persistent pulmonary hypertension of newborn

1. PERSISTENT PULMONARY
HYPERTENSION OF THE
NEWBORN

2. HISTORICAL ASPECTS
Previously k/a Persistent fetal circulation (PFC)
First described as “unripe births of mankind” by
William Harvey in 1628 in Exercitatio Anatomica
De Motu Cordis et Sanguinis in Animalibus .

3. Gersony et al in 1969 rediscovered this syndrome
and labelled it as “persistent foetal circulation
(PFC)”
However this term has now been abandoned (high-
flow, low-resistance circuit through the placenta, is
missing)

4. OTHER NAMES
Persistent fetal circulation
Persistent pulmonary vascular obstruction
Pulmonary vasospasm
Neonatal pulmonary ischemia
Persistent transitional circulation

5. FETAL vs ADULT CIRCULATION
FETAL ADULTS
Gas exchange Placenta Lungs
RV,LV circuit Parallel Series
Pulmonary circulation Vasoconstricted Dilated
Stroke volume RV>LV(1.2:1 TO 1.5:1) RV= LV
Intracardiac & extracardiac shunts No shunts

7. LA  LV  AORTA  DUCTUS ARTERIOSUS
FORAMEN OVALE
RV
IVC SVC  UPPER BODY
hepatic veins
55% THROUGH 45% TO LIVER
DUCTUS VENOSUS (PORTAL CIRCULATION)
UMBILICAL VEIN
Oxy.blood , nutrients
PLACENTA

8. • Upper part of fetal body (including coronary & cerebral arteries and those
to upper extremities) is perfused exclusively from LV with blood that has a
slightly higher PO2 , than the blood perfusing the lower part of the fetal
body, which is derived mostly from RV
Only a small volume of blood from the ascending aorta (10% of fetal
cardiac output) flows across the aortic isthmus to the descending aorta.

9. .

10. TRANSITIONAL CIRCULATION:
AT BIRTH
• Expansion of the lungs to normal resting volume,
establishment of adequate alveolar ventilation and
oxygenation, and successful clearance of fetal lung fluid
Rapid fall in PVR
• Removal of the placenta, the catecholamine surge a/w birth,
relatively cold extrauterine environment
Increase in SVR

11. TRANSITIONAL CIRCULATION:
Right ventricle output now flows entirely into
the pulmonary circulation.
Pulmonary vascular resistance becomes lower
than systemic vascular resistance,
Shunt through ductus arteriosus reverses &
becomes left to right.

12. TRANSITIONAL CIRCULATION:
High arterial PO2 (In several days)
Constriction of ductus arteriosus
It closes, becoming the ligamentum arteriosum.

13. TRANSITIONAL CIRCULATION
Increased volume of pulmonary blood flow
returning to left atrium
Increases left atrial volume and pressure
Closure of foramen ovale (functionally)
(Although the foramen may remain probe patent)
Becomes Fossa Ovalis

14. Removal of the placenta from the circulation
Also results in closure of the ductus venosus
The left ventricle is now coupled to the high-resistance
systemic circulation  its wall thickness and mass begin to
increase.
In contrast, the right ventricle is now coupled to the low-
resistance pulmonary circulation  its wall thickness and
mass decrease slightly.

15. If, for any reason, right-sided pressures remain
high relative to those on the left side, fetal
circulation will most likely persist through one or
both of the fetal channels mentioned above.
PPHN is defined as postnatal persistence of right
to left ductal or atrial shunting, or both in
presence of elevated pulmonary pressures & in
absence of congenital heart disease

16. FACTORS AFFECTING PVR
Lower PVR:
oxygen, nitric oxide
prostacyclin, PG E1, D2
adenosine
magnesium
bradykinins
atrial natriuretic factor
alkalosis
histamine
acetylcholine
beta-adrenergic stimulation
potassium channel activation
Increase PVR:
hypoxia
acidosis
endothelin-1
leukotrienes,
thromboxanes
platelet activating factors
prostaglandin F2- alpha
alpha-adrenergic
stimulation
calcium channel activation

17. Factors contributing to high PVR in-
utero:
Mechanical factors (compression of the small
pulmonary arterioles by the fluid-filled alveoli and a
lack of rhythmic distension)
Presence of low-resting alveolar and arteriolar
oxygen tensions, and a relative lack of
vasodilators(NO, prostacyclins)
Elevated levels of vasoconstictors (endothelin-
1,thromboxane,serotonin)

18. Normal Pulmonary Vascular Transition
The pulmonary vascular transition at birth is
characterized by :
rapid increase in pulmonary blood flow
reduction in PVR
clearance of lung liquid.

