As presented at the 16th Annual Respiratory Care Symposium on 6/26/15.

1. Joshua E Petrikin
June 26th
, 2015

2. ObjectivesDescribe the fetal circulation and the normal
transitional circulatory changes that occur at birth
Describe the problems that arise when there is
maladaptive cardio-respiratory transition at birth
Discuss the pathogenesis of persistent pulmonary
hypertension
Discuss the neonatal conditions that predispose to
persistent pulmonary hypertension
Describe the management of persistent pulmonary
hypertension

3. Contents
Introduction
Fetal and transitional neonatal circulation
Pathophysiology of PPHN
Conditions associated with PPHN
Clinical Presentation & Diagnosis
Management of PPHN
Prognosis & Follow-up

4. Introduction
Fetal adaptation to postnatal conditions
requires the transition of the pulmonary circulation from
a high resistance state in-utero to a low resistance state
results in a nearly 10 fold increase in pulmonary blood
flow (PBF)
Pulmonary Vascular Resistance (PVR) continues
to decline after birth
normally reaches 80% of total decrease by 24-48 hours
reaches nearly adult values around 6 weeks of life

5. Introduction
Persistent pulmonary hypertension of the newborn (PPHN)
the failure to achieve or sustain the normal decrease in PVR at birth
a clinical syndrome that can occur in association with diverse
cardio-respiratory disorders
These conditions share common pathophysiologic features,
including
high pulmonary vascular resistance
extra-pulmonary shunting (right to left) of blood flow across the
ductus arteriosus or foramen ovale
marked hypoxemia

6. Fetal Circulation

7. Transitional Circulation- Newborn
Inflation of the lungs
 ↓ the resistance to pulmonary blood flow
 results in ↑ blood flow to the lungs
 ↓ blood flows through the foramen ovale to the LA
Increased volume of blood returns from the lungs
 ↑ pressure in the LA
The LA pressure & RA pressure (due to↑ ↓ PVR↓ )  closes
foramen ovale
The ductus arteriosus, closes off shortly after birth  replaced
by connective tissue
The increased PBF flow
 distends the vasculature causing a “structural reorganization” of the vascular
wall
Local vasoregulatory mediators play an important role in this
transition

8. Pathophysiology of PPHN
Hallmarks of PPHN include
sustained elevation of PVR
abnormal vasoreactivity
structural remodeling of the pulmonary vascular bed
Mechanisms leading to failure of postnatal
adaptation are poorly understood

9. Vasoregulation of the Normal Fetal
Pulmonary Circulation
Due to the high PVR in the normal fetus, the pulmonary
circulation receives ~ 10% of combined ventricular output
Factors that contribute to high basal PVR include:
 low O2
 low basal production of vasodilator products ( PGI2 & NO Adenosine)
 increased production of vasoconstrictors (ET1, LT, TBX, PAF )
 altered smooth muscle cell reactivity
NO-cGMP cascade important role in vasoregulation of
the fetal pulmonary circulation:
 Modulating basal PVR in the fetus
 Mediating vasodilator response to physiologic & pharmacologic stimuli
 Opposing the strong myogenic tone in the normal fetal lung

10. L-arginine L-citrulline
NOS
Endogenous Nitric Oxide (NO) Effects
↑cGMP
NO
+cGMP kinase
↓IC Calcium
+sGC
Vasodilation5’GMP
Phosphodiesterase

11. Developing Lung Circulation
Intrauterine Injury
Hemodynamic Stress
Chronic Stress
Inflammation
Other (genetic)
Vascular Growth
Abnormal Vascular Reactivity
Altered Vascular Structure
↓ Angiogenesis
↓ Alveolarization ?
↓ Vasodilators (NO, PGI2, Adenosine)
↑ Vasoconstrictors (ET1, LT, TBX, PAF)
Enhanced Myogenic Tone
↑ SMC Proliferation
Altered Extracellular Matrix
Adventitial thickening
Pathogenesis of PPHN
Pulmonary hypoplasia
CDH
RDS, MAS, GBS
Chronic IU hypoxia
Idiopathic PPHN

12. Clinical Presentation & Diagnosis-
PPHN
Dx considered when hypoxemia is out of proportion to the
degree of parenchymal disease severity on the CXR
(idiopathic), a positive perinatal hx may be helpful
Physical examination
respiratory distress
Cyanosis
Tachycardia
Hypotension
O2 sat difference
single/loud S2
systolic murmur of TR
difference between preductal & postductal oxygenation

