Persistent

Pulmonary
Hypertension
Objectives
To discuss Persistent Pulmonary Hypertension in
the Newborn, specifically

To give a brief overview of normal fetal and neonatal

transitional circulation

To discuss the etiology and pathogenesis of PPHN

To discuss the diagnosis of PPHN

To discuss the management of PPHN including ventilatory,

pulmonary vasodilator

To discuss prognosis of patients with PPHN

 Fetal circulation
• In fetal circulation, the placenta serves as the
organ of gas exchange
• Most of the right ventricular output crosses
the ductus arteriosus to the aorta
• Only 13 to 21% of the ventricular output
perfuse the lungs due to high PVR
• High Pulmonary Vascular Resistance:
• Fluid filled lungs, hypoxic pulmonary
vasoconstriction, and circulating
vasoconstrictors (endothelin-1, leukotriene,
thromboxane)

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
 Transitional circulation
At birth fetal pulmonary circulation must rapidly adapt to direct blood
flow to the lungs as the organ of gas exchange

Rapid and dramatic decrease in PVR  redirects half of the combined

ventricular output from the placenta to the lung
 8 to 10 fold increase in pulmonary blood flow

Increase in pulmonary bloodflow  increase pulmonary venous return

and left atrial pressure  functional closure of the foramen ovale

Removal of the low resistance vascular bed of the placenta  increases

systemic vascular resistance at birth

Because PVR decreases lower than SVR, flow reverses across the ductus
arteriosus (L  R)  increased oxygen saturation leads to closure of the
ductus arteriosus and ductus venosus

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Pulmonary Vascular Transition
Near term, the small muscular pulmonary arteries demonstrate a
considerable increase in luminal diameter due to flattening of the
endothelial cells, spreading of the smooth muscle cells, and an increase
in external diameter caused by smooth muscle relaxation

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Vasoactive Mediators of the
Pulmonary Vascular Transition
• Nitric oxide (NO)– central mediator of pulmonary vascular tone
• Stimulates guanylate cyclase activity through the cGMP pathway
in vascular smooth muscle  decreased phosphorylation of
myosin light chain  smooth muscle relaxation

• Prostacyclin (PGI2) central vasodilator that is upregulated in

response to ventilation of the lung.
• Generated by cyclooxygenase and prostacyclin synthase from
arachidonic acid
• Stimulates adenylate cyclase to increase intracellular cAMP levels,
 decrease in intracellular calcium concentrations  decreased
phosphorylation of myosin light chain  smooth muscle relaxation

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Persistent Pulmonary Hypertension
• Failure of normal pulmonary vascular adaptation at birth

• Characterized by elevated pulmonary vascular resistance, and

right to left extrapulmonary shunting of deoxygenated blood
causing severe hypoxemia

• Complicates the course of about 10% of term and preterm

infants with respiratory failure

• Significant risk of death, pulmonary morbidity and

neurodevelopmental impairment

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Pathophysiology of PPHN

Lung parenchymal
MAS, RDS, Pneumonia
diseases

Maladaptation of Primary or Idiopathic

pulmonary vasculature PPHN

Maldevelopment/
Underdevelopment of Oligohydramnios, CDH
pulmonary vasculature

Polycythemia with
Intrinsic obstruction
hyperviscosity

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Pathophysiology of PPHN
• Vascular maldevelopment is a hallmark
of PPHN
• Significant pulmonary vascular
remodeling occurs antenatally in infants
with early, severe, PPHN
• Vessel wall thickening and smooth
muscle hyperplasia
• Extension of smooth muscle to the
level of the intra-acinar arteries

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
 Risk Factors: Maternal Exposures

• Maternal use of salicylates or NSAIDS

• One of the earliest triggers associated with PPHN
• More recent studies found no significant association with
NSAID/ibuprofen use during the last trimester and PPHN

• SSRI use – Use during 2nd half of pregnancy increased the risk for
PPHN
• Some evidence of concentration-dependent constriction of
the ductus arteriosus

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors: Genetic Factors

• Rarely familial, with few genetic risk factors identified

• Polymorphism in the rate-limiting enzyme of the urea cycle,
carbamoyl-phosphate synthetase-1  associated with
pulmonary hypotension, low arginine and low plasma nitric
oxide metabolites

