Persistent Pulmonary

Hypertension of the Newborn

Nursing Grand Rounds
Kendra Smith, MD
4/2/2020
425-785-7353
Kendra.Smith@seattlechildrens.org
Site PI for IV Sildenafil and IV/SQ Remodulin
study trials; Research funding provided to SCH
Liquid ventilation study for infants with Congenital
Diaphragmatic Hernia on extracorporeal life
support (ECLS); Funding to the SCH Foundation
from the Ladybug Foundation
No personal financial support
I will be talking about Remodulin, Sildenafil and
other medications to treat adult pulmonary
hypertension that are being used in neonates, as
well as liquid ventilation; none are FDA approved
for neonates
I am very honored to have been invited to speak
for the Nursing Grand Rounds today (Thank you,
Hai-Yen!!!)
I want to acknowledge Drs. Satyan
Lakshminrusimha, Steve Abman, and Robin
Steinhorn for sharing their slides
I want to thank the parents who have welcomed
me into their lives while taking care of their baby
I want to thank all of you!
Call me after the presentation at 425-785-7353 or
send me an e-mail with your question
(kmsmith@uw.edu)
Definition of persistent pulmonary
hypertension of the newborn (PPHN)
Normal pulmonary circulation
Pathophysiological changes in PPHN
Clinical assessment/
echocardiography
Effect of therapeutic modalities
Situations where iNO is
contraindicated
Elevated pulmonary
vascular resistance
relative to systemic
vascular resistance from
either vasoconstriction
or structural remodeling
of the pulmonary
vasculature
 Normal transition
Fetal blood flow:
2/3 of IVC flow is 1/3 of IVC flow
directed toward the mixes with
foramen ovale (FO) by blood from the
the eustachian valve SVC and enters
and septum primum the RV then the
and enters the left Pulmonary
atrium artery

Normally at birth:
• Air enters the lungs and improves oxygenation of the pulmonary vascular
bed
• Pulmonary blood flow increases
• Pulmonary vascular resistance (PVR) decreases to ½ of systemic resistance
• Left Atrial pressure increases and Foramen Ovale closes
• Systemic vascular resistance (SVR) increases due to removal of placenta
• PDA flow reverses from R->L to L->R
• PDA closes in response to increased oxygen tension and with postnatal
circulatory pattern

Courtesy of Satyan Lakshminrusimha

 Fetal Circulation
Ratio of blood entering
the pulmonary arteries to
the ductus arteriosus is
determined by the fetal
Physiologic pulmonary pulmonary vascular
resistance (PVR) and can
hypertension vary with fetal
Oxygen induced
oxygenation status and
vasodilation and lung
gestation
expansion decrease PVR
to ~1/2 of SVR

Normal transition: Abnormal transition:

Physiologic pulmonary Persistent Pulmonary Hypertension/HRF.
hypertension resolved PDA flows R-> L or bidirectional
Courtesy of Satyan
Lakshminrusimha
 Diseases and
2
Pathophysiology of
Hypoxic Respiratory
Idiopathic (“Black lung” PPHN) Failure
Meconium aspiration
at PDA syndrome,
Respiratory distress
syndrome,
Pneumonia***
1 4
Congenital
diaphragmatic
hernia,
RV LV
oligohydramnios
Alveolar or vascular
hypoplasia
LA

2 MAS, RDS,
R L shunt at PFO
RA Pneumonia, TTNB,
Atelectasis***

3
Asphyxia, sepsis, CDH Courtesy of Satyan
Lakshminrusimha
40-2/7 weeks gestation, 4.5 kg
Mother was pretreated with cefazolin for fever
Placental pathology showed chorioamnionitis,
funisitis and vasculitis suggesting congenital
sepsis but infant cultures were negative as was
viral workup
Suctioned for large amounts of meconium at birth
Apgars 3, 5, 5
Moderate encephalopathy so underwent
therapeutic hypothermia for 72 hrs
Respiratory/metabolic acidosis: pH of 6.6, PCO2
122 torr (16 kPa), base -25, PIP up to 40 in DR
Treated with surfactant and inhaled nitric oxide
Hypoxic Respiratory Failure/ARDS: HFOV Paw
30, Frequency 8, Amplitude 55, FiO2 1.0
Distributive/cardiogenic shock: NS (70 mL/K),
dopa 20, dobut 20, epi 0.25, HC and Decadron;
not coagulopathic
At Seattle Children’s 7.09/49/31/-17; lactate 12,
preductal sat 90, post-ductal sat 80

Echo showed elevated pulmonary pressures

Placed on VV ECLS

Had a pulmonary hemorrhage day 2

Had no improvement for 10 days

Underwent a biopsy with associated extensive

bleeding calling for massive transfusion protocol
Normal lung
architecture

Our case
 OI= 100
MAS/PPHN

• VV ECLS for 32 days

• Partial liquid ventilation for 5 days
MAP × FiO2 • Off ECLS 4 days after treatment with liquid
OI = ×100 • Off ventilation at 40 days of age (HFNC 8 LPM)
PaO2 • IV sildenafil for 30 days
• iNO off 2 weeks after coming off ECLS
The PPHN quagmire
*MAS + Pneumonia
can release
inflammatory
mediators that induce
PPHN can occur due
vasoconstriction
to an abnormal
pulmonary vascular
bed despite absence 1
of alveolar hypoxia,
hypercapnia and
lung inflammation
4 2
7
9

3*
8 6
Presence of meconium
Acidosis
Asphyxia at delivery
Maternal risk factors for infection
• Prolonged rupture of membranes
• Maternal fever
• Positive group B streptococcus status
Postmaturity
Maternal aspirin or SSRI (selective
serotonin reuptake inhibitors)
Persistent Pulmonary Hypertension
• Impaired pulmonary vascular
adaptation during the early
neonatal period
• Affects ~10% of all neonates
with respiratory failure
• Mortality is 7-8%
• 25% incidence of long-term
neurodevelopmental
impairment
• Some genetic factors identified
• Reversibility and impact on
adult pulmonary disease poorly
understood
Courtesy of Dr. Robin Steinhorn
Usually presents within first 24 hours of life with
severe cyanosis, respiratory distress
Labile hypoxemia: severe hypoxemia with wide
swings in arterial PO2 without changes in vent
settings (less effect on CO2 retention)
Hypoxemia out of proportion to the degree of
parenchymal disease severity
Single, loud S2, systolic murmur of tricuspid
regurgitation
Difference in arterial PO2 ≥ 10 to 20 mm Hg or
oxygen sats ≥ 5 to 10%
 Meconium aspiration – histology
(decreased ventilation to
perfusion)
Meconium

