1. Persistent Pulmonary Hypertension of the Newborn
Arthur E. D’Harlingue, M.D.
Director of Neonatology
Children’s Hospital & Research Center Oakland

2. Educational Objectives
Discuss the initial evaluation and diagnosis of pulmonary artery hypertension.
Describe some of the underlying causes and pathophysiology of pulmonary hypertension.
Discuss the management of pulmonary artery hypertension including the use of iNO and other therapies.

3. Disclosures No conflicts of interests to report
Will discuss some non-FDA approved uses of medications/treatments

4. Incidence and mortality from neonatal pulmonary hypertension
6.8/1000 live births
Most common cause is meconium aspiration
~10-20% mortality despite high-frequency ventilation, surfactant, nitric oxide, and ECMO
~ 40% non-responder rate with nitric oxide
Higher mortality when these therapies are unavailable

5. Related terminology……
Pulmonary hypertension
Persistence of the fetal circulation
Persistent pulmonary hypertension of the newborn (PPHN)

6. And what you see here is that in the fetus, the gas exchange occurs in the placenta. And of course, every organism, you’re going to direct 50% of your cardiac output to the organ of gas exchange. So for the fetus, that would, by definition, be the placenta.
Now, to maintain flow to the placenta, there has to be a resistor in the lungs. And that of course is the pulmonary vascular resistance remains quite high. Pulmonary blood flow is low, and output from the right ventricle is therefore maintained by right to left shunts across the foramen ovale in the heart and the ductus arteriosus.

7. Critical signals in transition at birth
Mechanical distention of the lung
Decrease in PCO2
Increase in PO2
Associated increase in endothelial NOS and COX-1
Above factors result in increase in pulmonary blood flow and improvement in oxygenation
Failure of this transition can results in pulmonary artery hypertension and right to left shunting

8. Transitional Circulation
PA pressure
Pulm blood flow
Oxygen tension
PDA
Fetus Newborn

9. Transitional Circulation
PA pressure
Pulm blood flow
Oxygen tension
PDA
Fetus Newborn
High LOW
Low HIGH
Open CLOSES

10. Transitional Circulation-PPHN
PA pressure
Pulm blood flow
Oxygen tension
PDA
Fetus PPHN
High
Low
Open

11. Transitional Circulation-PPHN
PA pressure
Pulm blood flow
Oxygen tension
PDA
Fetus PPHN
High HIGH
Low LOW
Open OPEN

12. Persistent Fetal Circulation
And when this process doesn’t go well, that’s when you have persistent pulmonary hypertension. And as you know then, pulmonary arterial pressure does not fall appropriately. Pulmonary blood flow stays low, and oxygen tension stays low. The right ventricle, then, must protect itself by maintaining these fetal shunts across the foramen ovale and the ductus arteriosus. When I was in training, we used to call this persistent fetal circulation. And the more I learn about this condition, the more I realize that’s a very appropriate name for the condition, because the right ventricle maintains those fetal shunts.

13. Normal Heart

14. Pulmonary Hypertension
Increased pre-ductal saturations (with right  left shunt thru PFO and PDA, saturations will be identical) PA Ao

15. Pulmonary Hypertension
Preductal Sp02
HIGH
Postductal Sp02
LOW PA Ao

16. Pathophysiology of neonatal pulmonary hypertension
Parenchymal lung disease
Primary disease process contributes to pulmonary hypertension, maladaptation of the lung to a disease process
Meconium aspiration syndrome
Lung hypoplasia
Smaller surface area for gas exchange
Associated vascular abnormalities
Congenital diaphragmatic hernia

17. Pathophysiology of neonatal pulmonary hypertension
Maldevelopment of the lung
Abnormal pulmonary vasculature and anatomy
Alveolar capillary dysplasia
Remodeling of the pulmonary vasculature
Premature closure of PDA
Obstruction to pulmonary venous return
Secondary changes to pulmonary vasculature
TAPVR

18. Histologic Changes in PPHN
the infant who died of persistent pulmonary hypertension, and you see a very thick layer of vascular smooth muscle, and even some adventitial proliferation there.

19. Abnormal Muscularization in PPHN
In normal infants less than one week of age, no muscular arteries are found past the bronchioles.
All patients with PPHN had “ extension” of muscle into the small intra-acinar arteries.

20. Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of vascular tone
Normal post natal transition: Increased expression of endothelial nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC), results in increased NO production.
Prostacyclin (PGI2) pathway: upregulation of COX-1 in late gestation, increases PGI2, which increases cAMP levels
Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Copyright ©2007 American Academy of Pediatrics

21. Regulation of the Relaxation of Vascular Smooth Muscle by Nitric Oxide
Figure 1. Regulation of the Relaxation of Vascular Smooth Muscle by Nitric Oxide.
Nitric oxide activates soluble guanylyl cyclase, leading to the activation of cyclic guanosine 3' 5'-monophosphate (cGMP)-dependent protein kinase (cGKI). In turn, cGKI decreases the sensitivity of myosin to calcium-induced contraction and lowers the intracellular calcium concentration by activating calcium-sensitive potassium channels and inhibiting the release of calcium from the sarcoplasmic reticulum. cGMP is degraded by phosphodiesterase type 5, which is inhibited by sildenafil and zaprinast. GTP denotes guanosine triphosphate.
Griffiths M and Evans T. N Engl J Med 2005;353:

