Persistent Pulmonary Hypertension of the Newborn

John Salyer RRT-NPS, MBA, FAARCDirector Respiratory Therapy

Seattle Children’s Hospital and Research Institute

Sense and Sensibility??!?

• Of the deaths in England in 1859, no less than 184,264 -- two in every five of the deaths of the year -- were of children under five years of age

• Above half of these -- 105,629 -- had scarcely seen the light, and never saw one return of their birthday.”

• 43 to 45 infant deaths take place in every 100 births -- 45 per cent! Almost half of the children who are born, die -- perish miserably!

• And this is far from representing the whole mass of pain and suffering, which it is the calamity of children to endure.”

M.A. Barnes 1862: Excessive Infant Mortality: How Can It Be Stayed? British Social Science Association

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It’s the Best Time to Be Alive(So Far)

Improvement in Survival of Low Birth Weight Infants

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Birthweight Strata

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Fetal Circulation

PPHN Pathophysiology• Pulmonary hypertension is a normal and

necessary state for the fetus • In utero, only 5 -10% of the combined ventricular

output is directed to the pulmonary vascular bed.• 80% of drop in pulmonary artery pressure occurs

in 1st 24 h, by local vasodilatation• Neonatal vessels greater vasoconstrictive

response• Oxygen vasodilates vessels• Hypoxemia may release vasoconstrictive

mediators, perpetuating vasospasm

PPHN Pathophysiology

• At Birth– Rapid PVR and in pulmonary artery pressure– 10-fold rise in pulmonary blood flow. – Signals for these transitional changes

• mechanical distension of the lung, • PaCO2, • PaO2

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Epidemiology• Severe PPHN has been estimated to occur in 2

out of 1000 live-born term infants, and • Some degree of pulmonary hypertension

complicates the course of more than 10% of all neonates with respiratory failure.

• Respiratory failure and hypoxemia in the term newborn results from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease.

• Idiopathic pulmonary hypertension is responsible for 10-20% of all infants with PPHN.

D ecreased # o fArteries

(C D H, H ypoplasia,Alv-Cap dysplasia)

Developm entalIm m aturity

M aladaptation;Acute In jury

N orm alm uscularization

Chronic in jury;Vessel

Rem odeling

M alform ation

IncreasedM uscularization

N orm al # o fArteries

PPHN

Clin Perinatol 11: 525, 1984.

PPHN: Pathophysiology

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PO2

L -> R ductus arteriosus

shunt

Ventilation

Remove Placenta

Ductus Venosus Closes

Systemic Vascular Resistance

ß Umbilical venous return

ß IVC Return

ß RA pressure

Ý Pulmonary venous return

Ý LA pressure

Foramen Ovale closes

Pulmonary Vascular Resistance

Effects of lung volume on PVR

BAlveolar vessels compress with lung inflation

A Extra alveolar vessels have high resistance at low and high lung volumes

Hypoxia/low pHPulmonary problemsEndothelin-1 (hypoxia induced)Thromboxane A2 (hypoxia induced)Leukotrienes C4 and D4

Platelet-activating factorLow production of vasodilators (PGI2 and NO)Overinflation/UnderinflationExcessive muscularizationAltered mechanical properties of smooth muscleFetal vasculature opposing vasodilationHypothermia (pulmonary venous constriction)Polycythemia

NOPgI2

PDE5

AdenosineATPMagnesiumBradykininAtrial natriuretic factor

Decreased PVR

Vasodilation

OxygenLung inflationStructural changes in endothelial cellsChanges in interstitial fluid and pressureShear stress

IncreasedPVR

Vasoconstriction

Transition

1) PPHN mechanisms: Lung disease

Abnormally constricted pulmonary vasculature– MAS– Pneumonia– RDS

MAS

RDSGBS pneumonia

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Postulated Pathogenic Mechanisms• Repeated intrauterine closure of ductus

• May occur in Mothers taking high dose Aspirin near term• Abnormal responsiveness of pulmonary vasculature to

hypoxia with inability to relax after stimulus is removed – birth asphyxia

• Repeat intrauterine hypoxia = hypertrophy of medial muscles surrounding pulmonary arterioles

• Pulmonary hypoplasia• Alterations in vasoactive mediator levels

• Mediators participate in transition from fetal to neonatal circulation

• Nitric Oxide is one mediator• Microthrombus formation in pulmonary vascular bed