O2=40
CO2=45

CO2 45

Small rounded balls of

meconium are in the alveoli
 O2=150mmHg
CO2=0

O2=100
O2=40 CO2=40
O2=150
CO2=45 CO2=0
O2=40
CO2=45
CO2 =45
Normal V/Q Increasing V/Q
Decreasing V/Q

Diseased Vasoconstriction of
alveolus pulmonary vasculature bed

V/Q < 1 V/Q > 1

Under ventilated and Normally ventilated and
normally perfused OR under-perfused OR
normally ventilated but verventilated and
over perfused normally perfused
When pulmonary and
systemic arterial
pressures are similar,
small alterations in the
ratio of the two can
produce large changes in
extrapulmonary shunting:
Blood flow in PPHN
◦ When SVR > PVR, Normal blood flow

there is no R L shunt
◦ When PVR is close to or
exceeds SVR, variable
R L shunting at the
PFO and PDA results in
labile hypoxemia
 Clinical features
• If a ductus is present and there is no major
atrial/ventricular shunting,
– preductal O2 sat > postductal O2 sat
(=differential cyanosis)

10-20 point
difference between
pre-vs. postductal
arterial PO2
X
Or 5-10% difference
X between pre- vs.
postductal sats
KS1

Clinical features
• Absence of a difference in oxygen tension does not
exclude PPHN because shunting at the atrial level
produces no ductal gradient and is probably the most
common site of shunting
– preductal and postductal sats will be equal

≠
Slide 32

KS1 ??
Kendra Smith, 2/1/2020
Hyperoxia test:
◦ Obtaining an arterial gas at baseline in
room air and after 15 minutes of exposure
to 100% oxygen and/or hyperoxia-
hyperventilation (hyperoxia and alkalosis
to induce pulmonary vasodilation and
improve PaO2) is no longer practiced due
to known adverse effects of hyperoxia and
alkalosis.
Lakshminrusimha S, Kumar V. Pediatric Critical Care Fifth Edition. Ed Fuhrman
and Zimmerman. Chapter 56, Diseases of Pulmonary Circulation. Elsevier, 2017
Lability usually indicates PPHN
History of meconium at birth or suspected
chorioamnionitis in the mother may help
B-naturiuretic peptide (BNP) (used for Sildenafil
and Remodulin studies); used monthly to follow
BPD patients
Some patients may need to be transported on
both iNO and PGE
Ductal Atrial Diagnosis Management
shunt shunt

R L R L PPHN Oxygenation/iNO,
lung recruitment

L R L R Parenchymal lung disease Lung recruitment,

and V/Q mismatch specific therapy,
iNO may be
beneficial
R L L R PPHN with LV dysfunction Milrinone
with some pulmonary
venous hypertension
(common in CDH, asphyxia,
sepsis)
L R R L Tricuspid atresia/stenosis PGE1 and surgery
or pulmonic
atresia/stenosis
R L R L TAPVR (total anomalous Surgery
(Large Small LA/ no pulmonary venous return)
tricuspid
PA) regurg
Differential diagnosis of hypoxemia
and treatment
• R L shunting at the PDA and PFO: due to PPHN
• optimize lung inflation, treat with oxygen and iNO
Differential diagnosis of hypoxemia
and treatment
• L R shunting at the PDA and PFO with marked
hypoxemia suggests parenchymal lung disease with
predominantly intrapulmonary shunting (V/Q
mismatch)
• optimize lung inflation, iNO may help
Differential diagnosis of hypoxemia
and treatment
• R L shunting at the PDA with L R shunting at atrial
level suggests PPHN with LV dysfunction with some
pulmonary venous hypertension (common in CDH,
asphyxia and sepsis)
• Treat with milrinone

X
 Differential diagnosis of
hypoxemia and treatment
• L R shunting at the PDA with R L shunting at
atrial level
• Diagnosis Tricuspid atresia/stenosis or pulmonic
atresia/stenosis-> PGE and surgery
 Differential diagnosis of
hypoxemia and treatment
• R L shunting at the PDA with a large pulmonary
artery and R L shunting at atrial level with a small left
atrium and no tricuspid regurgitation
• Diagnosis TAPVR-> to surgery
 4

1
2
 PPHN may result in
• Eventual cardiac failure
 Causes of hypotension
3

7
6
 Premature babies develop PPHN
Kumar et al, J Perinatal 2007

Single center retrospective study

2% incidence of early pulmonary

hypertension for infants <33 weeks
(24/1202)

Aikio et al, J Pediatr 2012

2.2% incidence of early PH for

infants <32 weeks (17/765)

Both studies showed risk factors of

PPROM, oligohydramnios
 Epidemiology of PPHN
APPROACH:
• Case-control epidemiologic study of antenatal and perinatal
risk factors for PPHN
• Enrolled and interviewed 377 mothers with PPHN babies and 836
matched controls.
RESULTS:
• Pre-pregnancy conditions: maternal diabetes, asthma, high BMI
• SSRI use after 20th week (6-fold increase)* (disputed )**
• NSAID use may be associated with in utero PDA closure***
• Block prostaglandin which maintain ductal patency in utero and
are important mediators of pulmonary vasodilation in response to
ventilation at birth****
* Chambers CD, et al. N Engl J Med.
• C-section delivery (7-fold increase) 2006;354: 579-587
** Wilson KL, et al. Am J Perinatol.
• Near term (34-37 weeks) (2-fold increase) 2011;28:19-24
*** Talati AJ, et al. Am J
• Post-term (> 41 weeks) Perinatol.2000;17(2):69-71
**** Alano MA, et al. Pediatrics.
• Large for gestational age (BW > 90 %ile)
th 2001;107(3):519-23
Courtesy of Satyan Lakshminrusimha
 Normal Fetus
Ratio of the blood entering the pulmonary arteries to the
ductus is determined by the fetal PVR and can vary with fetal
oxygenation status and gestation. Maintaining a high PVR in
utero is important because gas exchange is done by the
placenta.

