A case of persistent pulmonary hypertension of the newborn (PPHN) is presented. The infant was born via emergency cesarean section at 37 weeks gestation to a mother with uncontrolled hypertension during pregnancy. At birth, the infant had meconium stained liquor and required respiratory support. On day 6, the infant began to develop desaturations down to 84% while on routine follow up. The infant is diagnosed with PPHN based on clinical presentation and laboratory findings. PPHN is managed through a combination of respiratory support, hemodynamic support, pharmacologic therapies including inhaled nitric oxide and sildenafil, and potentially extracorporeal membrane oxygenation for severe cases.

1. Welcome to
Seminar
Presenter:
Dr. Tishat Yeasmin, resident Y-1
Dr. Abdullahel Amaan, resident Y-4
Dept. of Neonatology, BSMMU

2. Mrs. Nasrin had developed PIH at her 30 weeks of gestration. Αlpha methyl
dopa , nifedipin, labetalol was subsequently added to her in their highest
dose but her BP remained uncontrolled.
At 37 weeks an emergency LUCS was done due to her uncontrolled HTN &
less fetal movement and a male baby weighing 2760g was delivered.
At birth, liquour was found meconium stained & he was non vigorous. After
ensuring endotracheal suction, he needed bag & mask ventilation to cry. He
was admitted immediately & respiratory support was started with CPAP.
Distress was gradually improving & he could be weaned to O2 1L/m through
nasal catheter.
On day 6, the baby was found developing desaturation upto ~ 84% while on
routine follow up.

3. Persistent Pulmonary
Hypertension of the Newborn
(PPHN)

4. Definition
Epidemiology
Pathophysiology
Clinical presentations
Laboratory evidences
Treatment

7. Definition:
 PPHN is a condition resulting from a disruption of the normal ‘fetal to neonatal
circulatory transition’ characterized by sustained elevation in pulmonary vascular
resistance (PVR), rather than the decrease which normally occurs at birth.
 In 1969, Gersony et al. defined PPHN as a condition having disproportionately severe
hypoxia (a PaO2 < 45mmHg in an FiO2 of 1.0) with mild lung disease & evidence of R-L
shunts in a structurally normal heart on echo.

8. Incidence
• 1.2 to 4.6 per 1000 live births.
(Ref: Narongsak N, Suksham J, Kishore K, Shigeharu H, Majeda
H, Yasser YE, et al. An Asian multicenter retrospective study on persistent pulmonary hypertension of the newborn:
incidence, etiology, diagnosis, treatment and outcome, The Journal of Maternal-Fetal & Neonatal Medicine, 2018)
• 13.59 per 1000 live births.
(Ref: Fatema NN. Persistent Pulmonary Hypertension of the Newborn:
Analysis of 181 cases over one Year. Cardiovasc. j. 2018 )

9. Why PPHN occurs

10. Risk factors for PPHN
• Pulmonary parenchymal disease:
oRDS
oPneumonia
oMAS
• Abnormality in Pulmonary
development:
oCongenital Diaphragmatic hernia,
oPulmonary parenchymal
hypoplasia.
• Systemic disorders:
oAsphyxia, Sepsis, Acidosis
oHypoglycemia, Hypocalcemia
oPolycythemia
oHypothermia
• Congenital heart disease:
Particularly TAPVR, HLHS, CoA,
critical aortic stenosis, endocardial
cushion defects, Ebstein anomaly,
TGA.
• Genetic predisposition

11. Mohsen AH, Amin AS. Risk factors and outcomes of persistent pulmonary hypertension of the
newborn in NICU of al-minya university hospital in Egypt. J Clin Neonatol 2013;2:78-82.
• Materials and Methods: Prospective study was performed enrolling the term & post term
newborn admitted to the NICU of Al-Minya University Hospital, Egypt from January 2009 to
April 2012.
• Results: Out of the studied 640 infants, 32 infants (5%) developed PPHN. MAS, PNA, RDS,
neonatal septicemia, post-term birth, LGA, LUCS, maternal overweight, and GDM were
associated with an elevated risk for PPHN.
• Conclusion: PPHN was found in 5% of the studied population. Meconium aspiration, birth
asphyxia, neonatal septicemia, post-term were associated with an elevated risk for PPHN.

