This document discusses persistent pulmonary hypertension of the newborn (PPHN). It defines PPHN as sustained elevation of pulmonary vascular resistance, disrupting normal circulatory transition after birth. PPHN carries risks of chronic lung disease and neurodevelopmental issues. Treatment aims to reverse hypoxemia through respiratory support, pulmonary vasodilation (e.g. inhaled nitric oxide), and hemodynamic support (e.g. medications, ECMO). The prognosis of PPHN depends on the underlying cause and response to treatment.

1. By Dr Robin Thomas
Resident in Pediatrics
JJMMC, Davangere

2.  Defn :Disruption of normal perinatal to neonatal
circulatory transition-sustained elevation in
Pulmonary vascular resistance.
 Risk for chronic pulmonary disease &
neurodevelopmental disabilities.
 Incidence: 1-2 per 1000 live births.
 Perinatal risk factors: MSAF,
Maternal condn- fever, anemia, pulmonary d/s
Maternal D.M, U.T.I during pregnancy,
SSRIs, aspirin, NSAIDS & C.S

3.  Rapid fall in pulmonary vascular resistance
(PVR)-first breath & increase in systemic
vascular resistance (SVR) –clamping of
umbilical cord.
 Circulating biochemical mediators - increased
arterial O2 content & pH & lowered PaCO2 –
constriction of ductus- arteriosus &
vasorelaxation of pulmonary circulation.

4.  Physiological events raise SVR relative to PVR
–functional closure of foramen ovale.
 Persistent fetal circulation-mimics fetal
circulation-PVR exceeds SVR & right to left
hemodynamic shunting occurs tru foramen
ovale or ductus arteriosus.
 Dimnished pulmonary perfusion & systemic
hypoxemia.

6.  1.Severe fetal hypoxemia (Birth asphyxia) –
common association
 Prolonged fetal stress & hypoxemia –
remodeling & abnormal muscularization of
pulmonary arterioles.
 Acute birth asphyxia-release of
vasoconstricting humoral factors &
suppression of pulmonary vasodilators-
pulmonary vasospasm.

7.  2.Pulmonary parenchymal diseases-surfactant
deficiency, pneumonia, MAS.
 Fetus with advanced gestational age.
 3.Abnormalities of pulmonary dvp. – PPHN
Congenital diaphragmatic hernia, Porter
syndrome, Pulmonary parenchymal hypoplasia -
pruning of vascular tree.
Alveolar capillary dysplasia-malalignment of
pulmonary veins & arteries.

8.  4.Myocardial dysfunction, myocarditis,
intrauterine constriction of ductus arteriosus,
severe congenital heart disease-PPHN.
 5.Pneumonia or sepsis of bacterial or viral
orgin -PPHN. Suppression of endogenous NO
production.
endotoxin mediated myocardial depression,
pulmonary vasoconstriction assoc. with
release of thromboxanes.

9.  6.Familial recurrence-uncommon , infants
with PPHN –low plasma levels of arginine &
NO metabolites & specific polymorphism at
1,405 position of carbamoyl phosphate -
synthetase gene.

10.  1.Pulmonary vascular remodelling-abnormal
muscularization of non muscular intra-acinar
arteries with increased medial thickness of
larger muscular arteries-decreased cross
sectional area of pulmonary vascular bed &
elevated PVR.
 Fetal hypoxemia-stimulus for pulmonary
vascular remodelling.

12.  Humoral growth factors released by hypoxia
damaged endothelial cells promote
vasoconstriction & overgrowth of pulmonary
vascular muscular media.
 Vascular changes –fetal exposure to NSAIDS-
cause constriction of fetal ductus arteriosus &
fetal pulmonary overcirculation.

13.  2.Pulmonary hypoplasia
Affects both alveolar & pulmonary arteriolar
dvp.-congenital diaphragmatic hernia,
oligohydramnios syndrome, Porter syndrome
(renal agenesis).
 3.Reversible pulmonary vasospasm
Infants with nonfatal PPHN. Hypoxia induces
pulmonary vasoconstriction –acidemia.
Neural & humoral vasoactive substances.

14.  Suppression of endogenous NO, prostacyclin
or bradykinin production & release of
thromboxanes (A2,B2) , leukotrienes(C4,D4)-
increased PVR –Sepsis & hypoxemia.
 4. Myocardial dysfunction with elevated PVR-
1.Right ventricular dysfunction-
Intrauterine constriction of ductus arteriosus-
post natal pulmonary hypertension,
RV failure, atrial R-L shunt.