20. Central role in the pulmonary vascular
transition
Pulmonary endothelial cells
NO
Arachidonic acid metabolites

21. Vascular endothelium releases several vasoactive
products that play a primary role in pulmonary
transition at birth.
Pulmonary endothelial NO production increases
markedly at the time of birth.

22. NO
Oxygen-important catalyst for increased NO
production
Shear stress resulting from increased pulmonary
blood flow- induce endothelial nitric oxide synthase
(eNOS) expression
Nitric oxide exerts its action through sGC and cGMP.

23. Increased cGMP concentrations produce
vasorelaxation via decreasing intracellular calcium
concentrations.
Pulmonary expression of both endothelial nitric
oxide synthase (eNOS) and its downstream
target, soluble guanylate cyclase (sGC), increases
during late gestation.

24. THE PROSTACYCLIN PATHWAY
Cyclooxygenase (COX)- rate-limiting enzyme that
generates prostacyclin from arachidonic acid.
COX-1 in particular is upregulated during late
gestation
Increased O2 concentration also stimulates COX-1
activity

25. - There is evidence that the increase in estrogen
concentrations in late gestation play a role in
upregulating PGI synthesis.
- Prostacyclin interacts with adenylate cyclase to
increase intracellular cyclic adenosine
monophosphate levels, which leads to
vasorelaxation.
- Inhibition of prostacyclin production by NSAIDs
during late pregnancy has been associated with PPHN
although this association has been recently called
into question

26. Oxygenation also causes pulmonary dilatation
through the activation of K channels and inhibition
in Ca channels in pulmonary artery smooth muscles
Atrial natriuretic peptide (ANP), B-type natriuretic
peptide (BNP) and C-type natriuretic peptide (CNP)
dilate fetal pulmonary vasculature by increasing
cGMP and may play a role in pulmonary vascular
transition at birth.

27. PPHN
Presence of elevated PVR and rightleft shunt
through the ductus arteriosus and/or foramen ovale(
in absence of congenital heart disease) , resulting in
hypoxemia and labile oxygen saturations
Contrary to primary pulmonary hypertension in
adults, the newborn syndrome is not defined by a
specific pressure of the pulmonary circulation

28. Occurs due to failure of the pulmonary circulation
to undergo the normal transition after birth

29. Incidence and mortality
Affects mainly at-term or post-term newborns,
although also present in premature infants
Reported incidence: 0.43-6.8 per thousand
newborns.
It is likely to be much more in developing
countries, where little data is available

30. North America- 1.9/1,000 in the population of
neonates born at term, with a mortality of 11%
UK- 0.4 to 0.68/1,000 live births
Brazil- 2 /1,000 live births, and mortality rates of
11.6%.

31. PATHOGENIC MECHANISMS FOR
PPHN
Pulmonary vascular underdevelopment (decreased
vascular growth)
Mal-development (abnormal vascular structure)
Mal-adaption (perinatal hypoxia-induced vascular spasm)
Functional obstruction to pulmonary blood flow due to
increased blood viscosity (polycythemia)

32. UNDERDEVELOPMENT
Reduced cross sectional area of pulmonary
vasculature resulting in a relatively fixed elevation
of PVR
Occurs with pulmonary hypoplasia associated
with a variety of conditions like:
 congenital diaphragmatic hernia (CDH),
 cystic adenomatoid malformation of the lung,
 renal agenesis, oligohydramnios
accompanying obstructive uropathy
 intrauterine growth restriction.

33. Although some degree of postnatal pulmonary
vasodilatation can occur, this adaptive
mechanism is limited.
As a result, mortality risk is greatest in this
category of patients.

