Persistent pulmonary 

Hypertension of the newborn
Ashley S. Ross, M.D.
ANGELS Perinatal Pre
ANGELS Perinatal Pre‐‐Conference
May 5, 2010

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 Objectives
1
1. Describe the differences between 
Describe the differences between
fetal and newborn cardiovascular 
physiology
h i l
2. Discuss common causes of PPHN
3. Evaluate common approaches to the 
treatment of PPHN
treatment of PPHN

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 PPHN‐‐Background
PPHN
z First described in 1969 by Gersony et al
First described in 1969 by Gersony et al
z First described as “persistent fetal 
circulation”
i l ti ”
„ Systemic blood flow through fetal 

shunts (PDA and PFO)
„ Systemic hypoxia
y yp
„ Similar to fetal circulation

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 Case Presentation
Case Presentation
z 37 week twin gestation, di‐di twins
37 week twin gestation di‐di twins
z Uncomplicated pregnancy
z C‐section for transverse
z A female healthy mild resp distress
A‐female, healthy, mild resp. distress, 
tx to NICU
z B‐significant respiratory distress soon 
after delivery, transfer to NICU
y

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 Case Presentation
Case Presentation
A female
A‐female B male
B‐male
z X‐ray consistent with  z Continued respiratory 
TTN distress
z Transferred to NICU z X‐ray with 
z Within 2 hours,
Within 2 hours,  pneumothorax
p
respiratory distress  z Chest tube, CPAP
resolved z PaO2 50 mmHg on 
g
z Roomed in 100% oxygen

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 What is wrong?
What is wrong?
z Is this PPHN or something else?
Is this PPHN or something else?
z Is it the heart?
z How do you figure it out?
z What are the treatments?
What are the treatments?

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 PPHN‐‐Background
PPHN
z PPHN is defined by a failure of 
PPHN is defined by a failure of
pulmonary vascular resistance to 
d
decrease after delivery
ft d li
z Results in failure of systemic 
oxygenation (hypoxia)
„ Multi‐organ system failure
Multi organ system failure
z Absence of congenital heart disease

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 PPHN‐‐Background
PPHN
z Low oxygen levels normal as fetus
Low oxygen levels normal as fetus
z Low oxygen levels not well tolerated 
after delivery
z Spectrum from mild respiratory
Spectrum from mild respiratory 
symptoms to complete collapse 
needing advanced neonatal intensive
needing advanced neonatal intensive 
care

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 PPHN‐‐Background
PPHN
z Incidence 2/1000 live births
Incidence 2/1000 live births
z Prompt diagnosis important
z Mortality <10%
„ 11‐34% in 1980
11 34% in 1980’ss
z Early treatment improves outcome
„ Referral to tertiary care center

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FETAL CARDIOVASCULAR AND
FETAL CARDIOVASCULAR AND 
TRANSITIONAL PHYSIOLOGY

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 Aorta
SVC
Ductus
Lung Arteriosus

ryology.ch/anglaais/pcardio/umsteellung01.html
LA
RA
Pulmonary
Foramen Artery
LV
Ovale RV

IVC Ductus
Venosus

http://www.embr
Umbilical Aorta
Vein

h
Umbilical
Placenta Artery

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 Fetus characteristics that allow 
for low oxygen levels
z No heat generation
No heat generation
z No significant respiratory effort
z No digestion
z Reduced movement
Reduced movement

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 Fetus Cardiovascular 
Characteristics
z Oxygen consumption reduced in the 
Oxygen consumption reduced in the
fetus
z Lower PaO2/saturations in the fetus
z When delivered
When delivered
„ Increased oxygen demands

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 Ascending Aorta

http://www.embbryology.ch/anglais/pcardio/popuupcardio/p9umsttellung/oxygenvoor.html
SVC

Aorta

Pulmonary DA
Artery

LA
RA

IVC LV

LA
Fetal Oxygen Saturations

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 Changes at Birth‐
Changes at Birth‐
Changes at Birth
Birth‐Lungs
z The lungs become the organ of gas 
The lungs become the organ of gas
exchange
z Continuous breathing
z Expansion of lungs with air
Expansion of lungs with air
z Surfactant synthesis
z Fetus becomes more oxygenated

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 Changes at Birth‐
Changes at Birth‐
Changes at Birth
Birth‐Cardiovascular
z Removal of the placental circulation
Removal of the placental circulation
z Decreased pulmonary vascular 
resistance (PVR)
z Increase in pulmonary blood flow
Increase in pulmonary blood flow
z Closure of the ductus arteriosus, 
f
foramen ovale, and ductus venosus
l dd t

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 Changes at Birth‐
Changes at Birth‐
Changes at Birth
Birth‐Other
z Glucose homeostasis
Glucose homeostasis
z Thermogenesis
z Hormonal and metabolic

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 Desmond M, et al: The transitional care nursery. Pediatr Clin North Am 13:651, 1966.

