates a difference of greater than 10

percent between the pre- and postductal (right thumb and either great toe) oxygen saturation.

• This differential is due to right-to-left shunting through the patent ductus arteriosus (PDA).

• Absence gradient in does not exclude the diagnosis of , since right-to-left shunting can occur predominantly through the foramen ovalerather than the PDA.

Arterial blood gas• Low arterial partial pressure of oxygen

(PaO2 <100 mmHg receiving 100 %FiO2). • Unlike cyanotic lesions, PPHN have at least one

measurement of PaO2 >100 mmHg early in the course of their illness.

• The arterial partial pressure of carbon dioxide (PaCO2) is normal in infants without accompanying lung disease.

• Differences in PaO2 (>10-15mm Hg )between samples obtained from the right radial artery (preductal sample) and the umbilical artery (postductal sample)

Hyperoxia Test:

Hyperoxia-hyperventilation test.

• Manually ventilated at a rate of 100-150 bpmfor 10 minutes.

• Result in a decrease in PaCO2 to 25 mmHg and a concomitant increase in the arterial PH.

• In PPHN, an increase of PaO2 by at least

30 mmHg is considered a positive response and little or no response is seen in infants with cyanotic CHD.

40 – mortality risk > 80-90% 25-40 – Moratlity risk 50-60%

Alveolar Arterial O2 gradient:

Alveolar Arterial O2 gradient:

• In normal person breathing room air, the AaDO2 is less than 10 mmHg.

• In a neonate due to higher physiological dead space , this may be upto 25-35 mm of Hg .

• Large gradients (high AaDO2) are noted in CCHD, MAS and PPHN.

• AaDO2 > 620 for 12 hr on FiO2 100% is an indication for ECMO in West, because risk of mortality is > 80%

Chest radiograph

• The chest radiograph is usually normal or demonstrates the findings of an associated pulmonary condition (eg, parenchymaldisease, air leak, or CDH).

• The heart size typically is normal or slightly enlarged.

• Pulmonary blood flow may appear normal or reduced.

Echocardiography:

• MPAP >25 mm Hg, PVR>3 Wood units/m2

• Catheter measurements gold standard for diagnosis

• Echocardiography:

Non invasive

Serial evaluation

Hemodynamic assessment

• Inferior venacava: Dilatation ,Lack of inspiratory collapse

• Right atrium:Bulging interatrial septum into LA ,Rt to left shunt across IAS

• Right ventricular pressure overload- flattening of IVS in end-systole into LV - ‘D-shaped LV’

• IVS Flattening: Quantitative assessment of severity of PH-mild, moderate, or severe.

• Maximal TR jet velocity (CW Doppler)

Modified Bernoulli equation

RVSP = SPAP = 4 (TR Vmax)² + mean RAPe

Differentials:• Cyanotic congenital heart disease (CHD), which is

distinguished from PPHN by echocardiography.• Primary isolated parenchymal lung disease -

pneumonia, TTN, and RDS differentiated clinical setting and chest radiography. - most patients with PPHN will also have an associated lung disorder echocardiography confirms the diagnosis of PPHN.

• Sepsis distinguished by the clinical setting, positive blood cultures, and echocardiography.

• Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD-MPV) ,have initial period of stability and develop severe hypoxemia later than PPHN , further evaluation including catheterization and lung biopsy are needed to confirm the diagnosis.

Summary:• Persistent high PVR,with Rt to Lt shunt.

• Incidence 2/1000 live births.

• Etiological classification-Primary(idiopathic) and secondary

• Pathological classifiction-Underdevelopment,maldevelopment,maladaptation.

• C/F:Cyanosis and Respiratory distress.

• CVS:Narrowly split & accentuated S2,systolic murmur in L parasternal area

• Spo2 and Pao2 gradient btw pre and post ductal artery.

• Hyperoxia –hyperventilation test.

• Echo-structurally N heart,PASP>25mm Hg.

References:• 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.

• Ann R Stark, MD et al.Persistent pulmonary hypertension of the newborn.Uptodate April 2017.

• Abman SH, Hansmann G, Archer SL, et al. PediatricPulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation 2015; 132:2037.

• Robin H. Steinhorn and Steven H. Abman. Persistent Pulmonary Hypertension of the Newborn .Avery Diseases of Newborn 2014;732-740.

• Linda J. Van Marte,Christopher C. McPherson. Persistent Pulmonary Hypertension of the Newborn.Cloherty and Stark’s Manual of Neonatal care 2017;468-480

• Update on PPHN: mechanisms and treatment. Nair J, Lakshminrusimha S, Semin Perinatol. 2014 Mar;38(2):78-91

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