Approach to a neonate with PPHN

1. Persistent pulmonary
hypertension of the newborn
Presenter: Dr Shivraj B Naik

2. Objectves
Statistics
Etiology
Pathophysiology
Diagnostic criteria
Management with other interventions

3. Introduction & Definition
• The prevalence of PPHN has been estimated at
1.9 per 1000 live births.
• Persistent pulmonary hypertension of the
newborn (PPHN) results from disruption of the
normal perinatal fetal to neonatal circulatory
transition. The disorder is characterized by
sustained elevation in pulmonary vascular
resistance (PVR), rather than the decrease in PVR
that normally occurs at birth.

4. • Survivors of PPHN are at risk for adverse
sequelae including chronic pulmonary disease
and neurodevelopmental disabilities.
• Contemporary ventilator management,
treatment with inhaled nitric oxide (iNO), and
extracorporeal membrane oxygenation
(ECMO) have improved survival among infants
with PPHN.

5. Fetal and postnatal circulation
• In the fetus, the pulmonary and systemic
circuits operate in parallel. Both the right and
left ventricles (RV/LV) eject blood into the aorta
with subsequent perfusion of the placenta, the
fetal organ of respiration The RV is dominant,
and blood is shunted right-to-left through the
foramen ovale and ductus arteriosus, mostly
bypassing the lung, which is not participating in
gas exchange.

8. Mature postnatal circulation
• All venous return passes through the right side
of the heart and into the lung, where gas
exchange occurs.
• The oxygenated blood returns to the left side
of the heart and is pumped into the systemic
circulation for oxygen delivery to the tissues.
• No mixing occurs between the two sides of
the circulation.

9. Transitional circulation
• Major circulatory adjustments occur at birth as the
organ of gas exchange changes from the placenta to
the lung.
• Under normal circumstances, a progressive fall in
pulmonary vascular resistance (PVR) accompanies the
immediate rise in systemic vascular resistance (SVR)
that occurs after birth.
• For a short period, a transitional circulatory pattern
exists that combines features of both the fetal and
adult circulatory patterns. The decline in the PVR/SVR
ratio results in a steady increase in pulmonary blood
flow and oxygen uptake in the lung.

10. • Factors in increasing SVR
1. Removal of the placenta.
2. The catecholamine surge associated with
birth.
3. The relatively cold extrauterine environment.

11. • Factors in promoting the postnatal decrease
in PVR.
1. Expansion of the lung to normal resting
volume,
2. Establishment of adequate alveolar
ventilation
3. Oxygen tension, and successful clearance of
fetal lung fluid.

12. Pathogenesis
• PPHN occurs primarily in term or late preterm
infants ≥34 weeks gestation.
Three types of abnormalities of the pulmonary
vasculature underlie the disorder:
Underdevelopment
Maldevelopment
 Maladaptation

13. Underdevelopment:
Cross sectional area of the pulmonary vasculature is
reduced, resulting in a relatively fixed elevation of
pulmonary vascular resistance (PVR).
• Congenital diaphragmatic hernia (CDH),
• Congenital pulmonary (cystic adenomatoid)
malformation
• Renal agenesis, oligohydramnios accompanying
obstructive uropathy,
• Fetal growth restriction.

14. Maldevelopment :
 Post Term delivery
 MAS
• Occurs in lungs that are normally developed, including
branching and alveolar differentiation, and have a normal
number of pulmonary vessels.
• Abnormal thickening of the muscle layer of the pulmonary
arterioles, and extension of this layer into small vessels that
normally have thin walls and no muscle cells.

15. Maladaptation :
• Perinatal depression
• Pulmonary Parenchymal diseases
• Bacterial infections, especially those caused by
group B streptococcus (GBS).

16. Prenatal Factors
• In utero exposure of selective serotonin
reuptake inhibitors (SSRIs) during the second
half of pregnancy has also been associated
with a sixfold increased risk of PPHN
compared with nonexposed infants.
• Serotonin-norepinephrine reuptake inhibitors
(SNRIs).

17. • Although PPHN is rare in VLBW preterm
infants, prolonged premature rupture of the
membranes (PPROM) appears to be a
common feature.

18. Causes of PPHN in Neonates
• Meconium aspiration syndrome (MAS, 41 percent
• Pneumonia (14 percent)
• Respiratory distress syndrome (RDS, 13 percent)
• Pneumonia and/or RDS, when they could not be
distinguished (14 percent).
• Congenital diaphragmatic hernia (CDH, 10 percent)
• Pulmonary hypoplasia (4 percent)
• Idiopathic (no other respiratory condition observed, 17
percent)

19. Rare causes
Malignant TTN
• Absorption atelectasis can develop secondary to
high concentrations of inspired oxygen
(approximately 100%) without positive pressure
(oxygen hood) can lead to absorption
atelectasis.
• Reactive oxygen species from the high alveolar
oxygen can lead to increased pulmonary
vascular reactivity, thereby contributing to
PPHN.