• Significant association with genetic variants for corticotropin

releasing hormone receptor-1 (CRHR-1) and CRH-binding
protein and with significantly increased levels of 17-
hydroxyprogesterone

• Higher incidence of PPHN in children with Down syndrome

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors:

• Elective cesarean section

• Delays the decrease in pulmonary arterial pressure and
increases the risk of PPHN

• Other maternal factors:

• Diabetes
• Asthma
• Black or Asian race
• High body mass index

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors:

• Perinatal asphyxia:
• Fetal hypoxemia, ischemia, acidosis, meconium aspiration,
and ventricular dysfunction  delay the fall in PVR 
increased the risk for PPHN
• Acute asphyxia  reversible pulmonary vasoconstriction
• Chronic in utero asphyxia  vascular remodeling

• Disruption in production and function of vasoactive mediators

• Disruption in NO-cGMP, prostacyclin-cAMP, and endothelin
signaling pathways  vascular dysfunction seen in PPHN

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors: Congenital Diaphragmatic
Hernia
• ~8% of all major congenital anomalies and affects 2500-3000
pregnancies
• Develops early in the course of lung development
• Arrest in the normal pattern of airway branching occurs in both
lungs  reduced lung volume and impaired alveolarization
• After birth, PVR remains at the suprasystemic levels 
extrapulmonary right-to-left shunting across the PFO and PDA 
significant hypoxemia

Factors that lead to high PVR in CDH

1) small cross-sectional area of pulmonary arteries
2) structural vascular remodeling
3) vasoconstriction with altered reactivity
4) LV dysfunction causing pulmonary venous hypertension

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors: Alveolar Capillary
Dysplasia
• Rare form of interstitial lung disease that presents as severe
PH and hypoxemia early in life
• Remodeling of the pulmonary arterioles, simplification of
the alveolar architecture, and development of congested
“misaligned pulmonary veins”
• Diagnosis: microscopic examination of the lung, hence post
mortem evaluation is recommended.

• 40% of infant with ACD has identified mutation or deletion in

the FOXF1 transcriptor factor gene or deletions upstream to
FOX1

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors: Pulmonary Hypertension
in Premature Infants
• Degree of hypoxemia is out of proportion to the parenchymal
lung disease.

• Bronchopulmonary dysplasia - important cause of chronic

pulmonary hypertension
• Complex interaction between antenatal factors such as
growth restriction, preeclampsia, oligohydramnios, or fetal
inflammation, and postnatal injury due to ventilator-induced
lung injury, hyperoxia, hemodynamic stress, and infection

• The morphologic vascular alteration are accompanied by

increase in PV tone and heightened vasoconstrictor responses
to acute hypoxia. Overtime, reduced vascular growth, limits
vascular surface area and promotes high PVR

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Risk Factors and Pathogenesis of PPHN

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Clinical Manifestations
• PPHN presents with:
• Respiratory distress and cyanosis
• Differential saturations
• Labile oxygenation
• Profound hypoxemia despite oxygen and
mechanical ventilation

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Diagnosis of PPHN
• Thorough history and PE
• Pulse oximetry – differential saturations (5-10%
difference)
• Blood gas - PaO2 difference of 10 – 20mmHg
• Xray

• 2D Echocardiography
• To rule out congenital heart disease
• To Establish an accurate diagnosis of PPHN
• To Identify any extra pulmonary shunting
• Also used to determine ventricular function
• LV insufficiency can cause pulmonary venous
hypertension that can be aggravated by a
pulmonary vasodilation
M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Echocardiography
The direction of the shunt at atrial and ductal level also provides clues to management

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
 General Care of PPHN

• Maintenance of normothermia
• Correction of metabolic derangements (electrolytes
particularly calcium, and glucose
• Maintenance of intravascular volume and normal blood
pressure
• Primary goal: optimization of left and right ventricular
function
• Enhance systemic O2 transport

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
General Care of
• Minimize stimulation
PPHN
• Adequate sedation and
analgesia
• Maintain preductal
saturation in low to mid 90’s
as long as there is no
metabolic or lactic acidosis
and oliguria is not present
• Adequate lung recruitment
• Maintenance of adequate
blood pressure

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Oxygenation Targets
• Mainstay of PPHN Therapy: Providing adequate oxygenation
• Hypoxia increases PVR and contributes to the pathophysiology of PPHN
• Hyperoxia does not further decrease PVR and instead results in free radical
injury
• Brief exposure to 100% oxygen in newborn lambs results in increased
contractility of pulmonary arteries and reduces response to iNO

• The short-term pulmonary vascular benefits of hyperoxia should be carefully

weighed against the risks of increased pulmonary vascular contractility,
diminished vasodilator responses, as well as potential systemic risks.