34. MALDEVELOPMENT
Lungs have normal branching and alveolar
differentiation, and have a normal number of
pulmonary vessels.
Abnormal thickening of muscle layer of pulmonary
arterioles, and extension of this layer into small
vessels that normally have thin walls and no muscle
cells
Excessive extracellular matrix

35. Pulmonary vasculature responds poorly to stimuli
that normally result in a decrease in PVR, such as
↑ed O2 tension and the establishment of effective
ventilation
• Egs: Chronic intrauterine asphyxia, post-term
delivery, meconium staining
Remodeling of the pulmonary vascular bed is
thought to occur during the first 7 to 14 days after
birth, with an accompanying fall in PVR.

36. Disorders producing excessive perfusion of the
fetal lung also may predispose to vascular
maldevelopment.
Egs: premature closure of the ductus arteriosus
(eg, caused by nonsteroidal antiinflammatory
drugs) or foramen ovale, high placental vascular
resistance, and total anomalous pulmonary
venous drainage.

37. It is believed that in these cases, the maintenance
of pulmonary vasoconstriction with an increase in
pulmonary artery pressure for a prolonged period
of time leads to vascular remodeling
Central role of vasoactive mediator imbalance
(eg: ↑ed endothelin, ↓ed NO)

38. Genetic predisposition may influence the
availability of precursors for NO synthesis and
affect cardiopulmonary adaptation at birth.
This was illustrated in a report in which infants
with pulmonary hypertension had lower plasma
concentrations of arginine (a precursor of NO and
a urea cycle intermediate), and NO metabolites
than control infants with respiratory distress

39. A functional polymorphism of the gene encoding
carbamoyl-phosphate synthetase, which controls
the rate-limiting step in the urea cycle, has also
been implicated in genesis of pulmonary
hypertension

40. MALADAPTATION
Pulmonary vascular bed is normally developed
However, adverse perinatal conditions cause
active vasoconstriction and interfere with the
normal postnatal fall in PVR.
Conditions include perinatal depression,
pulmonary parenchymal diseases, and bacterial
infections, especially those caused by group B
streptococcus (GBS).

41. ETIOLOGY OF PPHN
IDIOPATHIC PPHN-: 10-20% cases
No obvious predisposing factors
Possible causes include hypoxia, acidosis,
hypothermia, hypoglycemia, etc, and some of
them may not have been documented.

42. SECONDARY PPHN
Most commonly seen in
infants with lung diseases
Other causes
• Asphyxia
• Sepsis/infection
• Pneumonia (bacterial)
• Congenial Diaphragmatic
Hernia
• Transient Tachypnea of
the Newborn
• Respiratory Distress
Syndrome (RDS/HMD)
most common cause being
meconium aspiration
• Polycythemia/hyperviscosity
• Metabolic disturbances
(hypoglycemia, hypocalcemia,
hypomagnesemia)
• Hypothermia
• Systemic hypotension

43. Potential risk factors for the
development of PPHN
Male gender
African or Asian maternal race
Pre-conception maternal overweight
Maternal diabetes, Maternal asthma
Late preterm and large for gestational age
Chorioamnionitis
Antenatal exposure to SSRIs, NSAIDs
Infection(mainly GroupB Streptococcus)
Hypothermia
Hypocalcemia
Polycythemia

44. CLINICAL MANIFESTATIONS
Usually occurs in term infants, although it may
also present in late preterm or postterm infants
The diagnosis is rare in very low birth weight
(VLBW) infants
PPHN is characterized by both prenatal and
neonatal features

45. Prenatal factors - signs of intrauterine and
perinatal asphyxia including fetal heart
abnormalities (ie, bradycardia and tachycardia)
and meconium-stained amniotic fluid

46. Neonatal findings
Most present within 1st 24 hours of life with signs
of respiratory distress (eg, tachypnea, retractions,
and grunting) and cyanosis, low apgar scores
Physical examination : cyanosis, signs of respiratory
distress; there may be meconium staining of skin
and nails, which may be indicative of intrauterine
stress.
Differential cyanosis may appear in severe cases
(with a pink upper body and a cyanotic lower body)

47. Chest Examination-
A prominent RV impulse and a single and loud S2
Occasional gallop rhythm (from myocardial
dysfunction) and a soft regurgitant systolic
murmur of TR may be audible.
Breath sounds may be normal (If pneumonia or
meconium staining exists, crackles or wheezes
may be present)
Severe cases of myocardial dysfunction may
manifest with systemic hypotension.