12. Razzaq A, Quddusi AI, Nizami N. Risk factors and mortality among newborns with persistent
pulmonary hypertension. Pak J Med Sci 2013;29(5):1099-1104.
• Methods: This was an observational study conducted at The Children’s Hospital & the
Institute of Child Health, Multan, Pakistan, from July 2011 to June 2012.
• Results: There were 79 patients, including 61 males and 18 females. The most common risk
factors observed in our study were male gender(72.1%), LUCS (54.2%), PPV while
resuscitation (44.2%), birth asphyxia (40.4%) and MAS (35.4%)
In premature infants, male sex (88.8%), LUCS (77.7%), RDS 44.8% and sepsis
(44.4%) were more associated with PPHN.
• Conclusion: Male gender, LUCS, MAS and RDS are the major risk factors for PPHN in any age
group.

13. Asphyxia & hypoxia
• Acute birth asphyxia (PNA) 
hypoxia & acidemia  release of
Endothelin 1 (a potent
vasoconstrictor) pulmonary
arterial spasm prevents
normal postnatal change in
circulation.

14. Asphyxia
• Prolonged fetal stress & hypoxemia 
↓ in pulmonary VEGF expression 
structural remodeling of pul
vasculature  increased muscularity
in PA  muscle extends to the vessels
surrounding the alveoli (normally,
muscular pulmonary arteries rarely
extends beyond the terminal
bronchiole)  increased PAP  PPHN.
(Ref: Lessus et al. 2001, Grover et al. 2003)

15. Ahmed T, Abqari S, Shahab T, Ali SM, Firdaus U, Khan IA. Prevalence and outcome of PPHN in
perinatal asphyxia. J Clin Neonatol 2018;7:63-6
• Results: A total number of neonates screened were 41, of which 18 (43.9%) cases had PAH.
Out of 18 cases, 8 (44.4%) had a reversal of shunt at the level of patent ductus
arteriosus/patent foramen ovale.
Eleven neonates expired before 6 weeks of age and rest seven cases were screened at 6
weeks. Only one case showed the persistence of PAH at 6 weeks.
• Conclusion: PNA have a significant association with the development of PAH, and the
mortality is high in neonates with PNA once it is complicated by the development of PAH.

16. Sepsis
obacterial endotoxins 
- suppresses endogenous NO production,
- direct myocardial depression,
- recruitment of leucocytes in the lungs release of constrictor
leukotriens (LTC4, LTD4), Thromboxane A2, TNF  pulmonary arterial
constriction.
(Ref: Gibson et al. 1988, Navarreta et al. 2003)

17. Pulmonary pathologies
oPulmonary parenchymal diseases (RDS, Pneumonia, MAS) Pumonary
vasospasm raised PAP.
oCDH  pruning of the vascular tree, causing reduction of number of
interlobar arteries  abnormal development & reduced cross sectional
area of pulmonary vasculature (Ref:Geggel et al. 1985)
• pulmonary parenchymal hypoplasia malalignment of pulmonary vessels
 increased PAP  PPHN

18. Drug effects
• Adminstration of PGSI (PG synthatase inhibitors,e.g.Aspirin) in pregnant
women  PGSI crosses placenta  prolonged t ½ of PGSI in fetus 
direct pulmonary vasoconstriction & constriction of ductus arteriosus in
utero  fetal pulmonary hypertension in utero  Smooth muscle
hypertrophy in pulmonary arterioles, extension of muscles into arterioles
---after birth  PPHN
Ref: Turner & Levin 1984

19.  Genetic predisposition: Infants with PPHN have -
• mutation in the ABCA3 gene & polymorphisms of the CPS (carbamoyl-
phosphate synthetase) gene resulting in  diminished expression of
endothelial NO synthase (eNOs)  low plasma levels of NO metabolites.

20. Clinical features
• Usual presentation is a neonate having risk factor/s found developing
significant desaturation while on routine care.

21. Clinical presentation
- Respiratory distress despite adequate respiratory support
- significant decreases saturation with routine nursing care or minor stress
- A preductal and postductal SpO2 difference of >5% and PaO2 difference
>10–15 mmHg (indicative of a R-L shunt).
• A +ve Hyperoxia test
• Hyperventilation test: differentiates PPHN vs Cyanotic CHD.

