Persistent Pulmonary Hypertension of the
Newborn
John Salyer RRT-NPS, MBA, FAARC
Director 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)
Percent Survival
Improvement in Survival of Low Birth Weight Infants
100
90
80
70
60
50
40
30
20
10
0
1991-92
1993-94
1995-96
1997-98
1999-01
450600 g
601700 g
701800 g
801900 g
Birthweight Strata
9011000 g
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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.
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PPHN: Pathophysiology
PPHN
Decreased # of
Arteries
(CDH, Hypoplasia,
Alv-Cap dysplasia)
Normal # of
Arteries
Normal
muscularization
Developmental
Immaturity
Maladaptation;
Acute Injury
Increased
Muscularization
Chronic injury;
Vessel
Remodeling
Malformation
Clin Perinatol 11: 525, 1984.
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 Pulmonary Vascular Resistance
 Pulmonary venous return
 LA pressure
Ventilation
Foramen Ovale
closes
 PO2
L -> R ductus
arteriosus
shunt
 RA pressure
Remove
Placenta
 IVC Return
 Umbilical venous return
 Systemic Vascular Resistance
Ductus
Venosus
Closes
Effects of lung volume on PVR
A
Extra
alveolar
vessels have
high
resistance at
low and high
lung volumes
B
Alveolar
vessels
compress
with lung
inflation
Transition
Increased
PVR
Vasoconstriction
Hypoxia/low pH
Pulmonary problems
Endothelin-1 (hypoxia induced)
Thromboxane A2 (hypoxia induced)
Leukotrienes C4 and D4
Platelet-activating factor
Low production of vasodilators (PGI2 and NO)
Overinflation/Underinflation
Excessive muscularization
Altered mechanical properties
of smooth muscle
Fetal vasculature opposing vasodilation
Hypothermia (pulmonary venous constriction)
Polycythemia
Decreased
PVR
Vasodilation
Oxygen
Lung inflation
Structural changes
in endothelial cells
Changes in interstitial
fluid and pressure
Shear stress
NO
PgI2
PDE5
Adenosine
ATP
Magnesium
Bradykinin
Atrial natriuretic
factor
1) PPHN mechanisms: Lung disease
Abnormally constricted pulmonary vasculature
– MAS
– Pneumonia
– RDS
MA
GBS pneumonia
RDS
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
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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%)
MAP FiO
OI 
 Oxygenation Index (OI) > 15-20
2
PaO2
 Echocardiogram: document shunting, PA
pressure
100
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 disease
2. 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
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PPHN: Treatment #1
• 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 #2
Ventilation strategies
• Maintain pH 7.35-7.50
• Try high frequency
ventilation
• Consider sedation,
paralysis
Other Strategies
• Induce metabolic
alkalosis
• Elevate systemic
pressure
• Maximize cardiac
output (preload, and
Dobutamine)
 Consider NO if OI > 20
 Consider ECMO if OI >40
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
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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
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
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