13. Clinical Presentation
& Diagnosis of PPHN
Lability of Oxygenation : wide swings in PaO2
2DTTEcho
level & direction of shunt
PAP estimated (Bernoulli equation)
abnormal septal motion
flat septum, increase RA
Disease severity suggested by oxygenation index
OI = 100 X (MAP)(FiO2) / PaO2
 OI > 25 receive care at ECMO center
OI >40- ECMO

14. Differential Diagnosis
Congenital Heart Disease
PAPVR */ TAPVR
PA with intact ventricular septum
Transposition of Great Arteries (TGA)
Tricuspid Atresia
Pulmonary Alveolar Capillary Dysplasia
failed formation & growth of alveolar capillaries and medial
musculature hypertrophy

15. Conditions Associated with PPHN
MAS( 41%)
Idiopathic (17%)
RDS (13%)
Sepsis/Pneumonia (14%)
CDH (10%)
Pulmonary Hypoplasia (4%)

16. Meconium Aspiration Syndrome
(MAS)
Most severe condition associated with meconium
passage in utero
MAS occurs in 2-5% of infants with meconium stained
amniotic fluid (MSAF)
Meconium in utero may be a response to stress
 chronic hypoxia, acidemia or infection
Most infants with MSAF are asymptomatic
MSAF rarely occurs before 38 weeks gestation
 incidence increases with longer gestations
 30% of newborns born at 42 weeks have MSAF
Diagnosis based on
clinical history of MSAF
meconium aspirated from below the vocal cords
an infant with respiratory distress
coarse opacification seen on CXR

17. Meconium Aspiration Syndrome
Mechanism of respiratory distress leading to PPHN
include
blockage of the airway
inactivation of surfactant
direct damage to the lung parenchyma
atelectasis & V-Q mismatch
Infants usually present with mild to moderate respiratory
distress, but rapidly progress to respiratory failure with
cyanosis & PPHN
These infants are prone to air leaks- pneumothorax

18. Meconium Aspiration Syndrome
CXR shows
coarse infiltrates
widespread consolidation
hyperinflation
pneumothorax
pneumomediastinum
Treatment includes
supplemental O2
ventilatory strategies to prevent air-trapping
therapy for PPHN- iNO & ECMO

19. Meconium Aspiration Syndrome
bilateral patch opacity
with hyperinflation &
air leak

20. Meconium Aspiration Syndrome
Rt pneumothorax

21. Idiopathic Persistent Pulmonary
Hypertension (“black lung”)
Profound hypoxemia &
hyperlucent lung fields
Constriction of ductus
in-utero > exposure to
NSAID
Exposure to SSRI
Down Syndrome
Unknown factors-
genetic or biologic
susceptibility

22. Congenital Diaphragmatic Hernia (CDH)
Developmental defect in the diaphragm
allows abdominal viscera (liver, spleen, stomach, intestine) to
herniate into the thoracic cavity
secondary to persistence of the pleuroperitoneal canal in the
posterolateral portion of the diaphragm
 90% on left through foramen of Bochdalek
10% on right through foramen of Morgagni
1: 2200 live births
Pulmonary hypoplasia and abnormal vascular
development with
Decreased bronchial and pulmonary arterial branching
Pulmonary arterial muscle hyperplasia leading to PPHN

23. Congenital Diaphragmatic Hernia (CDH)
Affected neonates present in first a few hours of
life with respiratory distress
CXR- postnatally is diagnostic
May be asymptomatic in newborn period
Definitive treatment – surgical
not emergent
elective repair when hemodynamically stable & PPHN
resolved/under control
With advent of antenatal Dx & improvement in
neonatal care, survival has improved, but remains
significant risk of death (population-based studies
no improvement in survival)

24. Congenital Diaphragmatic Hernia (CDH)

25. Congenital Diaphragmatic Hernia (CDH)
pattern of bowel in the
left hemithorax. There
is mediastinal shift to
the right.

26. Congenital Diaphragmatic Hernia (CDH)

27. Congenital Diaphragmatic Hernia (CDH)
Prenatal Dx, monitoring, labor induced in controlled
setting at 38-39weeks
At delivery, minimize bag-mask ventilation and intubate
Insert NG tube for gastric decompression
Maintain adequate systemic blood pressure
Avoid barotrauma to the hypoplastic lungs
Contributes to CDH mortality
Attempt to ventilate with low peak pressure (<25cmH2O) to
minimize/ prevent lung injury
Sedation as needed
iNO and surfactant of unproven benefit
iNO frequently used as a bridge to ECMO