22.  Hyperoxia test. Because of intracardiac R-L shunting,
the infant with cyanotic CHD in contrast to the infant
with pulmonary disease is unable to raise the arterial
saturation.
• Measure PaO2 on room air. Then place the infant on
100% oxygen for 10–20 minutes. Then remeasure
arterial oxygen.
• A value of >150 mm Hg does not always rule out
cyanotic CHD.
 Hyperventilation test may differentiate PPHN from
cyanotic CHD. It has been suggested that infants
subjected to this test should be hyperventilated for
10 minutes. In case of PPHN, PCO2 will ↓, pH ↑
PVR decreases, there is less right-to-left shunting,
and PaO2 will ↑ (>30 mm Hg). In cyanotic CHD, there
will be no change.

23. B. Cardiac signs:
- prominent right ventricular impulse, a single, accentuated S2, and a murmur of TR.
- In extreme cases, there may be hepatomegaly and signs of heart failure.
C. Imaging: The CXR may show
- cardiomegaly or a normal-sized heart,
- normal or diminished pulmonary vascularity.
- Disease specific findings.
D. The ECG most commonly shows RV predominance.

25. Echocardiography remains the gold standard
diagnostic tool in PPHN. A R-L shunting of blood
at the foramen ovale and/or the ductus
arteriosus , TR or a bowing of ventricular
septum to the left, to evaluate ventricular
function and to exclude CHD (e.g. infra
diaphragmatic TAPVR, HLHS). Ref: Jayasree Nair
et al. 2015

29. • Cyanotic congenital Heart Disease
Differential diagnosis

30. Differential diagnosis
Cyanotic CHD
• The newborn developed cyanosis
• O/E: weak pulses, dynamic
precordium, cardiomegaly, Grade 3 +
murmur
• In response to 100% O2, PaO2 will not
rise above 100 mmHg
• Disease specific changes in CXR,ECG &
Ecocardiography
PPHN
• Having risk factors (PNA, MAS, Sepsis
ect.)
• Desaturation on minor stimulus.
• A pre & postductal SpO2 diff of >5%
• Suggestive hyperoxia & hypervent
test.
• RV heave with single S2
• CXR-Normal/oligemic lung field
• Echo: R-L shunt, normal cardiac
anatomy.

32. How to Manage a Case of PPHN

33. • General Mx:
- Minimal handling
- Maintaining temp, euvolemia
- Correction of hypoglycemia,
hypocalcemia,
• Respiratory Mx:
- Liberal O2
- Mechanical ventilation
- ECLS
• Pharmacological MX:
- iNO
- Sildenafil
- Bosentan
- Adenosine
- PGI2
- MgSO4
• Follow up

34.  Minimal handling: Because catecholamine release activates pulmonary
adrenergic receptors, thereby potentially raise PVR, infants with PPHN are
extremely labile with significant deterioration after seemingly “minor”
stimuli.
Noise level and physical manipulation should be kept to a minimum. a
narcotic analgesic that blocks the stress response, such as fentanyl, morphine
sulfate, midazolam (0.06mg/kg/h) infusion are often used.

35. Temperature control is also crucial. Significant acidosis should be avoided.
Correction of metabolic abnormalities: Correction of hypoglycemia and
hypocalcemia is important in treating infants with PPHN in order to provide adequate
substrates for myocardial function and appropriate responses to inotropic agents.
Hemodynamic support : Adequate SBP should be maintained to combat R-L
shunt & optimal CO to maximize tissue oxygenation either by volume
expansion, or by using inotropes (dobutamine, dopamine, epinephrine),
milrinone when cardiac function is poor.
 Hb level should be kept >13gm/dl (PCV 40%) to maximize O2 transport to the
tissue.
 Broad spectrum antibiotic cover should be given to all babies with PPHN.

36. Respiratory support
Supplemental oxygen: Hypoxia is a powerful pulmonary vasoconstrictor.
Therefore, adequate supplemental oxygen is used to maintain saturation,
to reduce abnormally elevated PVR.
However, as there is also chance of O2 free radical induced injury, therefore,
the aim is to maintain postductal SaO2 >90% to ensure adequate tissue
oxygenation and preductal <98% to avoid hyperoxemia.