Pulm blood flow –

Placenta 25% in human fetus

1. Konduri GG, et al. Am J 1. Kiserud et al. Physiology of the

Physiol. 1997;272:H2377-
H2384
2. Lakshminrusimha S. Clin
Perinatol. 2012;39:655-683.
3. Diseases of Pulmonary
Circulation, Page 707
fetal circulation, Seminars in
Fetal & Neonatal Medicine.
2005
2. Gao Y, Raj JU. Regulation of
Courtesy of Satyan pulmonary circulation in fetus
and newborn, Physiol Rev. 2010
Lakshminrusimha
 Fetal pulmonary circulation: first stage of transition
(fetus is in state of physiologic pulmonary hypertension)
Pulmonary
venous PO2
Pulmonary 17-19 mmHg Characterized by high pressure and
arterial PO2 low flow because of both passive and
17-19 mmHg active elevation of PVR

Fluid in • Passive resistance due to

alveoli compression of pulmonary
capillaries by fetal lung fluid
• Active vasomotor tone resulting
Constricted blood from various mediators and
vessels (high PVR hypoxic stimuli
• PVR > SVR
Low alveolar oxygen R-L flow at PFO and PDA
(17 mmHg)

1. Kiserud et al Physiology of the fetal circulation, Seminars in Fetal & Neonatal Med 2005
2. Gao Y, Raj JU, Regulation of pulmonary circulation in fetus and newborn, Physiol Rev 2010 Courtesy of Satyan Lakshminrusimha
Histology
 Endothelin pathway in utero promotes
vasoconstriction
ET-1 (Synthesized by vascular Pulmonary
endothelial cells) vasodilators
•Potent vasoconstrictor mediated by Ca
•Vasodilator mediated by NO

•Two SMC receptor subtypes:

•ETA receptor plays a role in
vasoconstriction in utero

increases
•ETB receptor plays a role in
vasodilation; may be less active
in fetal life.
•Mediated by endothelium-
derived nitric oxide
•May decrease PVR at birth
 NO pathway in utero promotes vasodilation
• ETB on the endothelial cell
stimulates NO release and
vasodilation.
• eNOS produces NO, which
diffuses from the
endothelium to the SMC
and
• stimulates sGC to
produce cGMP which Soluble guanylate cyclase

is broken down by
increases
PDE5 to
• GMP
 Stages of lung development

Pseudo- Terminal sac

glandular
6-16 weeks
Canalicular
16-26 weeks

Terminal sac Respiratory

bronchiole
26-36 weeks

Alveolar
36 weeks-3 years
Terminal
bronchiole
Alveoli

Increase in cross-sectional area of pulmonary vascular bed. Pulmonary vessels

become more sensitive to vasoconstrictive mediators, such as endothelin and relative
hypoxemia, resulting in active pulmonary vasoconstriction and an increase in the PVR
 Variations in conformation of the lung during
development affects PVR
Alveolar,
after birth,
and over
the first few
weeks,
PVR
Canalicular Alveolar, decreases
Saccular
before birth

High PVR is caused The broad Despite rapid After birth lung
by low density of intersaccular increase in the liquid is absorbed
the vasculature septae contain the number of small and an air-liquid
double capillary pulmonary interphase is
network and, with arteries, high PVR established with
increasing vascular is maintained by juxtaposition of
density, the PVR active capillaries and
decreases vasoconstriction alveolar epithelium
to promote
effective gas
Lakshminrusimha, S. Clin Perinatol 2012; 39:655-683
exchange.
 PPHN: Failure of postnatal adaptation-usually
associated with perinatal hypoxia

Pulmonary vascular resistance PPHN (hypoxic

pulmonary
vasocontriction)

• Stretch (lung expansion)

• Increased O2 (arterial + alveolar)
• Ventilation
• Increase in pH
• Blood flow through the lung
• Vasodilators
Normal

Birth Time
Fetus Neonate Takes weeks to months for
the PAP to fall to adult levels
 In utero vasoconstrictors
Increased
PVR: Decreased
Vasoconstriction PVR:
Vasodilation
Cause high vascular tone in the fetal lung:
• Low oxygen tension
• Compression of pulmonary capillaries by
fetal lung liquid
Contribute to vascular tone:
• Arachidonic acid metabolites:
1) Cyclooxygenase pathway
• Prostaglandin F 2 alpha
• Thrmoboxane A 2
• 2) 5-lipoxygenase pathway
• Leukotrienes
• Endothelins (ET-1, ET-2, ET-3): response is
tone-dependent (i.e. ET-1 and ET-2 dilate
the fetal pulmonary vasculature and
constrict the bed when the tone is reduced
by ventilation
 What happens at birth? Second stage
Dilated blood vessels
4 (reduced PVR)
1
Entry of air
into the
alveoli
2
3
Clearance of Increased
lung fluid alveolar oxygen
(100-150
mmHg)

Drop in PVR is accompanied by

production of prostacyclin
Within 5 minutes after birth, oxygen-
(PGI2) and NO synthesized by
induced vasodilation and lung
endothelial cells causing
expansion decrease PVR to ~ half of
relaxation of the smooth
SVR
muscle cells
 Pulmonary vascular changes: 3rd stage
In 12-24 hours
Rapid structural
remodeling of the entire
pulmonary bed from the
main pulmonary artery to
the capillaries further
decreases PVR

Changes in shape and

geometric orientation
of endothelial and
smooth muscle cells
cause luminal
enlargement
Courtesy of Satyan Lakshminrusimha
Changes in small PA during transition

Fetal PA-near Neonatal PA-24

term gestation hrs after birth

Courtesy of Satyan Lakshminrusimha

 Birth-Related Stimuli:
Role of O2 along with ventilation and shear stress
L-Arginine
Endothelial
Nitric Cell
Oxide
L-Citrulline NO Synthase

