pphn in resource limited settings

1. Management of PPHN in
resource limited settings
DR.Rakesh kotha
MD DM(JIPMER)
Asst prof Neonatology(Niloufer)

2. First described as “unripe births of mankind” by Willam
Harvey in 1628
Gersony et al 1969 labeled as PFC(Persistent fetal
circulation)
The phrase “persistent pulmonary hypertension of the
newborn” was first used by Levin et al 1976

3. Fetal to Neonatal Transition
• Crying of infant--- opening of lungs—O2(most potent pulmonary
vasodilator even though it acts through NO) Nature creation?
– Fall in pulmonary vascular resistance
• Cutting of the cord
– Increase in systemic vascular resistance
• Closure of ductus arteriosus
• Closure of ductus venosus
• Closure of foramen ovale
• Pulmonary hypertension is necessary in fetus
Park: Pediatric cardiology for practitioners, 5th
ed.

5. • mPAP = (PBF × PVR) + PCWP
• Pulmonary vasoconstriction and vascular
proliferation and remodeling contribute to
elevated pulmonary vascular resistance (PVR) in
PPHN
• Our aim is to selectively decrease the pulmonary
pressures
• PVR is main culprit in PPHN

6. PPHN is a syndrome associated with diverse neonatal
cardiac and pulmonary disorders that are characterized by
high PVR causing extra pulmonary right-to-left shunting of
blood across the ductus arteriosus and/or foramen ovale
Shunt is more important than pressures (25mmHg)
Avery s disease of new born 10th edition

8. Maladaptation
Structurally normal but abnormally constricted
pulmonary vasculature due to parenchymal
disease
Meconium aspiration syndrome
Respiratory distress syndrome (MOST COMMON)
Excessive muscularization
Normal parenchyma but remodeled pulmonary vasculature
Chronic In-utero hypoxia (IUGR)
Post maturity(41WKS)
Hypoplastic vasculature
Underdevelopment of pulmonary vasculature
CDH
Hypoplastic lungs

9. PPHN
CHRONICACUTE
IRREVERSIBLEREVERSIBLE
pulmonary
Non
pulmoanry
late
CDH
CNDL
TRISOMY 21
PULMONARY OVER CIRCULATION
ASD DOWNS
RDS
TTN
CDH
GDM
HYOPOPLASIA
HIE
DRUGS
POLYCYTHEMIA
INFECTION
ADRENALINE INSUFFICIENCYU
HYPOLASIA
MALFORMATIONS
SURFACTANT DEFICIENCY

10. Pathophysiology
(VASO DILATATION)CAMP CGMP=ET Rho(VASO CONSTRICTION)
CGMP CAMP PATHWAY DEVELOP IN LATER GESTATION (Kinsella et al., 1994
proved role of NO in preterms also).

12. Resource limited settings ?
Only approved therapy s NO(1999) & ECMO
Mild to moderate PPHN non invasive
ECMO few centers and many
limitations
Only beneficial in pphn?
Cost effective ness ?
30-40% will not respond to NO
> 34WKS &reserved for severe PPHN

13. Hyperoxia (free radical injury) and alkalosis (deaf ness)
In Patent PFO no preductal and post ductal difference(5-
10%)
For proper management ECHO
is necessary

15. Antenatal
Perinatal nutrition
GDM
Obesity
Smoking
NSAIDS SSRIs chorioamnionitis Role of sildenafil
?(PDE 3 retina)
Sepsis (Group B)
Natal
PROM (below 29 wks. hours of leakage also cause pulmonary
hypoplasia)
Mode of delivery(LSCS)
Antenatal scans( CCAM CDH)
NST to find out fetal distress

16. Postnatal
Early diagnosis as it is a medical emergency
Temperature(Transport)
Decrease over distention/suction labour room cpap ELBW
Early initiation of inotropes/Severe IUGR
Hyperoxia 91-97%Hypocalcemia
Noninvasive ventilation for mild PPHN gentle ventilation
Early referral considering severity ( meconium nails and
lanugo) Sepsis (preterm)

17. SUPPORTIVE MEASURES
Avoid sound and bright light exposure
Analgesia by opioids morphine fentanyl as stress
releases catecholamine's
Maintaining systemic blood pressures
Gentle ventilation
Fluid bolus
Inotropes ?
DOPAMINE Pulmonary vasoconstriction ,reserve of
catecholamine's in preterm
Dobutamine systemic vasodilatation
Norepinephrine acidosis
Epinephrine better to avoid (acidosis and increases the
PVR)

18. • OUR AIM IS TO DECREASE PVR KEEP THE
BABY NORMOTENSIVE NOT HYPERTENSIVE

19. DRUGS MECHANISM SIDE EFEFCT
SILDENAFIL PDE5 inhibitor Hypotension
hypoxemia
MILRINONE PDE3 inhibitor HYPOTENTION
thrombocytopenia
arrhythmias
BOSENTAN Endothelin receptor
antagonists
hepatic injury and teratogenic
effect edema
VASOPRESSION V2R and NO release by OTR Hyponatremia
Arrhythmias anuria
MAGNESIUM SULPHATE Calcium antagonist hypotension
PROSTACYCLIN potent vasodilator
CAMP activation
Inhibits platelet aggregation,
inflammation flushing
REBOUND PH
LUNG SETTING
OXYGEN Free radical injury
91-97%
SURFACTANT ONLY IN PARANCHYMAL
DISEASES
CDH MORTALITY