20. RARE CAUSES
Pulmonary Hypertension in Premature Infants
• Preterm infants with RDS present with PPHN
in the first few days after birth.
• preterm infants with bronchopulmonary
dysplasia (BPD) may be diagnosed as having
pulmonary hypertension later in the hospital
stay.

21. RARE CAUSES
Alveolar capillary dysplasia with misalignment
of the pulmonary veins (ACD-MPV) is a rare
disorder.
• Infants with ACD-MPV typically have initial
period of stability and develop severe
hypoxemia later than PPHN after the first few
hours or days of life.
• Lung biopsy are needed to confirm the
diagnosis.

23. How do we diagnose
• Pulse oximetry assessment : Difference of
greater than 10 percent between the pre- and
postductal (right thumb and either great toe)
oxygen saturation.
• What if there is no difference in gradient ?
PFO

24. Arterial blood gas:
1. Contrast to infants with cyanotic lesions, many
infants with PPHN have at least one
measurement of PaO >100 mmHg early in the
course of their illness .
2. (PaCO2 ) is normal in infants without
accompanying lung disease.
3. Right-to-left shunting of blood through the PDA
can also be documented in differences in PaO2
between samples obtained from the right radial
artery and the umbilical artery.

25. Chest radiograph :
The chest radiograph is usually normal or
demonstrates the findings of anassociated
pulmonary condition (eg, parenchymal
disease, air leak, or CDH).
The heart size typically is normal or slightly
enlarged.

26. Definitive diagnosis
• ECHO is the gold standard
• Measurement of the direction of the ductal
and foramen ovale shunt.
• Flattening or left deviation of the
interventricular septum.
• Doppler studies show right-to-left shunting
through the patent ductus arteriosus and/or
foramen ovale.

27. • Continuous-wave Doppler measurement of the
velocity of a tricuspid regurgitation (TR) jet (if
present) using a modified Bernoulli equation can
be used to estimate right ventricular (RV) systolic
pressure.
• Estimation of right ventricle pressure (RVp), using
assessments of TR jet and/or changes in septal
position, is compared with systemic blood
pressure (BP), and the degree of atrial and/or
patent ductus arteriosus shunting is determined.

29. Grading by ECHO
1. Mild to moderate PPHN – Estimated
RVp is between one-half to three
quarters systemic BP.
2. Moderate to severe PPHN – Estimated
RVp is greater than three-quarters
systemic BP but less than systemic BP.
3. Severe PPHN – Estimated RVp greater
than systemic BP.

30. • Evidence of RV dysfunction suggests severe
PH.
• Evidence of biventricular dysfunction may
represent global insult (eg, perinatal
depression).

31. Differential Diagnosis
1. Cyanotic congenital heart disease (CHD), which
is distinguished from PPHN by
echocardiography.
2. Primary isolated parenchymal lung disease such
as neonatal pneumonia, transient tachypnea of
the newborn (TTN), and respiratory distress
syndrome (RDS). These disorders are usually
differentiated from PPHN by the clinical setting
and chest radiography.

32. • Sepsis is distinguished by the clinical
setting, positive blood cultures, and
echocardiography.
• However, PPHN may occur as a
component of sepsis in a neonate.

34. MANAGEMENT
• OI = [mean airway pressure x FiO ÷ PaO2 ] x 100.
• A high OI indicates severe hypoxemic respiratory
failure.
• A term or late preterm infant with an OI ≥25
should receive care in a center where high-
frequency oscillatory ventilation (HFOV), iNO, and
ECMO are readily available in addition to general
supportive care.
• In patients with OI <25, general supportive care is
typically adequate and no further invasive
intervention is usually required.

35. 1. Supplemental Oxygenation
2. Mechanical ventilation
3. Fluid therapy and Inotropic agents for
circulatory support
4. Correction of acidosis.

36. Supplemental Oxygenation
• Oxygen concentration should be adjusted to
maintain preductal oxygen saturation target of
90 to 95 percent.
• If the oxygen saturation cannot be maintained
above 90 percent ,maintenance of a
hemoglobin concentration between 15 and
16g/dL and optimizing circulatory function.