O2
Guanylate Cyclase

Smooth
GTP
Muscle
cGMP
5’GMP Cell

PDE5
VASODILATION
Courtesy of Dr. Robin Steinhorn
Because pulmonary vasodilation at birth
is a vital step in establishing postnatal
life, there are sufficient redundant
vasodilators to compensate for failure or
inadequacy of any single pathway.
 Important mediator to
Dilation of fetal NO pathway dilates SMC decrease PVR at birth
pulmonary
circulation is
caused by an Fetal pulmonary vasodilators
increase in stimulate endothelial NO
oxygen tension production
mediated by
eNOS
BNP: B-type natriuretic
peptides dilate fetal
pulmonary vasculature
cGMP

activates

Diminished eNOS 2) Soluble

guanylate
expression may **
Cyclic guanosine cyclase
contribute to both monophosphate activated
(2nd messanger)
cGMP induces relaxation
abnormal of SMC through activation
vasoreactivity + of cGMP-dependent
excessive protein kinase that
muscularinization produces a lowering of
3) activates cytosolic ionic Ca, in part
Lowered via through activation of K
4)
activation of 5) Relaxation of channels
K channel

Premies have low arterial sGC, a likely reason for their poor response to iNO
Important in
maintaining
Prostaglandin pathway dilates SMC
ductal patency Potent
pulmonary
vasodilator in
fetus

cyclooxygenase enzyme
PPHN seen in Arachidonic
mothers taking Prostacyclin acid
aspirin or receptor metabolite,
NSAIDS that stimulates prostacyclin
inhibit COX (PGI2),
activity and relaxes
Broken down by
cause prenatal smooth
constriction of SR muscle by
the ductus or by producing
decreasing PGI2 cAMP
synthesis at (PGI2 analogs
birth are
(association Remodulin,
called into Flolan,
question) Iloprost)
 Transition
Increased
PVR: Decreased
Vasoconstriction PVR:
Vasodilation
• Hypoxia/low pH/Pulmonary problems
• Thromboxane A2 (via COX; hypoxia induced)
• Acetylcholine
• Prostaglandin F2α (via COX pathway) Stim
• Bradykinin production
• Seratonin
• Histamine of NO
• Endothelin-1 (hypoxia induced) • Lung inflation** • NO
• Leukotrienes C4 and D4 • Structural changes • PGI2, PGE1, PGE2,PGD2
• HETEs (attenuate pulm myogenic response) in endothelial cells • ATP
• Rho/Rho kinase • Oxygen • Adenosine natriuretic
• Low production of vasodilators (PGI2 + NO) • Changes in peptides (ANP, BNP,
• Overinflation/Underinflation interstitial CNP)
• Excessive muscularization fluid and pressure • Arachidonic acid
• Altered mechanical properties • Shear stress metabolites
of smooth muscle
• Atrial natriuretic
• Fetal vasculature opposing vasodilation
factor
• Hypothermia (pulmonary venous
• EETs
constriction)
• Magnesium
• Polycythemia
 Critical Windows of Vascular Development

Failed Transition
PA Pressure

Irreversibility
Transitional
Zone from
Normal

Transitional
Zone to
Normal

Courtesy of Dr. Robin Steinhorn Age Modified from Aschner JL et, 2011
 Excessive muscularization
• Thickening of media
and adventitia
• Increased matrix
protein in pulmonary
vessel walls
• Does not necessarily
imply
hypercontractile
tendencies, rather
impaired dilation
Courtesy of Dr. Steve Abman.
PPHN. NeoPrep 2014
Bancalari E, Keszler M, Davis P. The Newborn
Lung. 3rd Edition. 2019. Chapter 3
Normal versus abnormally muscularized arteries
• Fully • Increase in
muscularized vascular
thick-walled smooth
preacinar muscle
arteries extend ---------------- resulting from
to level of peripheral
terminal ---------------- extension into
bronchioles vessels not
normally
• Intra-acinar nonmuscular containing
arteries, muscle layers
accompanying
respiratory • Can occur
bronchioles, prenatally or
are partially postnatally
muscular or
nonmuscular * In utero ductal ligation 1-2 weeks before
delivery can result in distal extension of
the vascular smooth muscle in lambs
Wild LM, Nickerson PA, Morin FC. Pediatr Res 1989;25:251
 Excessive muscularization
• Impaired dilation
1) Changes in relaxant properties of pulmonary
vascular smooth muscle cell
• Decreased pulmonary vascular content of
myosin chain phosphatase (key enzyme
responsible for muscle relaxation in pulmonary
vasculature)
2) Dysfunctional endothelial cell function
• Failure to produce dilators, overproduction of
constrictors, failure to metabolize and remove
constrictors
• Belik J, Majumdar R, et al. Pediatr Res 1998: 43:57
• McQuestron JA, Kinsella JP, et al. Am J Physiol 1995; 268:H288
Transient tachypnea of
the newborn (TTN)
Aspiration syndromes -
meconium or blood
Congenital
Diaphragmatic Hernia
(CDH)
HYaline membrane
disease (RDS)
PNEumonia/Sepsis
Air leaks/Asphyxia
Pneumothorax

Courtesy of Satyan Lakshminrusimha

 1) PPHN Mechanism
Parenchymal lung diseases:
cause acute alveolar hypoxia leading to
acute pulmonary vasoconstriction

MAS GBS pneumonia RDS

PPHN can result from alveolar hypoxia, inflammatory
mediators, or abnormal pulmonary vascular muscularization
 2) PPHN mechanism
Remodeled vasculature:
cause maladaptation of pulmonary circulation

CDH Chronic Intrauterine

intrauterine closure of the
hypoxia PDA
 3) PPHN mechanisms
Pulmonary hypoplasia:
cause maladaptation of pulmonary circulation

CDH CPAM Hypoplasia

congenital pulmonary (oligohydramnios
adenomatoid due to renal
malformation disease, chronic
(intrathoracic space- amniotic fluid leak)
occupying lesion)
Congenital diaphragmatic hernia
Bowel, part of
liver,
stomach, and
spleen
through
diaphragmatic
defect

Keller RL. 2007.

