1. Persistent Pulmonary Hypertension (PPHN) F. Hazel R. Villa, MD PL1

2. Objectives to review the fetal,transitional and postnatal circulation in relation to PPHN to review the fetal,transitional and postnatal circulation in relation to PPHN To understand the pathophysiology of PPHN as it applies to clinical manifestations and management To understand the pathophysiology of PPHN as it applies to clinical manifestations and management

3. Pulmonary vessels VASOCONSTRICTORS (Maintain high fetal PVR) Norepinephrine A-adrenergic stimulation HypoxiaEndothelinThromboxanesLeukotrienes Platelet activating factor PGF2aVASODILATORS (Decrease PVR during transition) PGI2, PGD2, PGE2 Nitric oxide Cyclic GMP Cyclic AMP OxygenAdenosineBradykinin

5. Fetal circulation

6. pO2, PGI2, NO pO2, PGI2, NO ADMA -- competes with arginine ADMA -- competes with arginine inhibit NOS inhibit NOS Vasoconstriction Vasoconstriction

7. Postnatal circulation

8. Transitional circulation

9. Transitional to postnatal At birth At birth increase in NO, NOS-  cGMP increase in NO, NOS-  cGMP increase guanylate cyclase-  cGMP increase guanylate cyclase-  cGMP increase in PGI2 (effect of estrogen)  cAMP increase in PGI2 (effect of estrogen)  cAMP DDAH metabolizes ADMA DDAH metabolizes ADMA Vasodilatation Vasodilatation

10. Transitional to postnatal At birth At birthventilation increase pulmonary blood flow Oxygenation Oxygenation

11. Transitional to postnatal Oxygen- stimulates NOS, COX1 Oxygen- stimulates NOS, COX1 Pulmonary blood flow- release of NO, PGI2 Pulmonary blood flow- release of NO, PGI2 Evidence: NO-cGMP pathway is a more potent modulator of pulmonary vascular tone Evidence: NO-cGMP pathway is a more potent modulator of pulmonary vascular tone

12. Increase in SVR Removal of the placenta Removal of the placenta Catecholamine associated with birth Catecholamine associated with birth Cold environment Cold environment

13. Postnatal decrease in PVR Expansion of the lung Expansion of the lung Adequate ventilation, oxygenation Adequate ventilation, oxygenation Clearance of fetal lung fluid Clearance of fetal lung fluid

14. 3 types of abnormalities Maladaptation Maladaptation Maldevelopment Maldevelopment Underdevelopment Underdevelopment

15. Maladaptation Prototype: Meconium aspiration pneumonia Prototype: Meconium aspiration pneumonia Pneumonia, RDS Pneumonia, RDS Obstruction of the airways Obstruction of the airways Chemical pneumonitis Chemical pneumonitis Release of endothelin,thromboxane  vasoconstrictors Release of endothelin,thromboxane  vasoconstrictors

16. Maldevelopment Prototype: Idiopathic PPHN Prototype: Idiopathic PPHN (“black lung” PPHN) (“black lung” PPHN) Vessel wall thickening Vessel wall thickening Smooth muscle hyperplasia Smooth muscle hyperplasia Cause – intrauterine exposure to NSAID Cause – intrauterine exposure to NSAID constriction of ductus arteriosus constriction of ductus arteriosus genetic genetic

17. Disruption of NO-cGMP pathway Disruption of NO-cGMP pathway Disruption of PGI2-cAMP pathway Disruption of PGI2-cAMP pathway Guanylate cyclase is less active Guanylate cyclase is less active Increased ROS (reactive oxygen species)  vasoconstrictor Increased ROS (reactive oxygen species)  vasoconstrictor Increased thromboxane, endothelin Increased thromboxane, endothelin Maldevelopment

18. Underdevelopment Prototype: Congenital diaphragmatic hernia Prototype: Congenital diaphragmatic hernia Pulmonary hypoplasia Pulmonary hypoplasia Decreased cross sectional area of pulmonary vasculature Decreased cross sectional area of pulmonary vasculature Decreased pulmonary blood flow Decreased pulmonary blood flow Abnormal muscular hypertrophy of the pulm arterioles Abnormal muscular hypertrophy of the pulm arterioles