37. Mechanical ventilation (MV): When hypoxemia persists despite maximal O2
supplementation, evidenced by marked hypercapnia and acidemia, MV is
needed to ensure adequate oxygenation.
The strategy is to maintain adequate and stable oxygenation, using the
lowest possible MAP, PEEP to minimize barotrauma.
Hyperventilation is also avoided.

38. Those who cannot be adequately oxygenated with conventional ventilation,
HFOV is considered early. HFJV is used in meconium aspiration pneumonitis
and air leak.
When PPHN complicates pulmonary parenchymal disease, ventilator
strategies changed accordingly.
In the presence of parenchymal lung disease, infants treated with HFOV
combined with iNO.

39. Additional pharmacologic agents are directed to optimize CO, systemic BP and
reducing PVR.
iNO: an smooth muscle relaxant.
Sildenafil, a PDEi, (1-2 mg/kg/dose 6 hourly) is an option as a treatment for
PPHN which increases endogenous NO by inhibiting its metabolism.
Other promising agents are:
- Endothelin receptor antagonist: bosentan (Nakwan et al. 2009),
- adenosine,
- MgSO4 (Ho & Rasa, 2007),
- Ca+2 channel blocker: diltiazem (Islam et al. 1999),
- inhaled prostacyclin (de Luca et al. 2007),
- inhaled ethyl nitrite (Moya et al. 2002).

40. ECMO: ECMO is lifesaving therapy for PPHN who fail on conventional management.
Among term or near-term infants meeting ECMO criteria (alveolar-arterial oxygen
difference (AaDO:z)>600 or oxygenation index (OI) >30 on two ABGs >30 minutes apart).
(OI = MAP x FiO2/ PaO2 x 100.)

41. Fatema NN. Persistent Pulmonary Hypertension of the Newborn: Analysis of 181 cases
over one Year. Cardiovasc. j. 2018; 11(1): 17-22
o Results: Most of the patient (69.06%) was diagnosed at first week of life. Associated
congenital lesions like ASD in 52 (28.72%) cases, PDA was found in 14 (7.73%) cases and VSD
was found in 2 (1.10%) cases. Combination of ASD & PDA was found in 75 (44.33%) cases.
Systolic PAP was > 60 mmHg in 103 (56.91%) cases, >50 mmHg in 53 (29.28%) cases and >30
mmHg in 25 (13.81%) cases.
100% patients received high flow O2 along with anti failure (66.30%) and sildenafil 98
(54.14%) therapy as per requirement of the patient.
Complete cure was achieved in 95.58% cases and mortality was only 1.10%.

42. Mamun AAM, Hussain M,Jabbar A. MgSO4 vs Sildenafil in the Treatment of PPHN: A
Randomized Clinical Trial. J of Sci and Tech Res, 2018.
• Abstract: It was a RCT to evaluate the effect of inj. MgSO4 and oral Sildenafil in the
Treatment of PPHN. , conducted from August 2015 to July 2017 among 50 neonates
having moderate to severe PPHN in the Pediatric Cardiac ICU of Dhaka Shishu (Children)
Hospital.
There was significant improvement of oxygenation and decrease in PVR at 72 hours after
treatment in both study groups (p<0.05).
Significant improvement of oxygenation was found in Sildenafil study group than MgSO4
group after 72th hour of treatment (p=0.01).
There was no significant difference in time taken to improve and hospital stay between
two groups (p>0.05).
Sildenafil was more effective than MgSO4 in the treatment of PPHN with regard to
improvement of oxygenation.

43. Agha, H., Tantawy, A., Iskander, I., Samad A. Impact of Management Strategies on the
Outcome of PPHN. Cardiology and Cardiovascular Medicine,2017: 01(02), pp.74-84.
• Study Design: Prospective descriptive study in tertiary center included 40 neonates
having PPHN. All patients received the conventional therapy for PPHN, sildenafil as
adjuvant therapy was added in cases of failure.
• Results: … Sildenafil was effective in the reduction of the duration of NICU stay and SPAP
below 40 mmHg and (p = 0.001, p =0.0001, respectively).

44. Immediate outcome :
Immediate outcome varies with etiology. Outcome becomes guarded
when PPHN complicating RDS, MAS, sepsis, needs ECMO for with primary
PPHN.
Many neonates responds promptly to treatment & the mortality rate is
10-20%.