48. DIAGNOSIS
Consider PPHN when hypoxemia is out of
proportion to the degree of parenchymal
lung disease and there is no e/o cyanotic
CHD.

49. Laboratory Studies
Pulse oximetry -Hypoxia is universal,labile and is
unresponsive to 100% oxygen given by hood, but
may respond transiently to hyperoxic
hyperventilation(by bag and mask or after
intubation)
A difference >10% between the pre- and
postductal (right thumb and either great toe)
oxygen saturation (d/t RL shunt through PDA)

50. However, absence of a pre- and postductal
gradient in oxygenation does not exclude the
diagnosis of PPHN, since right-to-left shunting can
occur predominantly through the foramen ovale
rather than the PDA.

51. Arterial blood gas- PaO2 gradient of > 20 mmHg
between pre-ductal (upper extremity or head)
and post-ductal (lower extremity or abdomen)
ABGs
In contrast to infants with cyanotic lesions, many
infants with PPHN have at least one
measurement of PaO2 >100 mmHg early in the
course of their illness

52. Hyperoxia test
To distinguish PPHN & CHD from parenchymal
lung disease
Give 100% O2 x 10-15 min.
PPHN or CHD = PaO2 < 100 mmHg
Parenchymal = PaO2 >100 mmHg
If PaO2 > 100 mm of Hg , CHD more or less ruled
out

53. Hyperoxia - hyperventilation
test
To distinguish PPHN from CHD
Administer 100% O2
Hyperventilate (face mask or ET tube) to
"critical“ PaCO2 level(20-25 mm Hg)
PPHN = PaO2 > 100 mmHg
CHD = PaO2 little change (< 100 mmHg
Caution: Should be performed by skilled
personnel only

54. Response to iNO may help to differentiate PPHN
from cyanotic CHD
Most neonates with PPHN respond rapidly to
iNO, with an increase in PaO2 and oxygen
saturations.
Some neonates who have severe PPHN and
infants who have cyanotic CHD may experience a
small or no increase in oxygenation with iNO

55. CHEST RADIOGRAPH
Usually normal or demonstrates the findings of an
associated pulmonary condition (eg, parenchymal
disease, air leak, or congenital diaphragmatic
hernia).
The heart size typically is normal or slightly
enlarged.
Pulmonary blood flow may appear normal or
reduced.

56. ELECTROCARDIOGRAM
Right ventricular predominance, which is normal
for age.
Signs of myocardial ischemia, such as ST segment
elevation, may be present in infants with
perinatal depression

57. ECHOCARDIOGRAPHY
Gold standard for diagnosing PPHN
Normal structural cardiac anatomy with evidence
of pulmonary hypertension (eg, flattened or
displaced ventricular septum).
Right-to-left or bidirectional shunting of blood at
the foramen ovale and/or the ductus arteriosus

58. High pulmonary arterial/right ventricular systolic
pressure estimated by Doppler velocity
measurement of TR jet
In addition, echocardiography may be used to
assess ventricular function, which may be
impaired.

59. Cardiac catheterization
Needed rarely when echo is not definitive
A vasodilator trial using hyperoxia or short-acting
agents such as inhaled NO, at the time of the
catheterization, may be useful to identify those
likely to have a favorable long-term response to
pulmonary vasodilators.

60. DIFFERENTIAL DIAGNOSIS
Congenital heart disease, including transposition of the
great arteries, total and partial anomalous pulmonary
venous connection, tricuspid atresia, and pulmonary
atresia with intact ventricular septum
Primary parenchymal lung disease such as
bronchopulmonary dysplasia (BPD), neonatal
pneumonia, respiratory distress syndrome, pulmonary
sequestration, and pulmonary hypoplasia
Sepsis
Alveolar capillary dysplasia
Surfactant protein B deficiency

61. MANAGEMENT
General supportive cardiorespiratory care.
In severe/ non-responsive cases- use of vasodilatory
agents (eg, inhaled nitric oxid [iNO]), or
extracorporeal membrane oxygenation (ECMO)
Specific treatment for any associated parenchymal
lung disease (eg, antibiotic therapy for pneumonia, or
surfactant for neonatal respiratory distress
syndrome).

