lecture of 42 slide

1. Persistent Pulmonary Hypertension
of the Newborn
BY
DR. Magdy Shafik
Senior Pediatric Consultant
Diploma, M.S ,Ph.D of Pediatric

2. PPHN‐Background
 First described in 1969 by Gersony et al
 First described as “persistent fetal
circulation”
 Systemic blood flow through fetal
shunts (PDA and PFO)

3.  PPHN is defined by a failure of
pulmonary vascular resistance to
decrease after delivery
 Results in failure of systemic
oxygenation (hypoxia)
 Absence of congenital heart disease

4. Incidence 2/1000 live
births
Mortality <10%
􀂄􀂄11‐34% in 1980’s
 􀂄 Early treatment
improves outcome

6. Changes at Birth‐Lungs
􀁺 The lungs become the organ of gas
exchange
􀁺Continuous breathing
􀁺 Expansion of lungs with air
􀁺Surfactant synthesis
􀁺 Fetus becomes more oxygenated

7. Changes at Birth‐Cardiovascular
􀁺 Removal of the placental circulation
􀁺Decreased pulmonary vascular
resistance (PVR)
􀁺 Increase in pulmonary blood flow
􀁺 Closure of the ductus arteriosus,
foramen ovale, and ductus venosus

8. PPHN 8
Normal Pulmonary Vascular Transition
 In utero:
 Pulmonary pressures are equivalent to systemic pressures due
to elevated pulmonary vascular resistance (PVR)
 Only 5% to 10% of cardiac output goes through the lungs
 Multiple pathways maintain high pulmonary vascular tone.
 Known pulmonary vasoconstrictors include:
 Endothelin-1 (ET-1)
 Thromboxane
 Hypoxia
 Acidosis
 Various mediators of inflammation

9. PPHN 9
Normal Pulmonary Vascular Transition
 As gestation progresses, the mediators of the
vasodilatory pathways become more dominant. In
particular, Nitric oxide (NO) production
 Pulmonary expression of endothelial NO synthase (eNOS)
and its downstream target, soluble guanylate cyclase (sGC)
increases during late gestation
 Ultimately, increased sGC activity leads to increased cGMP,
which then leads to vasorelaxation via decreasing intracellular
calcium

10. PPHN 10
Synthesis and release of endothelium-derived NO and its effect on its target, vascular
smooth muscle. Increases in cGMP levels in the smooth muscle lead to vasodilation.
Phosphodiesterase limits the duration of the vasodilation by breaking down cGMP.

11. PPHN 11
Normal Pulmonary Vascular Transition
 Another potentially important vasodilatory pathway in the
normal transition to extrauterine life is the prostacyclin pathway
 Cyclooxygenase (COX) is the rate-limiting enzyme that generates
prostacyclin from arachadonic acid (AA)
 COX-1 in particular is upregulated in late-gestation
 This upregulation leads to an increase in prostacyclin production in late
gestation and early postnatal life
 Prostacyclin ultimately upregulates Adenylate cyclase to increase
intracellular cAMP levels, which leads to vasorelaxation

12. PPHN 12
Synthesis and release of PGI2 from arachidonic acid and endoperoxides by
cyclooxygenase and PGI2 synthase. Prostacyclin increases cAMP levels in vascular
smooth muscle leading to vasodilation, which is regulated by a specific
phosphodiesterase

13. PPHN 13
Vasodilatory Pathways

14. PPHN 14
Normal Pulmonary Vascular Transition
 The most critical signals for transition are:
 Mechanical distension of the lung
 Shear stress is known to regulate the synthesis of NO in the fetal circulation.
 Initial increase in pulmonary blood flow in response to ventilation or
oxygenation may lead to increased shear stress in the vasculature, which in
turn further increases NO production.
 Rising pO2 in the lungs: Oxygen stimulates:
 The activity of both eNOS and COX-1 directly.
 The release of ATP from oxygenated red blood cells  ↑ the activity of both
eNOS and COX
 Lowering pCO2

15. PPHN 15
Conditions associated with PPHN
 PPHN can be:
 Idiopathic _ 20%
 Associated with a variety of lung diseases:
 Meconium aspiration syndrome (50%)
 Pneumonia/sepsis (20%)
 RDS (5%)
 Congenital diaphragmatic hernia (CDH)
 Others: Asphyxia, Maternal diabetes, Polycythemia

16. PPHN 16
Pathophysiology
 PPHN is more common in term & near-term (> 34
wks G/A) neonates.
 The development of smooth muscle around the small
pulmonary arterioles in late gestation (> 28 wks) may
predispose term infants to increased resistance to the
pulmonary flow.
 PPHN can result from either:
 Underdevelopment
 Maldevelopment
 Functional maladaptation of pulmonary vasculature

17. PPHN 17
1- Underdevelopment
 Underdevelopment of the pulmonary vasculature is
observed in:
 CDH
 Renal agenesis
 Thoracic dystrophy
 Alveolar-capillary dysplasia
 Pulmonary hypoplasia or dysplasia.