Bancalari E, Keszler M, Davis P. The Newborn
Lung. 3rd Edition. 2019. Chapter 3
Angiograms in CDH show pruning of vascular tree
contralateral ipsilateral

Right lung of an Right and left lungs of infant with

infant without CDH who died at 79 days of age.
CDH who died There is significant “pruning” of the
from other causes distal pulmonary vascular tree.
while on ECLS
Keller RL. 2007.
 4) PPHN mechanisms:
Malformations of alveolar and vascular
development

Alveolar Acinar
capillary dysplasia
dysplasia
Acinar dysplasia:
Lung arrest at
pseudoglandular stage
Secondary to hyperviscosity often due to
polycythemia
 BPD
Preterms with fetal growth restriction and born after prolonged
rupture of membranes
 Treatment modalities
• Positive airway pressure
• Lung volume
• Surfactant*
• pH, paO2, paCO2
• iNO 20 ppm (5-20)
• Hydrocortisone***
• DOPA, Epi, Vasopressin
• Intravenous vasodilators
• Sedation
* Muscle relaxation
* Hyperoxia increases oxygen free radicals and reduces response to iNO
Lung recruitment
strategies and O2. If need
PIP 28 or VT > 6 mL/kg
High frequency
pH 7.3-7.4 (>7.25), PaCO2
40-60, PaO2 55-80 (sats
low to mid 90’s)
PULMONARY
VASODILATORS, Anti-
inflammatory agent,
Inotropes
Patients are sensitive to
agitation/pain
increased mortality
 *PPHN can occur due to an abnormal pulmonary
Asphyxia and PPHN vascular bed despite absence of alveolar hypoxia,
hypercapnia and lung inflammation

Hyperventilation
can cause impaired
cerebral perfusion
and neurosensory
deafness

*MAS + Pneumonia can release inflammatory

mediators that induce vasoconstriction
PaCO2 reported at baby’s temp (not corrected to
37 degrees-alpha-stat method)
Decreasing temp increases the solubility of CO2
in the blood and decreases PaCO2
May have implications for PPHN management
with potential of overventilation or
underventilation
Courtesy of Satyan Lakshminrusimha
PVR is PVR is increased
increased with with
atelectasis: loss overexpansion:
of support for compression of
extra-alveolar alveolar capillary
vessels bed

Hyperventilation should not be used due to

decreasing cerebral perfusion and neurosensory
deafness at extremes of respiratory alkalosis
 Effect of Ventilation: Pulmonary Vascular
Resistance PVR) is minimal at FRC

Low lung volume Optimal lung volume High lung volume

at FRC

FRC=functional residual capacity

 FRC

Functional residual capacity (FRC) or rest volume (<20% of total

lung capacity) is the point at which collapsing and distending
pressures balance out to zero pressure- is the gas that remains in
the lung after a normal expiration.
 Importance of PEEP= Paw

Paw= Mean Make PEEP a priority

Airway Pressure
 Model – PPHN with Remodeled Pulmonary
Vasculature
Increased
Hysterotomy and fetal shear stress
ductal ligation at 126 d
gestation

Delivery 9 days later by

C-section

Vascular remodeling with

smooth muscle
hypertrophy
Term ~ 145 days Courtesy of Satyan Lakshminrusimha
 Severe Hypoxic Pulmonary Vasoconstriction in Lambs
with PPHN; Change Point – Similar to Control Lambs

Change Point ~ 60 ± 7 mmHg

Recommendation for infants is to keep

saturations in the low to mid-90’s with PaO2
levels between 55-80

Lakshminrusimha S et al, Pediatr Res. 2009 Nov;66(5):539-44

 Hyperoxia accentuates vascular dysfunction
Brief exposure to 100%
PPHN 100% O2 oxygen in lambs resulted
in increased contractility
of pulmonary arteries
Reactive and reduced response to
ROS
oxygen iNO*
species
Vascular remodeling
eNOS expression
PDE5 activity

Blunted cGMP and iNO

response Vasoconstriction
Courtesy of Dr. Robin Steinhorn *Laksminrusimha, S, et al. J Appl Physiol.2011:111(5):1441-7
Histology of alveolus, smooth muscle and
endothelial cells
Respiratory
bronchiole

Alveoli

NO combines with hemoglobin to form methemoglobin and

does not exert a vasodilator effect on the systemic circulation
NeoReviews
Nitric oxide signaling pathway Prostacyclin signaling pathway
Indocin can inhibit COX
Arachidonic
pathway -> ongoing
Amino Acid acid
PVR
generated by urea
cycle

Oxygen + Oxygen +
Sheer Prostacyclin Sheer
stress stress

iNO
cGMP and cAMP
indirectly free
cytosolic calcium
leading to vascular
dilation

X X
Prostacyclin
Derivatives:

Inhibit PDE5: Inhibits Remodulin,

Methylxanthines function as PD inhibitors
Sildenafil, which play a key role in regulating PDE3: Flolan,
intracellular levels of cAMP and cGMP
Hydrocortisone Milrinone Iloprost
 Inhaled nitric oxide

No iNO iNO

• Enters only ventilated alveoli and redirects pulmonary blood by dilating

adjacent pulmonary arterioles so reduces V/Q mismatch
• Works best with adequate lung recruitment, preferably with high-
frequency ventilation (HFOV and HFJV)
• Doses >20 ppm do not increase the efficacy and are associated with more
adverse effects such as elevated methemoglobin and nitrogen dioxide
(especially if the inspired oxygen is high)
Courtesy of Ikaria
Initiation of iNO
20-20-20 rule

When: OI of 20
Dose: 20 ppm
Response: P/F
ratio increases by
> 20 mm Hg

Weaning iNO
60-60-60 rule

When: start 60
min after FiO2 <60
and PaO2 >60
SpO2 > 90%
Discontining abruptly can cause “rebound” pulmonary
hypertension and hypoxemia due to down regulation of
endogenous NO and elevations in free radicals and
endothelin-1 caused by iNO therapy
Continuing iNO in the absence of a response or not
weaning iNO or extremely slow weaning can potentially
lead to suppression of endogenous eNOS.
iNO is FDA approved for neonates >34 weeks but
given the fact that premature infants can develop
PPHN as well, it is beneficial in some cases

Patients with preexisting LV dysfunction treated

with iNO, even for short durations, are at risk for
developing pulmonary edema (package insert,
INOmax, 2009)
Neonates who have LV
dysfunction associated with
high left atrial pressures
and a

1) L R shunt at the
foramen oval

2) R L shunt at the PDA X

should NOT be treated with
iNO because it can
precipitate pulmonary
edema. Milrinone may be a
better choice.