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 Aorta
SVC
Patent Ductus
Lung Arteriostosis

ryology.ch/anglaais/pcardio/umsteellung02.html
LA
RA
Pulmonary
Patent Artery
LV
Foramen RV
Ovale
IVC Ductus
Venosis

http://www.embr
Umbilical Aorta
Vein

h
Umbilical
Placenta Artery

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 Review

http://www.embryology.ch/anglais/pcardio/umstellung02.html

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 Ascending Aorta

http://www.embbryology.ch/anglais/pcardio/popuupcardio/p9umsttellung/oxygennaach.html
SVC

Aorta

Pulmonary DA
Artery

LA
RA

IVC LV

LA
Fetal Oxygen Saturations

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COMMON CAUSES OF PULMONARY
COMMON CAUSES OF PULMONARY 
HYPERTENSION

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 Common to All Causes of PPHN
Common to All Causes of PPHN
z Pulmonary vasospasm
Pulmonary vasospasm
z Altered pulmonary vascular reactivity
z May have increased muscle mass in 
the pulmonary vascular bed
the pulmonary vascular bed

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 Factors exerting control over 
pulmonary vascular tone
z Hypoxemia
yp
z Acidosis
z Endogenous substances
„ Vasoconstrictors:  leukotrienes, 
thromboxane, endothelin, etc
„ Vasodilators:  oxygen, Nitric Oxide (NO), 
Vasodilators: oxygen Nitric Oxide (NO)
prostacyclin
z Systemic hypotension
y yp
„ Blood flows along pressure gradient –
i.e.:  path of least resistance

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 Causes
Causes of PPHN
of PPHN
z Parenchymal lungs disease
Parenchymal lungs disease
z No known lung disease (primary 
PPHN)
z Genetic or developmental lung
Genetic or developmental lung 
abnormalities

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 Parenchymal
Parenchymal Lung Disease
Lung Disease
z Meconium aspiration syndrome
Meconium aspiration syndrome
„ Most common cause

z H li
Hyaline membrane disease (RDS)
b di (RDS)
„ Third most common

„ Especially in 34‐37 weeks

o Increased pulmonary 
Increased pulmonary
vasoreactivity

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 Parenchymal
Parenchymal Lung Disease
Lung Disease
z Pneumonia/sepsis
„ Release of endotoxins

„ Hypotension

„ Acidosis

z Pneumothorax
„ Hypoxia and/or acidosis

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 Primary PPHN
Primary PPHN
z No recognizable lung disease or 
No recognizable lung disease or
predisposition
z Second most common cause
„ Prenatal constriction of ductus
Prenatal constriction of ductus
arteriosus implicated
„ NSAID

z SSRI’s

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Genetic or developmental lung
abnormalities
z Pulmonary hypoplasia
Pulmonary hypoplasia
„ Congenital diaphragmatic hernia

„ Oligohydramnios

o PPROM

„ Fewer vessels, more reactivity
l
z Lethal forms
„ Alveolar capillary dysplasia

„ Surfactant deficiencies

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 Summary:
Summary: Causes of PPHN
Causes of PPHN

Konduri GG, Kim UO.  Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn.  
, g g p p y yp
Pediatr Clin North Am. 2009 Jun;56(3):579‐600.

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 Diagnosis
Diagnosis of PPHN
of PPHN
z Respiratory distress
Respiratory distress
z Labile oxygenation
z Hypoxia out of proportion to degree of
Hypoxia out of proportion to degree of 
lung disease
z Exam
„ Respiratory distress, grunting, 

retractions, cyanosis
t ti i
„ Murmur from tricuspid regurgitation

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 Diagnosis
Diagnosis of PPHN
of PPHN
z Overlap with cyanotic heart disease
Overlap with cyanotic heart disease
z Chest x‐ray
z Arterial blood gas*
z Pre and post ductal pulse ox
Pre and post ductal pulse ox
„ ½ of babies with have a shunt across 

PDA
z Echocardiography
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 Hyperoxia Test
Hyperoxia Test
z Arterial blood gas obtained prior to and 5‐
g p
10 minutes after administration of 100% 
Oxygen
„ PaO2 < 50 mmHg ‐ cyanotic congenital 
heart disease or PPHN
„ PaO2 <150 mmHg ‐
P O2 150 H PPHN
„ PaO2 > 150 mmHg ‐ parenchymal lung 
disease
„ PaO2 > 300 mmHg ‐ normal

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 Echocardiography
z Pediatric trained echo techs needed
Pediatric trained echo techs needed
z Look for congenital heart disease
z Right to left/bidirectional shunts
z Flat intraventricular septum
Flat intraventricular septum
z Dilated right ventricle
z Tricuspid regurgitation to estimate 
pulmonary
pulmonary artery pressures
artery pressures
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APPROACHES TO TREATING
APPROACHES TO TREATING 
PULMONARY HYPERTENSION

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 Anticipation
Anticipation and Transition
and Transition
z Anticipating at risk infants
Anticipating at risk infants
„ MAS, sepsis, CDH, etc.