18. PPHN 18
2- Maldevelopment
 Maldevelopment of the pulmonary vasculature
 Extension of musculature from the pre-acinar into the
normally non-muscularized intra-acinar arteries.
 This vascular muscular hypertrophy encroaches on the
vascular lumen and obstructs blood flow.
Example:
 Chronic stress, increased blood flow in utero

19. PPHN 19
3- Maladaptation
 Maladaptation of pulmonary vasculature:
 The failure of the PVR to decrease despite normal anatomy.
 Can result from perinatal distress.
 Contributing factors include:
 Acidosis,
 Hypoxia,
 Hypercarbia,
 Aspiration,
 Hypothermia,
 Hypoglycemia,
 Hemorrhage.

20. Clinical Presentation
 Clinical Presentation
 Term infant
 codition started 6-12 hours after birth
 Cyanosis and resp. distress
 Pa O2 gradient between a preductal ( rt radial artery ) and
postductal (umblical artery) blood > 20 mmHg or
> 10% difference in O2 saturatuion is highly suggestive
of ductal right to lift shunt.
 in severe cases differantial cyanosis with pink upper body
and a cynotic lower body may be seen .
 systemic hypotension is present

21. The diagnosis
 Hyperoxia Test
 CXR:
 Primary disease or black!
 Echo ( is confirmatory)
 Right to left shunting
 Right sided hypertension: Tricuspid Jet
 Normal pulmonary artery!
 Response to NO

22. Hyperoxia Test
 Arterial blood gas obtained prior to and 5‐10 minutes
after administration of 100% Oxygen
 􀁺 PaO2 < 50 mmHg ‐ cyanotic congenital heart disease
or PPHN
 􀁺PaO2 <150 mmHg ‐ PPHN
 􀁺PaO2 > 150 mmHg ‐ parenchymal lung disease
 􀁺PaO2 > 300 mmHg ‐ normal

23. PPHN 23
Management Strategies
 Minimize handling , noise and physical manipulation.
 Administer 100% O2 to achieve preductal sat. > 95%
 Mechanical Ventilation:
Fio2 100% to stable preductal sat. > 95%
Lowest possible mean airway pressure
Avoid hyperventalion Pa CO2 (35- 40 mm Hg)
complication of hyperventilation : barotrauma ,
decrease cardiac output , decrease cerebral blood flow
 High frequency ventilation

24.  Sedation and analgesia :
 Fentanyl infusion (narcotic )(2-5 ug kg hr) is a useful advent
therapy
 paralysis of the patient with pancuromium. (neuromuscular
blocking agent)
 Alkalinization with sodium bicarbonate infusion (
0.5 – 1mEqukghr)
 To increase arterial PH to 7.50- 7.55
 Inotrop ic therapy
 Dopamine to suport bl. Pre. And perfusion
 Dobutamine in cases of myocardia dysfunction
 Tolazoline ( non selective alpha adrenageric
antagonist) infusion :
produce pulmonary vasodilation
given with volume support and pressor drugs if hypotension occurs .

25. PPHN 25
Vasodilators
 Numerous vasodilator therapies have been proposed or
used in infants with PPHN that persists despite the
correction of underlying metabolic disturbances and
adequate ventilation.
 With the exception of iNO, vasodilator therapies for
PPHN are limited by their lack of selectivity for the
pulmonary circulation.

26. PPHN 26
iNO
 iNO acts as a messenger molecule:
 iNO  ↑the activity of soluble guanylate cyclase (sGC)
 sGC  the formation of cyclic GMP (cGMP)
 cGMP  causes vascular smooth muscle relaxation acting through
the calcium-gated potassium channels
 Vasorelaxation induced with iNO is transient
 In the presence of oxygen, iNO rapidly degrades (<10 sec) to higher
oxides, losing its bioactivity.

27. PPHN 27
iNO
 iNO is an ideal pulmonary vasodilator:
 Is selective pulmonary vasodilator at doses <100 (ppm)
 Confined to the pulmonary vascular bed (due to the rapid
inactivation by hemoglobin in the pulmonary circulation)
 Its vasodilator effect is not altered by extra-pulmonary shunts
 It has the ability to improve ventilation-perfusion matching
(vasodilation occurs in the ventilated segments of the lung)
 It causes vasodilation even in the presence of endothelial cell
injury or dysfunction

28. PPHN 28
iNO dosing
 The current recommended starting dose in term infants with
respiratory failure is 20 ppm (RCTs)
 Other studies have shown that doses as low as 5 ppm were
effective
 Higher Doses:
 Are NOT more effective.
 Are associated with a higher incidence of side effects.
 Initiation of iNO at lower doses has the advantage of faster
weaning and lesser exposure to nitrogen oxides that cause
oxidant stress.

29. PPHN 29
Alternate approaches to iNO
 The alternatives include:
 Vasodilator prostaglandins such as prostacyclin or PGE1
 NO precursor L-arginine
 Phosphodiesterase inhibitors such as sildenafil
 The free radical scavenger SOD.
 Other agents that were investigated in pediatric and
adult pulmonary hypertension:
 Adenosine and ATP-MgCl2
 Magnesium sulfate
 Endothelin receptor antagonist Bosentan.