Clogged drain
Inhaled nitric oxide at the alveolar-capillary membrane
Release of reactive
Air O2 NO2 oxygen species
space such as superoxide
Nitric oxide

Formation of
Type I reactive nitrogen
Type II
alveolar species such as
Alveolar
cell peroxynitrite
cell
NO2 and O2-
Inactivation by
hemoglobin
Formation of
Red S-nitrosothiols
methemoglobin Leukocyte
cell
+ nitrate
ferrous
Hgb Plasma proteins Vascular space
Endothelial cell

• Is toxic at higher concentrations

• Reacts with superoxide anion to form peroxynitrite,
which causes lipid peroxidation and other oxidative
injury to cell membranes
• NO2 is even more toxic
• Use at 20 ppm is felt to be safe

Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. NEJM. 2005;353:2683-2695
 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
iNO is FDA approved for neonates >34 weeks

Patients with preexisting LV dysfunction treated

with iNO, even for short durations, are at risk for
developing pulmonary edema (package insert,
INOmax, 2009)
 iNO
• Overall rate of neurodevelopmental handicap in
infants treated with NO was 46%, with 25% mildly
affected and 21% severely affected at 1 year FU
Lipkin PH, et al. Neuodevelopmental and medical outcomes of
persistent pulmonary hypertension in term newborns treated
with nitric oxide. J Pediatr. 2002;140:306-310

• Mild neurodevelopmental handicaps in 14% and

12% had severe at 1 year
• Senorineural hearing loss present in 6-19%
Rosenberg A A, et al. Longitudinal follow-up of a cohort of
newborn infants treated with inhaled nitric oxide for PPHN. J
Pediatr. 1997;131:70-75
Decreases PDE5 activity so cGMP
increases which promotes vasodilation Inhibit PDE5:
Hydrocortisone,
Attenuates reactive oxygen species Sildenafil
production by induction of superoxide
dismutase
Stabilizes systemic blood pressure allowing
improved oxygenation possibly secondary to
hemodynamic stability
Treats pulmonary interstitial glycogenosis
Start early!
Perez M, et al. Hydrocortisone
normalizes PDE5 activity in pulmonary
artery smooth muscle cells from lambs
with PPHN. Pulm Circ, 2014;4:71-81
 Patchy Diffuse
• Abnormal accumulation of glycogen in interstitium
• Associated with lung disease (MAS, PPHN,
pneumonia)
• Diffuse infiltrates seen on CXR
• Improves with steroids
 Remodulin
Flolan
Iloprost

Potent, short-acting, cAMP-dependent

vasodilator of the pulmonary and systemic
circulations
Acutely relaxes vascular smooth muscle cell
Inhibits platelet aggregation
Ameliorates endothelial injury
Inhibits VSMC migration and proliferation
Reverses vascular remodeling
Reduces synthesis and improves clearance of
ET-1

See end of presentation for more details

• Phosphodiesterase-5 inhibitor
• Facilitates nitric oxide-cyclic-GMP-induced
vasodilatation in the lungs by inhibiting the
degradation of cGMP
• Used to prevent rebound PPHN in
weaning patients off iNO
• Used in oral form
• IV international study started 2013;
completed in December of 2018
Inhibits phosphodiesterase (PDE3) and increases
concentration of cAMP in pulmonary and systemic arterial
smooth muscle and in cardiac muscle.
Acts additively with iNO
Believed to improve cardiac function by
◦ Positive inotropy (improved contraction). Increases
cardiac output with reduction in filling pressures and
systemic vascular resistance
◦ Positive lusitropy (improved relaxation). Causes
peripheral vasodilation and improved relaxation of the
myocardium during diastole
◦ Reduced ventricular afterload
Minimally affects heart rate
Anticipate a drop in BP!!!
Systemic BPs should be maintained at a
normal range for age and gestation, as an
increased systemic resistance may decrease
the degree of R L shunting.
Increasing BP to supraphysiologic levels is not
recommended.
◦ PDA acts as a pop-off valve, limiting RV preload and
dysfunction.
◦ Increasing BP limits R L shunt across the PDA and
may add to right ventricular strain.
◦ If PBF (pulmonary blood flow) is forced by elevating
systemic pressure (+ limiting R L shunts) through
the constricted pulmonary circuit, endothelial
dysfunction due to increased shear stress can
exacerbate PPHN
Sharma V, et al. Maternal Health Neonatol
Perinatol BMC. 2015
Age Systolic Diastolic Mean

6 to 18 h 80 ± 13 43 ± 10 57 ± 12

18 to 30 h 83 ± 12 46 ± 10 60 ± 11

3d±6h 84 ± 14 48 ± 13 60 ± 12

7d±1d 91 ± 15 52 ± 11 67 ± 13

Gestational age goal is only at the 10th%

Start hydrocortisone early!
◦ Optimal therapy for reduced PBF is selective
pulmonary vasodilation (iNO)
◦ Dopamine at > 10 mcg/kg/min is not selective
to the systemic vasculature and can increase
pulmonary arterial pressure in PPHN*
◦ Norepinephrine and vasopressin are effective
◦ Caution not to use dobutamine which can
cause peripheral vasodilation