19. Clinical signs and symptoms PE: PE: meconium staining meconium staining Prominent precordial impulse Prominent precordial impulse Narrow split accentuated P2 Narrow split accentuated P2 Systolic murmur LLSB Systolic murmur LLSB

20. Labs CXR: CDH, decreased vascular markings, parenchymal disease CXR: CDH, decreased vascular markings, parenchymal disease ECG: RV predominance, ST elevation ECG: RV predominance, ST elevation ABG: hyperoxic test (pO2 < 100 at 100% O2) ABG: hyperoxic test (pO2 < 100 at 100% O2) Pre and postductal ABG (R radial artery: umbilical artery/lower extremity) Pre and postductal ABG (R radial artery: umbilical artery/lower extremity) 10-15% saturation and or 10-15mmHg pO2 10-15% saturation and or 10-15mmHg pO2

21. Labs Echocardiography Echocardiography Structural heart disease is determined Structural heart disease is determined R-L shunting (Ductus or FO) R-L shunting (Ductus or FO) Pulmonary arterial pressure is measured Pulmonary arterial pressure is measured

22. Management Oxygen 100% pO2 should be kept between 50-90mmHg (O2 saturation >90%) Oxygen 100% pO2 should be kept between 50-90mmHg (O2 saturation >90%) Correct factors promoting vasoconstriction: hypoglycemia, hypocalcemia, anemia, hypovolemia Correct factors promoting vasoconstriction: hypoglycemia, hypocalcemia, anemia, hypovolemia Optimize cardiac function (inotropic agents, volume expansion Optimize cardiac function (inotropic agents, volume expansion Mechanical ventilation Mechanical ventilation Surfactant Surfactant

23. Inhaled Nitric oxide- an ideal selective pulmonary vasodilator Inhaled Nitric oxide- an ideal selective pulmonary vasodilator OI of >25 OI of >25 OI=(MAP x FiO2)/pO2 x 100 OI=(MAP x FiO2)/pO2 x 100 Contraindications: CHD which are PDA dependent Contraindications: CHD which are PDA dependent (aortic stenosis, interrupted aortic arch, hypolastic heart syndrome) (aortic stenosis, interrupted aortic arch, hypolastic heart syndrome) May worsen pulmonary edema in obstructed TAPVR May worsen pulmonary edema in obstructed TAPVR Management Used to transport patient for ECMO

24. ECMO ECMO Goal of this treatment: Goal of this treatment: maintain adequate tissue oxygenation and maintain adequate tissue oxygenation and avoid irreversible lung injury, while PVR decreases and correcting pulm HTN avoid irreversible lung injury, while PVR decreases and correcting pulm HTN ECMO if OI is >40 ECMO if OI is >40 Management

25. Other Pulmonary Vasodilators Sildenafil- PDE5 inhibitor  increased cGMP Sildenafil- PDE5 inhibitor  increased cGMP Milrinone- PDE3 inhibitor  increased cAMP Milrinone- PDE3 inhibitor  increased cAMP Inhaled PGI2 Inhaled PGI2 Superoxide dismutase-superoxide scavenger  Superoxide dismutase-superoxide scavenger  Dilates pulm vessels, and increase endogenous NO Dilates pulm vessels, and increase endogenous NO

26. References http://neoreviews.aappublications.org/cgi/content/full/8/1/e14 http://neoreviews.aappublications.org/cgi/content/full/8/1/e14 http://neoreviews.aappublications.org/cgi/content/full/8/1/e14 http://www.utdol.com/utd/content/topic.do?topicKey=neonatol /1427&view=print http://www.utdol.com/utd/content/topic.do?topicKey=neonatol /1427&view=print http://www.utdol.com/utd/content/topic.do?topicKey=neonatol /1427&view=print http://www.utdol.com/utd/content/topic.do?topicKey=neonatol /1427&view=print www.emedicine.com/ped/topic2530.htm www.emedicine.com/ped/topic2530.htm www.emedicine.com/ped/topic2530.htm www.emedicine.com/PED/topic2530.htm www.emedicine.com/PED/topic2530.htm www.emedicine.com/PED/topic2530.htm phassociation.org/medical/.../Summer_2006/persisten t_ph_newborn.pdf phassociation.org/medical/.../Summer_2006/persisten t_ph_newborn.pdf

27. Thank you!