23. Disorders associated with pulmonary hypertension
Meconium aspiration syndrome
Persistent pulmonary hypertension of the newborn
Absent or mild parenchymal disease
Trisomy 21, infants of diabetic mother
Bacterial pneumonia - group B strep
Viral pneumonitis - enteroviruses

24. Disorders associated with pulmonary hypertension
Alveolar capillary dysplasia
Pulmonary venous obstruction
Total anomalous pulmonary venous return
Premature closure of fetal ductus arteriosus
Maternal prostaglandin synthesis inhibitors: ibuprofen, indomethacin, naproxen
Hyperviscosity syndrome

25. Pulmonary hypoplasia: etiologies
Congenital diaphragmatic hernia
Cystic adenomatoid malformation
Prolonged premature rupture of membranes
Renal dysplasia and fetal compression (Potter’s syndrome)
Fetal hydrops

26. Maternal (SSRI) and neonatal pulmonary artery hypertension
Excess of pulmonary hypertension cases among mothers on SSRI (selective serotonin reuptake inhibitors)
Serotonin: pulmonary vasoconstrictor
Pulmonary smooth muscle proliferation
Decrease in NO production
N Engl J Med 2006;354:579-87

27. Late causes of pulmonary hypertension
Post-op cardiac patients
L to R shunt lesions (reactive post-op PA hypertension)
TAPVR (PA hypertension may persist post-op)
Bronchopulmonary dysplasia
Tends to occur with the most severe BPD
May lead to right heart failure
Tends to improve as the BPD improves
Chronic hypercarbia
Superimposed infections
Bordatella pertussis pneumonia

28. Diagnosis of pulmonary hypertension
Clinical
Hypoxemia despite respiratory support
Pre/post ductal saturation difference
May be associated with poor cardiac output
Echocardiogram:
Elevated PA pressures
R to L shunting at PFO and/or PDA
Tricuspid regurgitation
Septal flattening
RV +/- LV dysfunction

29. Initial management of the newborn with pulmonary hypertension
Correct hypovolemia and support BP
Critical role of cardiac output and systemic BP
Correct metabolic acidosis
Metabolic acidosis contributes to pulmonary vasoconstriction
Correct any electrolyte imbalances, hypocalcemia, or hypoglycemia

30. Initial management of the newborn with pulmonary hypertension
Correct anemia
Improve oxygen carrying capacity
Correct polycythemia, if present
Intubation and ventilation
Adequate lung volume
Role for high frequency ventilation
Oxygen to reverse hypoxia
Avoid prolonged hyperoxia

31. Disease Components
Airway
Alveolar
Pulmonary Vascular
Myocardial

32. Treatment of Pulmonary Hypertension: Rationale for Old Approach
Hypoxia causes pulmonary vasoconstriction
Alkalosis/hypocarbia prevent pulmonary vasoconstriction
Therefore:
Keep PO2 high (> 100)
Keep pH high (> 7.45)
Keep PCO2 low (20s)

33. Risks of Hyperventilation
Air leak
Alveolar damage, capillary leak
Decreased cardiac output
Decreased cerebral blood flow

34. Effects of Alkalosis
alkylosis will have important effects on the hemoglobin saturation curve. alkylosis will force this curve to the left, which may increase your saturation, but will make it more difficult for hemoglobin to offload oxygen at the tissue level. So again, this is an important factor to remember if you’re inducing an alkylosis.

35. Alkalosis: Sustained vs. Acute Effects
Newborn piglets with hypoxia-induced pulmonary hypertension
Acute (20 min) resp alkalosis (25 torr) decreased hypoxia-induced increase in PVR
Sustained (70 min) respiratory alkalosis did not attenuate subsequent hypoxia-induced pulmonary hypertension
After stopping sustained (70 min) resp alkalosis, there was an increased PVR response to hypoxia
Gordon, Pediatr Research 46:735, 1999

36. CV Effects of Hypocarbia
Normal 5-10 day old dogs
2 hrs of hypo-CO2 (22+2) vs nl-CO2
40% decrease in cerebral blood flow
25% decrease in myocardial blood flow
Variable decrease in SVR and BP
Trend to decreased cardiac output, esp in 2nd hour
Cartwright, Pediatr Research 18:685, 1984

37. Hypocapnea and PVL Review of 799 babies born < 28 wks
Factors predisposing to periventricular leukomalacia
Hypocapnea in first day was a major risk factor
Odds Ratio 1.7
Highest in babies without other predisposing factors
Dammann, Pediatr Res 49:388, 2001

38. Lung Volume and Vascular Resistance
Pulmonary Vascular Resistance
Lung Volume

39. Effects of over-distention of the lungs
Alveolar and airway damage
Increased PVR
Increased shunt, decreased PaO2
May be interpreted as need for more pressure
Decreased pulmonary venous return to heart
Decreased cardiac output
Capillary stretch injury
Capillary leak, inflammation