Lakshminrusimha S. Clin Perinatol 2012;39:655-683

Start hydrocortisone early!!!
Treat hypotension due to hypovolemia aggressively
with volume replacement (particularly important for
septic shock)
Once euvolemic, use dopamine and epinephrine
(norepinephrine, vasopressin). (Dobutamine can
vasodilateW)
Maintain at normal range for age and gestation
◦ Rationale: Increased systemic resistance with
dopamine may decrease the degree of R L
shunting.
Evaluate ABG/CBG, gluc, CBC, iCa, lactate, coags
Evaluate neuro status: Is patient a candidate for
cooling?
Assure appropriate lung inflation
Anticipate shock (+ lactate) even if the BP is
normal; Tx hypovolemia aggressively with NS, start
hydrocortisone and dopamine early, shoot for BPs
for age (see table)
HFV and iNO are helpful adjuncts but iNO can
worsen an infant’s condition if there is LV
dysfunction
Milrinone therapy is associated with
hypotension and IVH and is not approved by
the FDA in neonates (use cautiously)
Anticipate DIC, get coags early
Give Na Bicarb or Acetate only if CO2 is in the
appropriate range
Avoid excessive noise and stress which can cause
the PO2 to plummet within minutes
Treat with narcotics for sedation (Fentanyl,
morphine) and sedatives (Ativan, ie. Lorazepam)
◦ Avoid excessive narcotic use which can cause
systemic hypotension and worsen R→L shunts.
(Can also happen with milrinone, also)
Avoid paralysis, if possible (associated with
increased mortality)
Beta-type natriuretic peptide (BNP) can be an early
indicator. Can serve as a biomarker to assess
efficacy of treatment and to predict rebound PPHN
(can be used in BPD patients to screen along with
monthly echocardiograms)
If patient requires a PIP > 28 cm H20 or tidal
volume > 6 mL/kg to keep PaCO2 < 60 o
conventional, switch to a high-frequency ventilator
Endothelin Receptor Antagonist
Stimulates endothelial
NO synthase
Endothelin
Superoxide
(vasoconstrictor)
dismutase
Superoxide anions
Diffuses to SMC

NO is a
Stimulates soluble guanylate cyclase free
radical and
Increasee can
Ionic Ca
combine
with
superoxide
anions to
Reduce form
ionic Ca
Stimulates peroxy-
PDE3A
nitrite, a
potent
vasocon-
strictor.
Therapeutic Targets in Pulmonary
Arterial Hypertension
Endothelial
NO PGI2 ET-1 Cell

ETA
ETB
guanylate cyclase adenylate cyclase
Smooth
GTP ATP Muscle
5’GMP cGMP cAMP AMP Cell
vasoconstriction
PDE5 PDE3
vasodilation

Prostacyclin derivatives (Remodulin, Flolan, Iloprost)

Endothelium-derived vasodilators: Prostacyclin (PGI2) and Nitric oxide
COX and PGIS are involved in the
production of Prostacyclin
cyclooxygenase

Prostacyclin
synthase
Remodulin*
Flolan
Iloprost

Soluble guanylate cyclase

Alprostadil
Adenylate cyclase
(PGE1, Prostin):
Used to maintain
ductal patency to
decrease RV
Reduces
afterload. ionic Ca
Aerosolized form
used in adults.
IV PEG1 is used in
CDH in combo with
iNO to promote
pulmonary
vasodilation +
reduce RV afterload. Endothelium-derived vasoconstrictor: Endothelin, ET-1
Fig. 56.1
 Remodulin
Prostacyclin (PGI2) Flolan
Iloprost
• Potent, short-acting, cAMP-dependent
vasodilator of the pulmonary and systemic
circulations
• Acutely relaxes vascular smooth muscle cell
• Inhibits platelet aggregation
• Ameliorates endothelial injury
• Inhibits VSMC migration and proliferation
• Reverses vascular remodeling
• Reduces synthesis and improves clearance of ET-1
 Remodulin/Tyvaso (treprostinil)
• For Class II, III, IV PAH
• Administer as continuous SQ or IV infusion
• Half life: 4 hours
• Metabolized by the liver
• Causes vasodilation of pulmonary and
systemic arteries
Adverse effects: inhibits effect
on platelet aggregation so
there is an increased risk of
bleeding; caution in patients
with impaired liver or renal
function, hypotension,
headache, dizziness, edema
 Remodulin. Prostacyclin (PGI2)

• Continuous SQ or IV infusion
• Dose 1.25 ng/k/min (or 0.625 ng/k/min if not
tolerated)
• Dose increase based on clinical response
(increments of 1.25 ng/k/min per week for
first 4 weeks of treatment, later 2.5 ng/k/min
per week)
 Prostaglandin (PGE1)

• Alprostadil (Prostin VR 500, Pfizer, New York,

NY, USA
• Dose: aerosolized at delivered at 150-300
ng/k/min diluted in saline to provide 4 mL/hr
via MiniHeart low-flow jet nebulizer
(WestMed Inc., Tucson, Arizona, USA)
• IV PGE1 has been used in CDH along with iNO
to promote pulmonary vasodilation and
maintain ductal patency and reduce right
ventricular afterload
 Prostacyclin (PGI2) Analogue
Flolan™ (epoprostenol)
• 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) Analogue
Flolan™ (epoprostenol)
• Dose: 10-40 ng/k/min continuous inhalation
or central line infusion
• 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
 Prostacyclin (PGI2) Analogue
Ventavis™ (Iloprost)
• For Class III and IV PAH
• IV
– Dilates systemic and pulmonary arterial vascular
beds
• Inhaled (½ life: 20-25 minutes)
– Selective pulmonary vasodilatation, increases
cardiac output, improves venous and arterial
oxygenation
 Inhaled Prostanoids

• Inhaled prostanoids -
40 Patient 1
Patient 2
Patient 3
experience largely
30
Patient 4
confined to case reports
OI • Iloprost or treprostinil –
20
newer generation
10
preparations specifically
designed for inhalation
0
-10 0 10 20 30 40
• Longer t1/2
Time (hours)

Kelly et al; J Pediatr 2002;141: 830

Therapeutic Targets in Pulmonary
Arterial Hypertension
Endothelial
NO PGI2 ET-1 Cell

ETA
ETB
guanylate cyclase adenylate cyclase
Smooth
GTP ATP Muscle
5’GMP cGMP cAMP AMP Cell
vasoconstriction
PDE5 PDE3
vasodilation

SILDENAFIL
 Sildenafil
• Phosphodiesterase-5 inhibitor
• Facilitates nitric oxide-cyclic-GMP-induced
vasodilatation in the lungs by inhibiting the
degradation of cGMP
• Used to prevent rebound PPHN in weaning
patients off iNO
• Used in oral form
• IV international study started 2013; completed
in December of 2018
 IV Sildenafil
• Load of 0.42 mg/kg over 3 hours (0.14
mg/kg/hr) followed by 1.6 mg/kg/day as a
continuous maintenance infusion (0.07
mg/kg/hour)
Sildenafil
Stimulates endothelial
NO synthase
Endothelin
Cyclooxygenase (vasoconstrictor)