15.  2.Left ventricular dysfunction-pulmonary
venous hypertension & secondary pulmonary
arterial hypertension-right to left shunting
through ductus arteriosus.
 5.Mechanical factors
Cardiac output & blood viscosity.
Low cardiac output-fewer pulmonary
arteriolar channels & raises PVR.
Hyperviscosity with polycythemia-reduces
pulmonary microvasculature perfusion.

16.  Physical examn-cyanosis, prom. Precordial
impulse, single or narrowly split &
accentuated S2 , systolic murmur.
 Invest.
1.Gradient of 10 % or more in oxygen
saturation b/w preductal & postductal ABG or
transcutaneous O2 saturation- ductus
- arteriosus right to left hemodynamic shunt
& absence of structural heart disease-PPHN

17.  CXR-normal /assoc. pulmonary parenchymal
d/s.
 ECG-RV predominance-cons. normal for age.
 ECHO-hemodynamic shunting, evaluate
ventricular function, exclude congenital heart
disease.
TR or flattened ventricular septum in ECHO-
PPHN.

18.  Color doppler examn.-intracardiac or ductal
hemodynamic shunting.
 Continuous wave doppler sampling of
velocity of TR jet-estimate pulmonary artery
presures.

19.  Cyanotic congenital cardiac disease over
PPHN:
 cardiomegaly
 grade3 murmur
 weak pulses
 active precordium
 pulmonary edema
 pulse differ.b/w upper & lower extremities
 persistent preductal & postductal arterial O2
tension less or equal to 40 mmHg.

20.  Aim: reverse hypoxemia, improve pulmonary
& systemic perfusion, preserve end organ
function.
 Adequate respiratory support-normoxemia &
neutral to slightly alkalotic acid base balance
–facilitate normal perinatal circulatory
transition.

21.  1.Supplemental O2: Hypoxia-powerful
pulmonary vasoconstrictor
 Preductal & post ductal SaO2 should be
monitored.
Supplemental O2 –reduce abnormally elevated
PVR, minimize end organ underperfusion & lactic
acidemia.
 Maintain post ductal SaO2 >90%-ensure tissue
oxygenation & <98% to avoid hyperoxemia.

22.  2.Intubation & mechanical ventillation:
Hypoxemia persists despite maximal O2
admns. or respiratory failure-marked
hypercapnia & acidemia.
 Maintain PaO2 & PaCO2 values & avoid
hyperoxia & hyperventilation.
 Target goals: SaO2 90-98%, PaCO2 40-50
mmHg, pH 7.30-7.40

23.  a. PPHN with pulmonary parenchymal d/s-
HFOV high frequency oscillatory ventillation
or HFJV high frequency jet ventillation.
HFJV-useful for meconium aspiration
pneumonitis & air leak.
HFOV-deliver iNO.
 b.Absence of pulmonary disease-
High intrathoracic pressure impedes cardiac
output & elevates PVR.

26.  Strategy for mechanical ventillation-rapid,
low pressure, & short inspiratory time-
minimize elevated intrathoracic pressure.
 3.iNO –produced by endothelial cells.
diffuses into smooth muscle cells, increases
intracellular cGMP, relaxes vascular smooth
muscle & causes pulmonary vasodilation.

27.  iNO –HFOV-doses of 1-20 parts per million-
causes pulmonary vasodilation-not systemic-
vasodilation –decreases PVR.
 Methemoglobinemia-serious potential toxicity of
iNO Rx.
Measure metHb levels 24 hrs after start of Rx.
metHb levels>7% -reduce iNO
 Rebound hypoxemia-if iNO discontinued
abruptly.
 iNO should be tapered very gradually.

28.  Starting dose of iNO is 20ppm-delivered via
ventilator circuit.
 As baby improves & inspired O2 conc.<50%-iNO
is tapered by halving the dose.
eg: 20 to10 to 5 ppm over a 12-24 hr period -
gradually to 2 then 1 ppm.
 iNO –given in infants with PPHN & diffuse
pulmonary disease by concomitant use of HFOV
& surfactant treat.

29.  Sildenafil
 Phosphodiesterase-5 inhibitor
 Increases endogenous NO by inhibiting
metabolism-Rx for PPHN
 Randomized clinical trials awaited.