21. AVAILABLE EVIDENCE
NO (1997) Large scale RCTS Met analysis
SILDENAFIL Small RCTS
BOSENTAN Small RCTS
PROSTACYCLINES Case series trails going on
VASOPRESSION Small RCTS going on case series
MGSO4 Observational studies case reports
MILRINONE Case reports

22. PROPOSED TREATMENT STRATEGIES
PROVEN BENIFICIAL UNPROVEN
O2,surfactant HFO Respiratory alkalosis
NO Avoidance of noise light Alkali infusion
DOPAMINE paralysis
ECMO

23. Surfactant
• PPHN with parenchymal lung disease early surfactant is
associated with better outcome, reduced requirement of
ECMO or death
Koundari et al J perinatol, 2013
• No benefit of surfactant
CDH registry, J Pediatr 2006
• In presence of pulmonary hypoplasia (CDH) use only 50%
dose of surfactant
• Lakshminrusimha, Keszler Neoreview 2015
Surfactant
– Severe HMD or MAS

24. GLUCOCORTICOIDS
Increasing SOD and PDE5 in lamb model an Indian study
showed by giving methyl prednisolone o2 requirement was
decreased in MAS babies
Tripathi S. Journal of tropical pediatrics. 2007;53:8–
12.

25. SILDENAFIL
The FDA warning and recommending against its use in children
Abman et al clarification ----considering by risk benfit ratio
Farrow kn et al showed in animal modeles it is usueful in prolonged hyperoxia
Mourani PM et al in retrospective studies showed it will decrease rt atrial pressure
Bauero et al in randomized controlled trail showed decreasing mortality 6/7 1/7
Behsrin j et al showed better results in CDH neonates
Wardel Aj et al studies showed retrospective historical studies showed better results in
sildenafil group

26. Oral dosing
− Oral bioavailability ~40% enteral doses are higher than IV doses −
0.5‐2 mg/kg/dose q6hr to q8hr
IV dosing in neonates
− Loading dose of 0.4 mg/kg over 3 hours
− Infusion of 1.6 mg/kg/day ~0.07 mg/kg/hr
− In neonates the volume of distribution is 4 times higher
clearance is slower half-life of 48 – 56 hours
Sildenafil clearance increases threefold in the first week of life
maturation of the CYP2C9 3A4
Mukherjee A et al 2009

28. Non‐selective pulmonary vasodilator—can cause systemic
Hypotension
Ventilation‐perfusion mismatch
PDE3 IN RETINA 80-1000 folds affinity for other PDE
After hyperoxia PDE5 will increase usueful in NO resistant
cases
During weaning of NO
OUR UNIT
oral/COST

29. Bosentan
The dose of bosentan used in newborns is
1–2 mg/kg twice daily
Bosentan is well absorbed following enteral
administration (~98% in adults) is metabolized in
the liver and is eliminated by biliary excretion no iv
form only oral availability restrict its use in
emergencies
BPD and Chronic CDH
we have used in chronic PPHN in HIE cases
It is endothelin receptor blocker ET A ETB (non selective)
ET1 is increased in PPHN

30. Vasopressin
• One of the first synthesized peptide hormone
• Acts via G protein coupled receptors
• V1-Vascular vasoconstriction V2-pulmonary additionally
some actions via OTR (oxytocin) and NO release
• Vasopressin also decreases pulmonary arterial pressure in
hypoxic condition mediated via ANP
Therapeutic application of vasopression in pediatric patients, Indian pediatrics Volume -49 april-16,2012

31. • An ideal agent
Vasopressin in PPHN

32. • Systemic AVP therapy treatment of refractory
vasodilatory shock in pediatric and ELBW population
Russel JA, Vasopressin in management of septic shock Crit Care 2011;15:226
• Retrospective study of neonates with PPHN who were
unresponsive to iNO Found improvement in oxygenation
with effect starting within 3 hrs of starting treatment
Mohamed A, Pediatr Crit Care Med 2014;15:148

33. • Low-dose AVP (0.00017–0.0007 U/kg/min) appears
to decrease catecholamine requirement without
associated hyponatremia
• In neonates high-dose AVP (0.001–0.02 U/kg/min)
also appears to be effective but is associated with
adverse effects including transient hyponatremia
• we have good experience with AVP

34. Prostacyclin's (PGI2) and PGE1
Epoprostenol Treprostinil Iloprost Beraprost
and Alprostidil
• Directly stimulate C AMP
• instability short half life
• Inhalation (PGE1 also)forms to selectively
decrease the PVR with out SVR (more effective
than sildenafil)
• At present we r not using

35. MAGNESIUM SULFATE
• The use of magnesium sulfate should be
limited especially that it can be associated with
systemic hypotension.
• Mean duration 75.5 hours
• According to Cochrane RCT Needed
• No other vasodilators to be used& no
hyperventilation
• 200mg/kg followed by20-150mg/kg hr3.5- 5 m
mol /l
• Not using in our unit

36. MILRINONE
Primacorp study 238 childrens post cardiac surgery
infants and childrens showed good results pharmacokinetics also well established
McNamara et al and Bassler et al reported an increase in PaO2 and decrease in OI in
response to milrinone infusion in neonates with PPHN who are unresponsive to iNO.
Milrinone has been shown to decrease pulmonary arterial pressure and resistance and
to act additively with iNO in animal studies - elitz et al., 2004
• Milrinone is administered as a loading dose of 50
μg/kg/min given over 30 min followed by 0.33
μg/kg/min as a continuous infusion. The dose may
be titrated up to 1 μg/kg/min
• Hypotension Thrombocytopenia arrythmias
• useful in LV dysfunction and CDH

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