62. Assessment of severity using oxygenation
index(OI)
OI - used to assess the severity of hypoxemia in
PPHN and to guide the timing of interventions
such as iNO administration or ECMO support.
OI = [mean airway pressure x FiO2 ÷ PaO2] x 100
A high OI indicates severe hypoxemic respiratory
failure.

63. Patients with OI ≥25 should receive care in a
center where high-frequency oscillatory
ventilation (HFOV), iNO, and ECMO are readily
available
In patients with OI <25, general supportive care is
typically adequate and no further invasive
intervention is usually required

64. General supportive therapy
Avoid hypothermia, hypoglycemia, hypovolaemia,
hypocalcaemia, anaemia, polycythemia
Correct metabolic acidosis
Treat underlying cause (e.g. sepsis)
Maintain systemic blood pressure (adequate
volume replacement, inotropes)

65. Hyperventilation & alkali infusions to maintain an
alkaline pH- strategies previously in use, now
considered outdated.
Lack of conclusive benefit & concerns of
neurological injury & sensorineural deafness with
respiratory alkalosis

66. Oxygen and optimal oxygen saturations
Providing adequate oxygenation forms the mainstay
of PPHN therapy.
However, there are currently no randomized studies
comparing different PaO2 levels in the management
of PPHN in a term infant
Hypoxia increases PVR and contributes to the
pathophysiology of PPHN, although hyperoxia does
not further decrease PVR and instead results in free
radical injury

67. It has been shown that brief exposure to 100%
oxygen in newborn lambs results in increased
contractility of pulmonary arteries and reduces
response to iNO
Maintaining preductal oxygen saturations of 90-
95% with PaO2 levels b/w 55-80 mmHg is
recommended

68. Intubation and mechanical ventilation
Indication
• Persistent hypoxaemia despite maximal
administration of supplemental oxygen

69. Ventilatory strategies include conventional positive
pressure ventilation with initial rates of 60–
80/minute, an I:E ratio of 1:1.2, a PEEP of 3 cm H2O,
and sufficient peak pressure to achieve a PaCO2 of
not greater than 35–45 mmHg with the pH between
7.35 and 7.45.
PaO2 should be maintained at 60–90 mmHg

70. If high frequency oscillatory ventilation (HFOV) is
available it can be advantageously used in infants
with pulmonary parenchymal disease and those
awaiting inhaled nitric oxide therapy.
However a recent meta analysis has failed to show a
clear benefit of HFOV over conventional ventilation
as an elective or as a rescue mode of ventilation in
term or preterm infants with PPHN

71. Sedation to minimize agitation (which ↑PVR)-
fentanyl(1 to 5 mcg/kg per hour), or morphine
sulphate(loading dose of 100 to 150 mcg/kg over
one hour followed by a continuous infusion of 10
to 20 mcg/kg per hour)

72. Surfactant
Does not appear to be effective when PPHN is the
primary diagnosis
Should be considered in patients with associated
parenchymal lung disease, in whom there is
either a suspected surfactant deficiency (eg,
neonatal respiratory distress syndrome) or
impairment (meconium aspiration syndrome)

73. Interventions for severe cases
Infants with OI>25 despite the use of HFOV are
candidates for iNO therapy or other vasodilatory
agents that decrease PVR.
Patients who fail to respond to these agents may
require ECMO

74. Nitric Oxide
FDA approved in 1999
Mainstay of PPHN treatment
Achieves potent and selective pulmonary
vasodilation without ↓ing SVR
In intravascular space combines with hemoglobin
to form methemoglobin, which prevents systemic
vasodilation (selective effect).
iNO reduces V/Q mismatch by entering only
ventilated alveoli and redirecting pulmonary
blood by dilating adjacent pulmonary arterioles

75. Large multi-center trials- demonstrated that iNO
reduces the need for ECMO by 40%.
A meta-analysis of 7 RCTs- revealed that 58% of
hypoxic near-term and term infants responded to
iNO within 30 to 60 minutes
While use of iNO did not reduce mortality in any
study analyzed, but the need for rescue ECMO
therapy was significantly↓ed

76. Indicated for patients with OI ≥25
Earlier initiation (for an OI of 15-25) does not
decrease the incidence of ECMO use and/or
death or improve other patient outcomes

77. Currently, the initial recommended concentration
of iNO is 20 ppm.
Higher concentrations are not more effective and
are associated with a higher incidence of
methemoglobinemia and formation of nitrogen
dioxide
In infants who respond, an improvement in
oxygenation is evident within few minutes.