37. Mechanical Ventilation
• Hypercarbia and acidosis increase PVR.
• Initial attempt to establish and maintain
normal ventilation (arterial partial pressure of
carbon dioxide [PaCO2 ] 40 to 45mmHg).
• After Infant's oxygenation and ventilatory
status become more stable, we maintain
PaCO2 in the range of 40 to 50 mmHg to
minimize lung injury associated with high tidal
volumes.

38. • Optimal lung recruitment (8- to 9-rib expansion
on an inspiratory chest radiograph) with the use
of positive end-expiratory pressure (PEEP) or
mean airway pressure decreases PVR.
• If peak inflation pressure of greater than 25 to 28
cm H2O or
• Tidal volumes greater than 6 mL/kg are required
to maintain a PaCO2 less than 60 mm Hg on
conventional ventilation switch over to high-
frequency (jet or oscillator) ventilation.

39. PPHN with no associated lung disease
• Hypoxemia is caused by right-to-left shunting
rather than ventilation-perfusion imbalance.
• So the ventilator strategy doesn’t help.
• Strategies elevating MAP may actually impede
cardiac output and increase PVR.
• Low inspiratory pressures and short
inspiratory times or volume targeted
ventilation can be helpful.

40. PPHN with associated lung disease.
• Atelectasis and the resulting maldistribution
of ventilation may exacerbate high PVR.
• PEEP is used to recruit atelectatic segments,
maintain adequate resting lung volume, and
ensure appropriate oxygenation and
ventilation.
• In severe lung disease if ventilator peak
pressures reach 28 to 30 cm H2O, go for HFOV.

41. • Studies have shown that , using both HFOV
and iNO2 together is beneficial rather than
using one alone.
• Chances of death or going onto ECMO is less.

42. Why Sedation in PPHN
• Pain and agitation cause catecholamine release,
resulting in increased PVR and increased right-to-
left shunting.
• ventilator asynchrony which can worsen
hypoxemia.
• Intravenous (IV) morphine sulfate (loading dose
of 100 to 150 mcg/kg over one hour followed by
a continuous infusion of 10 to 20 mcg/kg per
hour) .
• Fentanyl (1 to 5 mcg/kg per hour).

43. Circulatory support
• Maintaining optimal cardiac output and systemic
BP is important to reduce the right-to-left
shunting.
• Systemic BP targets are set at the upper limits of
normal (mean BP 45 to 55 mmHg; systolic BP 50
to 70 mmHg).
• Pulmonary arterial pressure in patients with
PPHN is at or near normal systemic levels.
• Maintain hemoglobin concentration above 15 g
(hematocrit above 40 to 45 percent).

44. • Dopamine has been the most commonly used
medication in neonates requiring
pharmacologic inotropic support. (2.5mics to
20 mics).
• Dobutamine may improve cardiac output if
ventricular dysfunction is present, but does
not reliably increase BP in neonates.
• Epinephrine can increase both systemic BP
and left ventricular (LV) output but increased
LV afterload due to increased PVR may
exacerbate right ventricle (RV) afterload.

45. • If ECHO demonstrates RV or LV dysfunction, IV
milrinone in conjunction with iNO Can be
used.
• Milirinone facilitates reduction in PVR while
enhancing myocardial performance and
forward flow of blood.
• Safety and efficacy is lacking in neonates.

46. Acidosis
• Acidosis increases PVR and attempts should
be made to maintain partial pressure of
carbon dioxide (PCO2 ) values between 40 and
50 mmHg.
• Sodium acetate may be added to infused IV
fluids at a dose of 2 to 3 mEq/kg per day.
• Rapid infusion of sodium bicarbonate in face
of impaired ventilation may worsen
intracellular acidosis and is not recommended.

47. • Hyperventilation and/or IV administration of
high doses of alkali therapy (eg, sodium
bicarbonate) to maintain "controlled" alkalosis
is not recommended.
• Persistent alkalosis may be associated with
reduced cerebral blood flow and impaired
release of oxygen from hemoglobin.

48. SURACTANT
• Not helpful in Primary PPHN.
• Can be of use in cases of RDS and
MAS.

50. What in Severe cases
• Here OI is >_ to 25.
• Infants with OI greater than 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.

51. iNO
Mode of Action
• Exogenous iNO is a selective pulmonary
vasodilator.
• Decrease the pulmonary artery pressure
and pulmonary-to-systemic arterial
pressure ratio.

52. Toxicity:
Methemoglobinemia.
Platelet Dysfunction
• Pulmonary injury related to increased levels of
nitrogen dioxide.
• contamination of ambient air.

