1. Persistent Pulmonary Hypertension of the Newborn
Khalid Altirkawi, MD, FAAP
King Saud University
College of Medicine
Department of Pediatrics / Neonatal Division

2. Introduction

4. 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
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5. 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
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6. 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.
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7. 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
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8. 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
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9. Vasodilatory Pathways
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10. Normal Pulmonary Vascular Transition
At the time of birth:
Multiple factors interact to regulate these pathways
Pulmonary artery pressure ↓ to ~ 50% of systemic pressure
Pulmonary blood flow increases by 10-fold
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11. 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
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12. 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
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13. 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
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14. 1- Underdevelopment
Underdevelopment of the pulmonary vasculature is observed in:
CDH
Renal agenesis
Thoracic dystrophy
Alveolar-capillary dysplasia
Pulmonary hypoplasia or dysplasia.
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15. 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
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16. 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.
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17. Clinical Presentation
Term infant
Cyanosis
Ductal-dependent differential oxygenation

18. The diagnosis Hyperoxia Test CXR: Echo Response to NO
Primary disease or black!
Echo
Right to left shunting
Right sided hypertension: Tricuspid Jet
Normal pulmonary artery!
Response to NO

19. Management Strategies
Treating underlying etiology:
RDS: Surfactant
MAS: Surfactant lavage.
Hypotension: vasopressors, volume expanders, …
Therapies to induce pulmonary vasodilation
Oxygen
Alkalanization (hyperventilation)
Vasodilators
Ancillary measures:
sedation and muscular paralysis
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20. Management Strategies
Oxygen
High enough to act as vasodilator, not just oxygenator
Ventilation
To keep CO2 normal
Studies of Hyperventilation showed immediate improvement but increased lung damage, decreased hearing
Studies of hypoventilation not ready yet
Jet – less PIP to achieve the desired paCO2 BP
High normal – To reduce differential pressure between pulmonary and systemic circulations

21. 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.
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22. 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.
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23. 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
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24. 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).
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25. 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.
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26. iNO dosing - RCTs
Initial RCTs used iNO in infants with severe respiratory failure and in those who are eligible for ECMO.
At oxygenation index (OI) >25, iNO decreased the use of ECMO, but mortality was NOT significantly altered.
The incidence of ECMO + mortality with iNO therapy was still close to 40%.
There are potential benefits to starting iNO early in the course of respiratory failure at an OI <25

27. RCTs meta analysis Ctl iNO ECMO ECMO Died Died Ctl iNO Ctl iNO
Totals % % % %
p < p = 0.477

28. Relation to CDH
The total number of infants cannulated for ECMO decreased over time. All of this decrease was in infants with respiratory failure due to MAS, sepsis, pneumonia, RDS, and idiopathic PPHN. The number of infants cannulated for CDH was stable over the three time periods.
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29. iNO does have some limitations
~ 30% of cases do not respond to iNO. The reasons for this failure include:
Severe parenchymal lung disease
Myocardial dysfunction
Problems with NO-cGMP signalling
The outcome of neonates with CDH is also not improved (there is a suggestion that outcomes are slightly worsened).
An association of prolonged iNO therapy with decreased endogenous NO synthase activity (PPHN rebound)
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30. iNO does have some limitations
Other important considerations:
The cost
Development of methemoglobinemia
Organ injury from higher oxides
Cell membrane damage from peroxynitrites.
Associated with a prolongation in bleeding time.
(there are no reports of morbidity following iNO therapy attributable to bleeding in neonates).
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31. 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.
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32. 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.
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33. 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.
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34. 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
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35. 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)
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36. 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.
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37. 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*)
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38. 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.
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39. 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
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40. 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)
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41. 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*)

42. 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.
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43. 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.
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44. References
Konduri, GG:New approaches for persistent pulmonary hypertension of newborn. Clin Perinatol 31: 591–611, 2004
Farrow, KN, Fliman, PF, Steinhorn, RH:The Diseases Treated with ECMO: Focus on PPHN. Semin Perinatol 29:8-14, 2005
Travadi, JN,Patole, SK: Phosphodiesterase Inhibitors for Persistent Pulmonary Hypertension of the Newborn: A Review. Pediatric Pulmonology 36:529–535, 2003
Merenstein, GB, Weisman, LE:Premature Rupture of the Membranes: Neonatal Consequences. Semin Perinatol 20: , 1996
Weinbergera, B, Weissa, K, Heckb, DE, Laskinb, et al : Pharmacologic therapy of persistent pulmonary hypertension of the newborn. Pharmacol Therapeutics 89:
McNamara, PJ, Laique, F, Muang-In, S, et al:Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Critical Care 21: 217–
Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates.Cochrane Database Syst Rev Jul 18;(3)
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