• Suggested targets: Maintain preductal oxygen saturations in low to mid-90s with

PaO2 levels between 55 and 80 mmHg
Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Ventilation Strategies

• Optimal lung expansion is essential for adequate oxygenation as well as the

effective delivery of iNO
• Lung recruitment using PEEP or MAP should be optimized to 9-10 ribs expansion
• Gentle ventilation strategies w/ optimal PEEP, relatively low PIP or TV, and
degree of permissive hypercapnia

• High-frequency ventilation and/or surfactant are often useful in infants with

severe parenchymal lung disease
• HFOV used to optimize lung inflation and minimize lung injury (when
conventional ventilation reaches PIP 25-28cm H2O, TV > 6mL/kg)

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Ventilation Strategies
• Surfactant
• Improves oxygenation, reduces air leak, and reduces need for ECMO in infants
with meconium aspiration, sepsis, and other parenchymal lung disease
• Ineffective and run the risk of lung overdistension or acute airway obstruction
in infants with idiopathic pulmonary hypertension
• iNO + HFOV resulted in greatest improvement in PPHN caused by parenchymal
lung disease
• Infants with failure of improvement in oxygenation with maintenance of good
hemodynamic function may be candidates for ECMO
• In the presence of an indwelling arterial line, severity of PPHN is assessed by
calculation of oxygenation index (OI).
OI = Mean airway pressure in cm H2O × FiO2 × 100 ÷ PaO2 in mmHg

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Endothelium-derived mediators
• Primary goal of PPHN therapy
is selective pulmonary
vasodilation

• Medications used in PPHN

• Inhaled nitric oxide (iNO)
• Prostacyclin
• Milrinone
• Bosentan
• Sildenafil

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Nitric Oxide
• Potent and selective pulmonary vasodilator without a significant decrease in
systemic blood pressure (selective effect of iNO)
• Preferentially distributed to the ventilated segments of the lung,  increased
perfusion of the ventilated segments < optimizing ventilation-perfusion
mismatch (microselective effect of iNO)
• iNO therapy reduces the need for ECMO in term neonates with hypoxemic
respiratory failure
• Initiation at an OI of 15 – 25 did not reduce the need for ECMO but did reduce
the risk of progression of disease severity.
• Starting dose: 20 ppm for OI of 20
• Complete response: Increase in PaO2/FiO2 ratio of 20mmHg or more

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Nitric Oxide
• Starting dose: 20 ppm for OI of 20
• Complete response: Increase in PaO2/FiO2 ratio of 20mmHg or more
• Monitoring of methemoglobin levels at 2 and 8 hours after initiating iNO then
once a day thereafter
• Weaning iNO should be gradual minimize the risk of rebound vasoconstriction
and resultant pulmonary hypertension
• If there is oxygenation response, FiO2 is first weaned below 60%, iNO is weaned
only if PaO2 can be maintained at 60 mm Hg or higher (or preductal oxygen
saturation as measured by pulse oximetry ‡90%) for 60 minutes (60-60-60 rule
of weaning iNO)
• Wean by 5 ppm every 4 hours  Once iNO dose is 5 ppm, gradual weaning by 1
ppm every 2 to 4 hours

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Other vasodilators
• Unavailability, high costs and failure of response to nitric oxide  research for
other therapeutic options
• Sildenafil’s inhibition of the cGMP degradation by PDE5 and Milrinone’s
inhibition of the cAMP degradation by PDE3 are two of the most promising
therapies

• Sildenafil: available both in oral and IV form

• Oral sildenafil (dose range 1-2 mg/kg q6h) improves oxygenation and reduces
mortality
• Milrinone:
• In the presence of ventricular dysfunction with normal BP, an inodilator such
as milrinone might be the preferred therapeutic agent in PPHN

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
Management of PPHN: Other Options
Postnatal systemic steroids - decreases the duration of hospital length of stay and
oxygen dependence in MAS.