„ Prompt treatment and evaluation

z Ensuring appropriate transition

Ensuring appropriate transition
„ Thermoregulation, glucose 

homeostasis, blood pressure, 
antibiotics

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 Principles of Treatment
Principles of Treatment
z Restore cardiopulmonary transition 
Restore cardiopulmonary transition
while avoiding lung injury
z Avoid oxygen toxicity
z Avoid compromise of systemic
Avoid compromise of systemic 
perfusion

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 Treatment
z Correct underlying metabolic 
Correct underlying metabolic
derangements
„ Body Temperature
Body Temperature
„ Acidosis

„ Surfactant

„ Glucose homeostasis

„ Electrolyte abnormalities
El t l t b liti
„ Treat anemia

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 Respiratory Treatment
Respiratory Treatment
z Mild respiratory distress
Mild respiratory distress
„ Treat with nasal cannula or CPAP

„ Follow ABG closely

„ Low threshold for UAC/UVC
Low threshold for UAC/UVC
„ Low threshold for ventilation

z Moderate to severe disease must be 
treated
treated aggressively
aggressively
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 Treatment
z Goal in moderate to severe disease is 
Goal in moderate to severe disease is
to
„ Reverse right‐to‐left shunts

„ Reduction of PVR
Reduction of PVR
„ Maintain systemic blood pressure

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 Respiratory Treatment
Respiratory Treatment
z Ventilation / oxygenation
„ High PaO2 (>100 mm Hg) and low PCO2 
High PaO2 (>100 mm Hg) and low PCO2
used traditionally
o Does not improve outcomes, 
Does not improve outcomes,
potentially harmful to lungs and 
cerebral perfusion
o No significant reduction in PVR with 
No significant reduction in PVR with
PaO2 > 100 mm Hg
o Sometime need 
Sometime need >100 100 mm Hg due to 
mm Hg due to
lability (flip flop)
„ High frequency ventilation

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 Cardiovascular Treatment
Cardiovascular Treatment
z Increase systemic blood pressure
Increase systemic blood pressure
„ Reduce right‐to‐left shunts

„ Dopamine, dobutamine, 
Dopamine dobutamine
epinephrine
o Optimize (not maximize) cardiac 
Optimize (not maximize) cardiac
function
„ Want normal to high blood pressure
Want normal to high blood pressure

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 Pulmonary vasodilators
Pulmonary vasodilators
z Inhaled nitric oxide
Inhaled nitric oxide
„ Most significant advancement in 
treatment
„ Selective pulmonary vasodilator

„ Supported by several large trials
Supported by several large trials
„ Decreased mortality and need for 
ECMO
z Milrinone, sildenafil (off label use)

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 Sedation/Paralytics
z Minimize stimulation
Minimize stimulation
„ Quiet, minimize movement of 
patient
„ Sedation / neuromuscular blocking 
agents?
o Reduce oxygen consumption
o Comfort

o Not tested in randomized trials

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 ECMO
z Extracorporeal membrane 
Extracorporeal membrane
oxygenation
z First used in the 1970’s
„ Used as rescue therapy for neonates 
Used as rescue therapy for neonates
with greater than 80% predicted 
mortality
z Respirator and cardiac support

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 ECMO
z Allows lungs to recover while on 
Allows lungs to recover while on
ECMO
z Only for >34 weeks
„ Complications greater in less mature
Complications greater in less mature
z Reduced numbers of ECMO cases
z ACH the busiest neonatal ECMO 
center in world in recent years
y

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 ECMO
z Early referral for PPHN and ECMO 
Early referral for PPHN and ECMO
essential
„ iNO started on ECMO candidate, 

should transfer to ECMO center
„ ECMO not a replacement for early, 

optimized therapy for PPHN
therapy for PPHN

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 Case Presentation ‐ Resolution
Case Presentation ‐
Case Presentation 
z Twin B placed on vent
Twin B placed on vent
z Echo showed flat septum, TR jet systemic
z Surfactant replacement
z Able to rapidly wean oxygen
p y yg
z Improved oxygenation, extubated DOL 6
z Discharged to home at 16 days
Discharged to home at 16 days

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archildrens.org arpediatrics.org uams.edu
 Summary
z Understanding fetal circulation and transition is 
g
to understand PPHN
z Good transitional care important in the 
prevention of PPHN
prevention of PPHN
z The most common causes of PPHN are MAS, RDS, 
and infection
z Treating PPHN includes providing adequate 
oxygenation and restoration of cardiopulmonary 
transition using optimal (not maximal) therapies 
g p ( ) p
appropriate to the cause of the PPHN

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 References
z Krishnan U.  Management of pulmonary 
g p y
arterial hypertension in the neonatal unit.  
Cardiol Rev. 2010 Mar‐Apr;18(2):73‐5.
z K d i GG, Kim UO.  Advances in the 
Konduri GG Ki UO Ad i th
diagnosis and management of persistent 
pu o a y ype te s o o t e e bo
pulmonary hypertension of the newborn.  
Pediatr Clin North Am. 2009 Jun;56(3):579‐
600.
z Kl
Klaus and Fanaroff, Care of the High‐Risk 
dF ff C f h Hi h Ri k
Neonate, 5th edition. 

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