30. PPHN 30
Phosphodiesterase inhibitors
 iNO  ↑guanylate cyclase (sGC) ↑ cyclic GMP
(cGMP)
 cGMP is hydrolyzed and inactivated by Type 5
phospho-diesterases (PDE5).
 The beneficial effects of PDE5 inhibitors may be optimized by using
them in combination with iNO.
 Pulmonary administration presumably minimizes the potential for
undesired systemic effects.
 PDE5 inhibitors include: Dipyridamole, Zaprinast,
Pentoxifylline and Sildenafil.

31. PPHN 31
Mechanism of selective effects of iNO
As NO diffuses from the alveolus to the adjacent pulmonary artery, relaxation of vascular smooth
muscle occurs. NO that diffuses into the lumen of the artery is bound to hemoglobin and inactivated in
the red cell to nitrite and nitrate (NO2 + NO3). PDE5 inhibitors action increases cGMP.

32. PPHN 32
Sildenafil
 A selective pulmonary vasodilator (animal model)
 As effective as iNO in pulmonary vasodilatation
(humans studies)
 When combined with iNO, it is more effective than
either therapy alone
 Attenuates the rebound PPHN upon withdrawal of
iNO

33. PPHN 33
Sildenafil
 Given its mechanism of action, sildenafil may NOT
have a role in rescue therapy following failure of iNO
 Concerns about its use:
 In situations of hepatic dysfunction
 In combination with antifungal therapy
 Possible retinal damage
 May worsen V/Q mismatching (non specific vasodilation)

34. Sildenafil
 Shah and Ohlson in cochrane database (2007):
 Two small RCTs (one abstract only with limited information).
The methodological quality was good. N=37. resource-
limited settings (iNO and HFV are not available)
 Conclusons:
 The safety and effectiveness of sildenafil in the treatment of PPHN
has not yet been established and its use should be restricted within
the context of RCTs.
 RCTs of adequate power comparing Sildenafil with other pulmonary
vasodilators are needed in moderately ill infants with PPHN.
PPHN 34

35. PPHN 35
Milrinone
 Is a bipyridine compound that selectively inhibits
phosphodiesterase III (PDE3) in cardiac myocytes and
vascular smooth muscle
 It reduces PVR and pulmonary artery pressure (PAP) in
experimental models of pulmonary hypertension, adult
humans, and neonates post cardiac surgery.
 Experience with this drug in neonates is limited (Case series*)
 Milrinone is used for: Treating congestive heart failure. it is
an inotrope and vasodilator.

36. PPHN 36
L-Arginine
 The rationale for using L-arginine infusion is twofold:
 L-arginine is a required substrate for NO synthesis
 It promotes NOS activity under stress conditions
 Plasma levels of L-arginine are decreased in neonates with
PPHN compared with infants requiring ventilation for other
causes.
 The vasodilatory effect is lesser compared to iNO
 It may help preserve the endogenous NOS activity and permit a
smoother weaning of iNO therapy.

37. PPHN 37
Superoxide dismutase (SOD)
 The rationale for SOD use is:
 To reverse the impaired vasodilation by reducing the production of O2
free radicals (ROS) and NO3 formation. (Several laboratory studies have
suggested that accumulation of ROS occurs in PPHN).
 Animal studies suggest
  superoxide formation in PPHN impairs vasorelaxation
  the ability of pulmonary arteries to respond to iNO.
 SOD protects the lung from oxidant damage caused by the combination
of exogenous NO and high inspired oxygen concentrations

38. PPHN 38
Prostacyclin
 A potent vasodilator
 Increases the cAMP level in vascular smooth muscle.
 A potential synergistic effect on the vascular tone when used
combined with iNO.
 Intravenous and aerosol administration
 Short half-life: spontaneous hydrolysis to a stable metabolite,
6-keto-PGF1-a. (aerosolized PGI2 is more selective)

39. Adenosine & ATP
 Pilot RCT:
 Selective pulmonary vasodilation when infused in low doses
 Adenosine infusion at 25 to 50 mg/kg/min improved
oxygenation in babies with PPHN (pilot RCT*)

40. PPHN 40
Magnesium sulfate
 Low cost and readily available.
 May cause systemic hypotension and CNS depression
 No RCTs of this agent in PPHN.
 Two uncontrolled trials (babies were not on any other
vasodilators): IV Mg SO4 improved oxygen-ation and
decreased the OI.
 Cochrane: Mg SO4 cannot be recommended in the
treatment of PPHN. RCTs are recommended.

41. PPHN 41
Conclusions
 With the advent of iNO the management of PPHN entered a
new era.
 The wider application of iNO therapy and improved
ventilation strategies led to a decrease in the need for invasive
life-sustaining therapies such as ECMO.
 Further decreases in morbidity and mortality are possible
with specific strategies targeted to correct the alterations in
NO and prostacyclin biology and strategies to reduce lung
injury.