78. Once initiated, iNO should be gradually weaned to
prevent rebound vasoconstriction.
Use of iNO has not been demonstrated to reduce the
need for ECMO in newborns with congenital
diaphragmatic hernia.
In these newborns, iNO should be used in non-ECMO
centers to allow for acute stabilization, followed by
immediate transfer to a center that can provide
ECMO.

79. Contraindications to iNO include congenital heart
disease characterized by left ventricular outflow
tract obstruction (eg, interrupted aortic arch,
critical aortic stenosis, hypoplastic left heart
syndrome) and severe left ventricular
dysfunction.

80. Extracorporeal membrane
oxygenation
About 40% of infants with severe PPHN remain
hypoxemic on maximal ventilatory support despite
administration of iNO
In these patients ECMO therapy should be
considered.
Goal- maintain adequate tissue oxygen delivery
and avoid irreversible lung injury from mechanical
ventilation while PVR decreases & pulmonary
hypertension resolves.

81. Cochrane review of 4 trials of ECMO showed a strong
benefit in terms of survival, without evidence of
increased risk of severe disability
Criteria for institution- elevated OI that is
consistently ≥40.
However, because mean airway pressures are higher
on HFOV than conventional ventilation, some
clinicians wait until OI is ≥60 when HFOV is used

82. Most patients weaned from ECMO within 7 days
However, occasionally ≥2 weeks may be
necessary for adequate remodeling of the
pulmonary circulation in severe cases.
Who fail to improve may have an irreversible
condition, such as alveolar capillary dysplasia or
severe pulmonary hypoplasia.
In one large series from a single institution from
2000 to 2010, the survival rate following ECMO
support was 81%

83. Other vasodilatory agents
SILDENAFIL, a PDE5 inhibitor- ↓ PVR in both animal
models and adult humans.
Reported to be successful in the treatment of infants
with PPHN in many small studies
In a Cochrane meta-analysis with 37 newborns from
centers that did not have access to NO and HFV,
significant improvement in oxygenation was observed
in the group receiving sildenafil. This study noted that
sildenafil may be a treatment option for PPHN.
Starting doses of 0.25–0.5 mg/kg/dose upto a
maximum of 2 mg/kg/dose; every 6-8 hourly

84. In 2012, the US FDA issued a warning that
sildenafil not be prescribed to children with
pulmonary arterial hypertension (PAH) because of
reports of associated mortality with
administration of high doses of sildenafil in
children between 1 and 17 years of age
Indicates the need for further assessment of the
efficacy and safety of sildenafil, especially with
long-term treatment

85. Inhaled or intravenous prostacyclin
Potential intervention in patients who fail NO
therapy
RCTs in adults and animal models have shown its
efficacy; however in neonates only case reports
are available
No longer commonly used (short t1/2 requiring
permanent vascular access, many adverse effects,
rebound fatal pulmonary hypertension in case of
drug interruption)

86. Bosentan
Endothelin-1 receptor antagonist, was reported to
be effective and safe in short-term treatment of
patients with PPHN in a single trial in 47 neonates
Potential for serious hepatic injury
Larger studies needed

87. Milrinone
Phosphodiesterase III inhibitor, has improved
oxygenation in infants refractory to iNO in small
case series
However, one of these series reported
intraventricular hemorrhage in three of four
treated infants
RCTs needed to evaluate efficacy and safety

88. Magnesium sulfate
Promotes vasodilatation by antagonizing entry of
calcium ions into smooth muscle cells
Small case series reporting its use
One RCT(2010) of iNO versus Mg in treatment of PPHN
in babies receiving HFOV, found better outcomes with
iNO
Pre-term neonates are at high risk for respiratory
depression due to magnesium sulfate

89. OUTCOMES & PROGNOSIS
With availability of both iNO and ECMO, mortality
in PPHN has reduced from 25–50% to 10–15%
Survivors- at ↑ed risk of adverse sequelae
including chronic pulmonary disease and long-
term development of neuro-developmental
disabilities, hearing impairment, and brain injury
and therefore need to be on long term follow-up.