28. Pulmonary Hypoplasia
Can occur in association with
Oligo/anhydramnios
bilateral dysplastic kidneys
severe PUV
CDH
Other congenital abnomalities
Arrest of lung development & differentiation
 Potters Syndrome: bilateral renal agenesis & pulmonary hypoplasia

29. Term gestation,
posterior urethral
valves
Post ECMO , Post
Dialysis

30. Respiratory Distress Syndrome (RDS)
Terminology
RDS: a clinical diagnosis
Hyaline Membrane Disease (HMD) a pathological diagnosis
Surfactant Deficiency: describing the typical appearances
on CXR
Most common respiratory disorder observed in
premature infants
Also occurs in near term & term infants
A leading cause of morbidity & mortality in
newborn period

31. Respiratory Distress Syndrome (RDS)
Caused by relative or total lack of surfactant
Deficiency of surfactant ---> FRC--->↓
atelectasis & V-Q mismatch
ABG: low PaO2, high PaCO2 & acidosis

32. Clinical Risk Associated with RDS
Prematurity (term & near- term))
Gender
male > females
androgen- delayed surfactant maturation
Race- Black infants lower incidence
Cesarean section- before onset of labor
Birth depression
Uncontrolled maternal diabetes- delayed surfactant
maturation
Genetic- SP B deficiency/ more likely in siblings
Twins- 2nd
twin more likely
Hypothermia- surfactant function impaired in cold

33. Respiratory Distress Syndrome (RDS)
Diffuse reticulogranular pattern, air bronchograms & atelectasis

34. Management of PPHN:
Investigations
CBC with manual diff
ABG
BMP,Glucose, Ca2+, Mg, LFT
Blood Culture, viral studies
Coagulation profile
CXR
Echo
HUS
Renal US

35. Management of PPHN: Objectives
Correct the underlying cause of PPHN (if known)
Maintain adequate systemic BP
Decrease pulmonary vascular resistance
Oxygen
Alkalosis (at least avoid acidosis)
iNO
Maintain optimal oxygen delivery to tissues
Minimize ventilator-induced lung injury

36. Management- PPHN
Proven therapy Unproven therapy
Hyperventilation
Gentle ventilation
Alkali infusion
IV Vasodilators
HFV
Surfactant*
INO
ECMO
X
X
X
X
X
X
X
X
Therapeutic options for PPHN are varied with wide range of
variations in their use

37. INO Therapy
Indications
 PPHN or hypoxemic respiratory failure
OI ≥ 15, reversible pulmonary disorder
ECHO -no evidence of CHD
Dosage : > 20ppm no additional benefit (optimal lung
inflation & adequate CO)
Treatment Failure : OI >25 transfer, OI > 40 ECMO
Discontinuation : OI < 10 , 2-6 days of iNO
Contraindications
(No benefit in CDH)

38. Management of PPHN
ECMO : Baseline ECMO criteria
 ≥ 34 weeks
Wt > 2000g (‘cannulas fit’)
no major ICH on HUS (no > Gr II)
reversible lung disease
No evidence of lethal congenital anomalies or inoperable
cardiac disease
UK trial impact of ECMO : survival ECMO group
68% compared to 41% in the control group

39. PPHN: Management Summary
Confirm Diagnosis
 Echo helpful to rule out congenital heart disease, assess cardiac function
Maintain systemic BP and assist cardiac function as needed
 Dopamine
 Milrinone
Oxygen & a conservative ventilation strategy
 aim for PaO2 60-90 mmHg
Modest hyperventilation
 pH 7.35-7.50, PaCO2 40-50mmHg
 Avoid acidosis
Sedatives as needed
Phosphodiesterase inhibitors
Surfactant: consider in individual patient
Inhaled nitric oxide
ECMO for iNO non-responders
Alkali infusion & paralysis no longer first line strategies

40. Post Recovery Issues & Care
Feeding Problems
BPD
Withdrawal - narcotic
Neurological evaluation
Hearing exam

41. PROGNOSIS & FOLLOW-UP
NINOS : INO not associated with an increase in
neurodevelopmental, behavioral or medical
abnormalities at 2 yrs of age
Conservative Mx without induced alkalosis &
paralysis : no hearing loss and good outcome
(Marron et al)

42. PROGNOSIS & FOLLOW-UPMortality varies by diagnosis
With all available therapies MR < 20-25%
MAS survival close to 100%
CDH- survival variable

Morbidities linked to severity of clinical course,
diagnosis and complications
At risk for neuro-developmental abnormalities
Hearing Loss: high risk of late onset sensorineural hearing
loss
Pulmonary recovery typically excellent if MAS
High risk for late pulmonary hypertension if CDH

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