30.  4.ECMO
 Absence of pulmonary hypoplasia-ECMO-
life saving therapy for 75-85% infants with PPHN
who fail conventional management or iNO.
 ECMO criteria-
Alveolar arterial O2 difference (AaDO2)>600 or
Oxygenation index(OI)>30 on two ABGs >30 min
apart.
 Brief trial of HFOV or iNO instituted before ECMO.

31.  Technique of life support for neonates –cardiac
or respiratory failure-not responding to
conventional therapy.
 Indications: Respiratory failure-reversible,
Cardiac failure, E-CPR, Ex utero intra partum
treatment to ECHMO.
 Contra. Irreversible brain damage,
intraventricular & intraparenchymal hemorrhage,
wt<1.5kg, gestat. age<34wk, congenital abn.
severe coagulopathy, continuous CPR >1hr.

39.  5.Sedation & analgesia
 Fentanyl 1-4 micro gm/kg/hr infusion
 Morphine sulphate 0.05-0.1 mg/kg/hr
infusion-infant should not be hypotensive.
 6.Metabolic alkalosis
 Neutral to alkalotic pH-physiologic stimulus
that reduces PVR.
 Normalize pulmonary gas exchange &
conservative use of sodium bicarbonate.

40. 7.Hemodynamic support
a.Volume expansion
 0.9 % NS 10ml/kg over 20-30 min-used in
hemorrhage or excessive capillary leak,
Packed red blood cells also used.
 Infants with marked capillary leak-avoid 5%
albumin-albumin also leaks from capillaries –
worsen intertitial edema.

41. b.Pharmacologic Rx
 1.Cardiotonic agents-Dobutamine
 2.Vasopressors-Dopamine, Epinephrine.
 Milrinone-cardiac function very poor & infant
unresponsive to dobutamine.
enhances cardiac output & lowers PVR.

42.  Dobutamine-beta1 adrenergic stimulation.
 Dopamine-alpha & beta adrenergic receptor stimulation.
Support of systemic BP & improved cardiac output.
High dose 6-20 micro gm/kg/min
Moderate dose 3-5 micro gm/kg/min
Low 1-2 micro gm/kg/min- enhances mesenteric & renal
blood flow.
 Dopamine may increase PVR-high infusion rates >10micro
gm/kg/min.

43.  Epinephrine 0.03-0.10 micro gm/kg/min-
stimulates alpha & beta adrenergic receptors.
 Raises systemic BP tru enhanced cardiac
output & peripheral vasoconstriction.
 Epinephrine infusion caution-alpha
adrenergic receptor stimulation results in
pulmonary vasoconstriction & elevated PVR &
end organ (renal & mesenteric) perfusion
reduced.

44.  8.Correction of metabolic abnormalities
 Biochemical abnorm.-right to left shunting by
imparing cardiac function.
 Correction of hypoglycemia & hypocalcemia –
proper myocardial function.
 9.Correction of Polycythemia
 Hyperviscosity assoc. with polycythemia –
increases PVR –release of vasoactive
substances tru platelet activation.

45.  Partial exchange transfusion -central
hematocrit exceeds 65%.
 10.Additional pharmacological agents
 Sildenafil, adenosine, magnesium suphate,
calcium channel blockers, inhaled
prostacyclin, inhaled ethyl nitrite, inhaled or
inravenous tolazoline.
 Data insufficient to support use of these
medications.

46. 11.Treatment contraversies
 Interinstitutional variations in approach to
diagnosis & management of PPHN.
 Few centres report successful Rx without use
of mechanical ventillation, iNO, ECMO.

47.  PPHN results from disruption of normal
perinatal fetal to neonatal circulatory
transition.
 Incidence 1-2 per 1000 live births.
 Sustained elevation of PVR
 Persistent fetal circulation
 Contemporary ventilator management,iNO,
ECMO have improved survival among infants
with PPHN.

48.  Survivors of PPHN are at risk for chronic -
pulmonary disease , audiological,
neurodevelopmental or cognitive
impairments.

49.  1.Kliegman, Stanton, Geme ST, Schor, Behrman.
Nelson Textbook of Pediatrics 19th edition ,2012
:1529-1530.
 2.Cloherty PJ, Eichenwald CE, Hansen RA, Stark
RA. Manual of Neonatal Care 7th edition, 2012 :
435-442
 3.John FK, James EL, Donald CF. Nadas Text book
of Cardiology 2 nd edition 2006 :113-125
 4.Myung PK .Pediatric cardiology for Practitioners
2012, 5th edition:120-124