53. iNO in Preterm infants
• Infants <34weeks have a RDS as the primary
disease.
• A study of 765 preterm infants (GA <32weeks)
reported that 2.2 percent of the cohort
developed hypoxic respiratory failure with
echocardiographic evidence of PH.
• So in such cases ECHO is a must to find out PH in
Preterms and then treat after other measures of
surfactant replacement and conventional
respiratory care have failed.

54. Approach
• Begin iNO therapy in term or late preterm infants
(GA ≥34 weeks) with severe hypoxemic
respiratory failure, defined as an OI ≥25 with
maximum respiratory support using conventional
mechanical ventilation or HFOV.
• Initial iNO dose of 20 ppm.
• Approximately 20 percent in PaO2 or arterial
oxygen saturation (SaO ) levels typically occurs
within 15 to 20 minutes.
• Ideally it’s a 3-4 days therapy.

57. NORMAL BP AND GOOD CARDIAC
FUNCTION
• iNO ,if fails.
• Sildenafil, administered by intravenous (preferred) or
oral route, is usually the firstline agent.
• Intravenous sildenafil is administered as a load of 0.42
mg/kg for 3 hours.
• followed by 1.6 mg/kg per day as a continuous
maintenance infusion.
• For iNO-resistant PPHN include aerosolized
prostaglandin E1 at 150 to 300 ng/kg per minute.
• Inhaled prostaglandin I2 at a dose of 50 ng/kg per
minute.

58. NORMAL BP AND GOOD CARDIAC
FUNCTION
• For iNO-resistant PPHN include aerosolized
prostaglandin E1 at 150 to 300 ng/kg per minute.
• Inhaled prostaglandin I2 at a dose of 50 ng/kg per
minute.
• Iloprost is a synthetic prostacyclin that can also
be delivered or by intravenous route.
• Scant data available on bosentan, an endothelin-
1 receptor antagonist, are conflicting regarding
efficacy. Given orally.

59. NORMAL BP AND CARDIAC
DYSFUNTION
• Inodilator such as milrinone might be the
preferred therapeutic agent in PPHN.
• Milrinone inhibits PDE3 and increases
concentration of cyclic adenosine
monophosphate in pulmonary and systemic
arterial smooth muscle and in cardiac muscle.
• Loading dose (50 mg/kg for 30–60 minutes).
• Maintenance dose (0.33 mg/kg per minute and
escalated to 0.66 and then to 1 mg/kg per minute
based on response).

60. LOW BP AND GOOD CARDIAC
FUNCTION
• 1 or 2 fluid boluses (10 mL/kg RL solution or
saline) followed by dopamine.
• Some centers prefer the use of
norepinephrine or vasopressin because these
agents are thought to be more selective
systemic vasoconstrictor.
• Stress dose of hydrocortisone can be
considered in baby needing high Inotrope
support and if levels are low.

61. LOW BP & CARDIAC DYSFUNCTION
• Hypotension is associated with cardiac
dysfunction, and rapid deterioration with
hemodynamic instability should precipitate
cannulation for ECMO.

62. ECMO
• Criteria for institution of ECMO include an
elevated OI that is consistently ≥40.
• However, because MAPs are higher on HFOV than
conventional ventilation, some clinicians wait
until OI is ≥60 when HFOV is used.
• Most patients with PPHN are weaned from ECMO
within seven days.
• Two or more weeks occasionally may be
necessary for adequate remodeling of the
pulmonary circulation.

63. Summary
• Because oxygen is a pulmonary vasodilator, we
recommend that supplemental oxygen should be
initially administered in a concentration of 100
percent to infants with PPHN in an attempt to
reverse pulmonary vasoconstriction (Grade 1A).
• PaO should be maintained subsequently in the
range of 50 to 90 mmHg (preductal oxygen
saturation 90 to 95 percent) to minimize lung
toxicity

64. Summary
• Mechanical ventilation to initially maintain PaCO
between 40 and 50 mmHg, as hypercarbia and
acidosis increase PVR.
• Maintenance of adequate systemic blood
pressure by providing sufficient vascular volume
and the use of inotropic agents.
• In term and preterm infants with a gestational
age greater than 34 weeks and who have severe
PPHN, defined as an OI ≥25, we recommend that
iNO be administered at a dose of 20 ppm (Grade
1B).

65. • Because data regarding efficacy and safety are
insufficient, we do not recommend enteral
sildenafil as initial therapy if iNO is available
(Grade 1C). It may be considered in a
resourcelimited setting.
• In patients who have an OI ≥40 despite the use of
iNO and high ventilatory support, we recommend
ECMO (Grade 1C).
• Survivors of severe PPHN and/or ECMO treatment
are at increased risk of developmental delay,
motor disability, and hearing deficits.

66. THANK YOU FOR
YOUR PATIENCE