45. Agha, H., Tantawy, A., Iskander, I., Samad A. Impact of Management Strategies on
the Outcome of PPHN. Cardiology and Cardiovascular Medicine,2017: 01(02),
pp.74-84.
Results: Male patients had significantly higher systolic pulmonary artery pressure
(SPAP) and higher mortality rate compared to females [7/23 (30.4%) versus 1/17
(5.9%), p = 0.04].
Infants of diabetic mothers had significantly higher mortality rate (p = 0.003).
The overall mortality rate was 8/40 neonates (20%), however, the mortality among
the patients who received sildenafil in addition to conventional therapy was 1/14
neonates (7.14%) of those group with p = 0.001).

46. Nakwan, N., Jain, S., Kumar, K., Hosono, S. An Asian multicenter retrospective study on
PPHN: incidence, etiology, diagnosis, treatment and outcome. The Journal of Maternal-
Fetal & Neonatal Medicine,2018.
• Methods: A retrospective chart review of patients with documented PPHN from 7 centers
in 6 Asian countries (Japan, Kuwait, India, Pakistan, Singapore, and Thailand) between
January 2014, and December 2016, was performed.
• Results: A total of 369 PPHN infants were identified. The all-cause mortality rate was
20.6%. Multivariate multiple regression analysis indicated GA < 34 weeks, CDH/lung
hypoplasia, treatment with HFOV with or without inhaled nitric oxide (iNO), and inotropic
agents were independently associated with increased risk of death.

47. Razzaq A, Quddusi AI, Nizami N. Risk factors and mortality among newborns with persistent
pulmonary hypertension. Pak J Med Sci 2013;29(5):1099-1104.
• Methods: This study was conducted at The Children’s Hospital & the Institute of Child
Health, Multan, Pakistan, from July 2011 to June 2012.
• Results: There were 79 patients, including 61 males and 18 females.
Out of the total 79 patients, death occurred among 7 preterm and 14 terms and post term
infants. As a whole, cesarean section mode of delivery (71.4%), birth asphyxia (57.1%) and
female sex (52.4%) were found major risk factors associated with mortality.
However, RDS, PNA and male sex were found to be associated with increased risk of mortality
in preterm than term and post term infants.
• Conclusion: RDS, Birth asphyxia and male sex are associated with increased risk of mortality
in pre term than term and post term infants.

48. The long-term outcome
• The long-term outcome of infants with PPHN may depend on:
- the underlying conditions/ risk factor for the PPHN &
- the therapeutic interventions that they had received at birth.
• The rate of neurodevelopmental disabilities including cognitive delays and
hearing deficit (SNHL) and long term bronchodilator therapy can be seen in
6.4% of PPHN survivors.
(Ref: Eriksen V, et al,. 2009 & Rosenberg AA et al,. 2010)

49. Mohsen AH, Amin AS. Risk factors and outcomes of persistent pulmonary hypertension of the
newborn in NICU of al-minya university hospital in Egypt. J Clin Neonatol 2013;2:78-82.
• Results: Out of the studied 640 infants, 32 infants (5%) developed PPHN. After 6 months
follow-up, 12 (37.54%) improved and followed-up without sequelae, 4 (12.5%) developed
some neurodevelopmental impairment, 8 (25%) died, 3 (9.3%) developed BPD, 2 (6.2%)
developed SNHL and another 3 (9.3%) missed follow-up.
• Conclusion: PPHN was found in 5% of the studied population. Meconium aspiration, birth
asphyxia, neonatal septicemia, post-term were associated with an elevated risk for PPHN.

50. Why such adverse outcome among the survivors:
• Depends of underlying risk factors (PNA, MAS, CDH) for the PPHN and
mode & duration of different treatment modalities used .
• The high incidence of SNHL has been reported to correlate with
duration of hyperventilation.
• Hyperventilation  hypocapnea reduce cerebral blood flow, (in
premature babies causes PVL).
• Hyperventilation barotrauma  air leakes & BPD.

51. • Thus, after discharge from the NICU, infants with PPHN warrant long-
term follow up.

52. Prevention
• Ensuring ANC.
• Identifying high risk pregnancy
• Prompt & adequate resuscitation and support since in such
preexisting conditions, e.g., adequate and timely ventilation of an
asphyxiated infant with appropriate attention to temperature control.