Hydrocortisone treatment postnatally has been shown to improve oxygenation,

increase cGMP levels and reduce ROS levels.

Care should be taken to avoid using steroids in the presence of bacterial or viral
infection.

Recent evidence that genetic abnormalities in the cortisol pathway are associated
with PPHN provide further basis for exploring the role of steroids in PPHN.

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Extracorporeal Memrane Oxygenation
• ECMO is a supportive measure that essentially gives
time for the neonatal heart and lung to recover from the
underlying pathology
• Prior to the introduction of ECMO in 1980’s the mortality
rate for severe hypoxemic respiratory failure was near
40% and prevalence of major neurologic disability in
survivors was estimated at 25-60%
• ECMO produced remarkable reduction in the mortality
rate of PPHN and based on the recent iNO clinical trials
contemporary mortality rates for PPHN are
approximately 7%-9%

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 Prognosis and Complications

Complications/Long term morbidities

1) Reactive airway disease: > 25% in the first year of life
2) Feeding Difficulty and/or poor weight gain: 15-20%
3) Need for supplemental oxygen by 2 years of age
4) Significant Neurodevelopmental delay in 25% of survivors
5) Late sensorineural hearing loss 0 6-10%
6) Severe (6-10%) and moderate intellectual disability (7%)

M a c D o n a l d , M G , S e s h i a M M K ( 2 0 1 6 ) Av e r y ’s N e o n ato l o g y Pat h o p hy s i o l o g y a n d M a n a g e m e nt o f t h e N e w b o r n
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
AHA/ ATS Management Guidelines for Persistent AHA/ ATS Management Guidelines for PPHN (cont.)
Pulmonary Hypertension of the Newborn
5. Sildenafil is reasonable adjunctive therapy for infants
1. iNO is indicated to reduce the need for ECMO with PPHN who are refractory to iNO, especially with OI
support in term and near term infants w/ PPHN or > 25 (class IIa level B)
hypoxemic respiratory failure who have OI that 6. Inhaled prostacyclin analogues may be considered as
exceeds 25 adjunctive therapy for infants with PPHN that are
2. Lung recruitment strategies can improve the efficacy refractory to iNO, and have OI that exceeds 25 (class IIa
of iNO therapy and should be performed in patients level B)
w/ PPHN associated with parenchymal lung disease 7. Intravenous milrinone is reasonable for infants with
(class I levelB) PPHN and significant left ventricular dysfunction (class
IIa level B)
3. ECMO support is indicated for term and near term 8. Inhaled NO can be beneficial for preterm infants with
neonates with severe PH and/or hypoxemia that is severe hypoxemia that is primarily due to PPHN
refractory to iNO and optimization of respiratory and physiology rather than parenchymal lung disease (class
cardiac function IIa level B)
4. Evaluation for disorders of lung development such 9. iNO and other PAH – targeted drug therapies should be
as alveolar capillary dysplasia and genetic surfactant used cautiously in subjects with CDH especially those
diseases, is reasonable for infants with severe PPHN with confirmed or suspected left ventricular dysfunction
who fail to improve after vasodilator, lung (class IIa level B)
recruitment and/or ECMO therapy (class II level B)

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn. NeoReviews/American Academy of Pediatrics
Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M. Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Elsevier.
 References

Lakshminurimha, S. et al. (2015) Persistent Pulmonary Hypertension in the newborn.

NeoReviews/American Academy of Pediatrics

OPENPediatrics [OpenPediatrics]. (2018, June 1). Persistent Pulmonary Hypertension of the

Newborn: Pathophysiology by Andrea Moscatelli [Video]. Youtube.
https://www.youtube.com/watch?v=WkBsat8Qh1w

MacDonald, MG, Seshia MMK (2016) Avery’s Neonatology

Pathophysiology and Management of the Newborn

Steinhorn, RH (2019). Pulmonary Vascular Development. In R. Martin, A. Fanaroff, & M.

Walsh, Fanaroff & Martin's Neonatal-Perinatal Medicine Diseases of the Fetus and Infant.
Elsevier.