Diffuses to SMC

Prostacyclin
synthase

Prostaclyclin Stimulates soluble guanylate cyclase

receptor

Increasee
Adenylate Ionic Ca
cyclase
Cyclic guanosine
monophosphate
Cyclic adenosine
monophosphate

Reduce
ionic Ca
Broken
down by
PDE3A Sildenafil
Increased cAMP->
pulmonary and
Inhibits
systemic
vasodilation and
PDE5 and
inotropy increases
cGMP in
SMC
Therapeutic Targets in Pulmonary Arterial
Hypertension

Endothelial
NO PGI2 ET-1 Cell

ETA
ETB
guanylate cyclase adenylate cyclase
Smooth
GTP ATP Muscle
5’GMP cGMP cAMP AMP Cell
vasoconstriction
PDE5 PDE3
vasodilation

MILRINONE inhibits PDE3

Milrinone
• Inhibits phosphodiesterase (PDE3) and increases
concentration of cAMP in pulmonary and systemic
arterial smooth muscle and in cardiac muscle.
• Acts additively with iNO
• Believed to improve cardiac function by
– Positive inotropy (improved contraction). Increases
cardiac output with reduction in filling pressures and
systemic vascular resistance
– Positive lusitropy (improved relaxation). Causes
peripheral vasodilation and improved relaxation of
the myocardium during diastole
– Reduced ventricular afterload
• Minimally affects heart rate
Milrinone
• Loading dose: 50 mcg/kg over 30-60 minutes
• Maintenance dose 0.33mcg/kg/min and escalated
to 0.66 mcg/k/min and then to 1 mcg/kg/min based
on response
• Loading dose not recommended in the presence of
systemic hypotension and in prematures
• Have a NS fluid bolus ready in the event of
hypotension
• May be choice of pulmonary vasodilator in PPHN
with left ventricular dysfunction
• Potential adverse event may be intracranial
hemorrhage
Bassler Dr, et al. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports.
Biol Neonate. 2006;89:1-5
 Milrinone Endothelial NO synthase
cyclooxygenase

Prostacyclin
synthase

Diffuses to SMC

Soluble guanylate cyclase

Stimulates
Adenylate cyclase

Milrinone: inhibits
PDE 3A +increases Reduces
ionic Ca
cAMP levels in
Breaks down cAMP
arterial SMC +
cardiac myocytes
resulting in pulmonary
(and systemic)
vasodilation and
inotropy.
Therapeutic Targets in Pulmonary
Arterial Hypertension
Endothelial
NO PGI2 ET-1 Cell

BOSENTAN
ETA
ETB
guanylate cyclase adenylate cyclase
Smooth
GTP ATP Muscle
5’GMP cGMP cAMP AMP Cell
vasoconstriction
PDE5 PDE3
vasodilation
 Endothelin Receptor Antagonist
Tacleer™ (bosentan)
• (ET-1 is a potent vasoconstrictor and vascular smooth
muscle cell mitogen whose concentrations in plasma and
lung tissue are elevated in patients with PH). Bosentan is
a nonselective inhibitor of both ETA and ETB. ETB is
thought to release NO and mediate vasodilatation.
• First oral drug approved for treatment of PAH in adults
• Used for refractory PH in infants with CDH, BPD and CHD
• NG: 1-2 mg/k twice daily
• Did not show additive effect when combined with iNO*
• May have a role in chronic pulmonary hypertension
associated with BPD or CDH
*Stenhorn RH, et al. Bosentan as adjunctive therapy for PPHN: results
of the FUTURE-4 study. Circulation. 2014;30:A13503
Endothelin Receptor Antagonist= 2
Inhibits ETA and TEB (vasodilation)
Stimulates endothelial
NO synthase
Endothelin acts on
Endothelin ET-B stimulating
Cyclooxygenase (vasoconstrictor)
NO release
+ vasodilation

Diffuses to SMC

Prostacyclin
synthase
1
Prostaclyclin Stimulates soluble guanylate cyclase Endothelin
receptor
acts on ET-A
Increases receptors in SMC
Adenylate Ionic Ca causing
cyclase vasoconstriction by
Cyclic guanosine
monophosphate increasing ionic
Cyclic adenosine
calcium
monophosphate

Reduces
ionic Ca
Broken
down by
PDE3A
Increased cAMP->
pulmonary and
systemic
vasodilation and
inotropy
• Lakshminrusimha S, Kumar V. Pediatric Critical Care Fifth Edition. Ed Fuhrman and Zimmerman.
Chapter 56, Diseases of Pulmonary Circulation. Elsevier, 2017
• Mathew B, Lakshminrusimha S. Saunders Elsevier, The Newborn Lung, Neonatology Questions and
Controversies.Third edition. Ed Bancalari E, Keszler M, Davis Peter G. Chapter 8. Elsevier, 2017
• Abman SH. Abnormal vasoreactivity in the pathophysiology of PPHN. Pediatr Rev. 1999: 20:e103
• Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. NEJM. 2005;353:2683-2695
• Kinsella JP, Abman SH. Inhaled NO and HFOV in PPHN. Eur J Pediatr. 1998;157:S28
• Konduri GG. New approaches for PPHN. Clin Perinatol. 2004;31:591-611
• Lotze A, Mitchell BR. Multicenter study of surfactant use in the treatment of term infants with severe
respiratory failure. J Pediatr. 1998;132:40-47
• Neonatal Inhaled Nitric Oxide Study Group. Inhaled NO in full-term and nearly full-term infants with
hypoxic respiratory failure. N Engl J Med. 1997;336:597-604
• NINOS. Inhaled NO and hypoxic respiratory failure in infants with CDH. Pediatrics. 1997:99-838.
NINOS Neurodevelopmental follow up. Pediatrics. 2000;342:469
• Steinhorn RH, Farrow KN. Pulmonary hypertension in the neonate. NeoReviews. 2007;8(1):e14-e21.
• Steinhorn RH, Kinsella JP, et al. IV Sildenafil in the treatment of neonates with PPHN. J Pediatr.
2009;155:841-847
• Van Meurs K, Congenitall Diaphragmatic Hernia StudyGroup. Is surfactant therapy beneficial in the
treatment of the term newborn infant with CDH? J Pediatr. 2004;145:312-316