• Most often associated with perinatal asphyxia, hypoglycemia, hypocalemia and sepsis

PPHN: Diagnosis Suggested by hypoxemia out of proportion to

severity of lung disease Swings of oxygenation without ventilator

change Inability to maintain PaO2 > 60 in 100% O2

Gradient in preductal (right radial) and postductal PaO2 (>20 mm Hg) or O2 saturations (> 6%)

Oxygenation Index (OI) > 15-20 Echocardiogram: document shunting, PA

pressure

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2

PaOFiOMAPOI

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Diagnosis of PPHN

• Term or near term• Cyanosis • Respiratory distress• Normal X-ray

• Unless aspiration, Hyaline membrane disease, CDH

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Three Classifications of PPHN

1. Primary PPHN• Radiographically normal lungs, no evidence of

parenchymal disease2. Secondary PPHN

• Hyaline Membrane Disease• Meconium Aspiration• Aspiration Pneumonia• Transient Tachypnea of the Newborn• Sepsis-Group B Strep

3. Associated with Hypoplasia of the Lungs• Most often Congenital Diaphragmatic Hernia

• Confirm diagnosis of PPHN (R/O Heart Disease

• Correct underlying abnormalities: – metabolic (hypocalcemia, hypoglycemia)– acidosis – hypothermia– polycythemia,– sepsis – surfactant Tx for IRDS– evacuate pneumothoraces

PPHN: Treatment #1

• Maintain pH 7.35-7.50• Try high frequency

ventilation• Consider sedation,

paralysis

• Induce metabolic alkalosis

• Elevate systemic pressure

• Maximize cardiac output (preload, and Dobutamine)

PPHN: Treatment #2

Other StrategiesVentilation strategies

Consider NO if OI > 20 Consider ECMO if OI >40

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Treatment of PPHN• Early diagnosis• Improve alveolar oxygenation• Minimize pulmonary vasoconstriction

• Hyperventilation – CO2 above 25 mmHG• Work to reduce pulmonary trauma• Consider different forms of ventilation

• Sedation and paralytics• Consider induction of alkalotic state – sodium

Bicarbonate • Vasoconstriction appears related to intracellular pH

rather than CO2 levels• End product of sodium bicarbonate is increased CO2

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Treatment of PPHN Continued• Maintain systemic blood pressure and

perfusion• In theory increasing systemic arterial pressure

may result in decreased right to left shunt – improving oxygenation

• Dopamine and Dobutamine are frequently used• Nitric Oxide

• Free radical gas• Increases cyclic GMP in smooth muscles =

vascular relaxation• Must get to pulmonary capillary bed

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Treatment of PPHN Continued• Vasodialators

• Tolazoline (Priscoline)• Appears to be a alpha-sympathetic blocker =

vasodialator• Can cause large drops in systemic vascular blood

pressure • Can be administered through endotracheal tube

• Prostaglandin 12• Major endogenous vasodialator in lung• Normally produced when pulmonary vessels are

constriced• May be helped if Tolazoline has failed

• ECMO

Contraindications for iNO use• Congenital heart disease that is dependent on

right-to-left shunting across ductus arteriosus • Critical Aortic Stenosis• Interrupted Aortic Arch• Hypoplastic Left Heart Syndrome

• May worsen pulmonary edema in patients with TAPVR due to the fixed venous obstruction

Prostacyclin (PGI2) Analogues

• Stimulates membrane bound adenylate cyclase, increases cAMP

• Acutely relaxes vascular smooth muscle• Inhibits pulmonary artery smooth muscle

cell proliferation in vitro; inhibits platelet aggregation; ameliorates endothelial injury

• Reverses vascular remodeling• Reduces synthesis and clears ET-1• Exerts positive inotropic effects

Prostacyclin (PGI2) Analogues

• Continuous i.v. infusion of epoprostenol (Flolan™)

• Costly, ½ life 3-5 minutes• Escalation of dosing is frequently required• Acute withdrawal can lead to fatal PH• May lower systemic vascular resistance,

worsening ductal or atrial level R -> L shunt• May worsen intrapulmonary shunts by

vasodilating non-ventilated areas of the lung

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Outcomes• Before ECMO death rates were above 50%,

with ECMO death rates are about 15%• Status post ECMO neonates have reported

45% morbidity rates• Moderate to severe lung disease• With high alkaline states, can have some

degree of deafness• Right ventricular hypertrophy• With CDH, can have many residual

complications