40. Ventilator Strategy Summary
Optimize lung volume
avoid atelectasis
avoid overdistension
Maintain “normal” blood gases
Tolerate mildly low SpO2, high PCO2

41. Past therapies which were inadequate or worked only transiently
Intentional hyperoxia
Intentional hyperventilation
Metabolic alkalosis
Sodium bicarbonate infusion

42. Surfactant and hypoxemic pulmonary failure
Meconium aspiration syndrome
Congenital diaphragmatic hernia
Randomized study in hypoxemic lung failure in term and near term infants
Lotze A et al. J Pediatr 1998;132:40-47
44 centers, 328 infants randomized to placebo or up to 4 doses of surfactant (4 additional if placed on ECMO)
No difference in mortality between groups
Primary outcome, need for ECMO

43. Reduction in need for ECMO with surfactant

44. Reduction in need for ECMO with surfactant

45. Need for selective pulmonary vasodilator…..
…and along came inhaled nitric oxide

46. Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of vascular tone
Normal post natal transition: Increased expression of endothelial nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC), results in increased NO production.
Prostacyclin (PGI2) pathway: upregulation of COX-1 in late gestation, increases PGI2, which increases cAMP levels
Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Copyright ©2007 American Academy of Pediatrics

47. Biochemical Fates of Inhaled Nitric Oxide at the Alveolar-Capillary Membrane
Figure 2. Biochemical Fates of Inhaled Nitric Oxide at the Alveolar-Capillary Membrane.
Small amounts of nitrogen dioxide (NO2) may be formed if inhaled nitric oxide mixes with high concentrations of oxygen (O2) in the air space. Depending on the milieu of the lung parenchyma, nitric oxide may react with reactive oxygen species (derived from activated leukocytes or ischemia-reperfusion injury) to form reactive nitrogen species such as peroxynitrite. In the vascular space, dissolved nitric oxide is scavenged by oxyhemoglobin (forming methemoglobin and nitrate) and to a lesser extent, plasma proteins (e.g., forming nitrosothiols, which are stable intravascular sources of nitric oxide activity).
Griffiths M and Evans T. N Engl J Med 2005;353: 47

48. Mechanism of Action and Inaction of Inhaled Nitric Oxide
Figure 3. Mechanism of Action and Inaction of Inhaled Nitric Oxide.
Panel A shows normal ventilation-perfusion. Hypoxic pulmonary vasoconstriction (Panel B) minimizes ventilation-perfusion mismatching in the presence of abnormal ventilation. Inhaled vasodilators with a short half-life improve oxygenation by increasing blood flow to ventilated lung units (Panel C). If a vasodilator is administered intravenously (Panel D) or if diseases are associated with dysregulated pulmonary vascular tone, such as sepsis and acute lung injury (Panel E), hypoxic pulmonary vasoconstriction is counteracted, leading to worsening oxygenation. Long-term administration of inhaled nitric oxide, with the accumulation of nitric oxide or leakage between lung units associated with collateral ventilation, as may occur in chronic obstructive pulmonary disease (Panel F), may negate the beneficial effects of inhaled nitric oxide on oxygenation.
Griffiths M and Evans T. N Engl J Med 2005;353: 48

49. Nitric oxide, term and near term infants with hypoxemic respiratory failure
Cochrane review
12 randomized controlled studies
Reduced incidence of the combined endpoint of death or need for ECMO. Reduction primarily from reduction in need for ECMO; mortality is not reduced
OI improved by (weighted) mean of 15.1 within 30 to 60 minutes after start of iNO
PaO2 increased by mean of 53 mmHg.
Response to iNO does not depend on clear echocardiographic evidence pulmonary hypertension
Diaphragmatic hernia group had no benefit from iNo

50. Nitric oxide for treatment of pulmonary hypertension
Starting dose 20 ppm
Decrease to 5 ppm after positive response
Slower wean, decreasing by 1-2 ppm
Discontinue when stable on 1-2 ppm
Monitor methemoglobin
Monitor concentration of NO and NO2
iNO suppresses endogenous NO synthesis

51. Indications for iNO
Term or near term infants with hypoxic respiratory failure
Documented pulmonary hypertension by echo
OI = Paw x FIO2 x 100/ PaO2
Oxygen index (OI) >25
Early initiation of iNO with OI improves oxygenation, but does not reduce death or need for ECMO

52. Possible mechanisms for iNO non-responsiveness
iNO delivery
Poor lung inflation (decreased iNO delivery)
Low dose of iNO (limited vasodilator response)
High dose of iNO (increases V/Q mismatching)
Abnormal pulmonary vasculature structure/function
Pulmonary hypoplasia, alveolar capillary dysplasia, severe muscular hypertrophy of pulmonary vessels

53. Contraindications of iNO
Congenital heart disease dependent on right to shunt
Hypoplastic left heart syndrome
Critical aortic stenosis
Interrupted aortic arch
TAPVR (may increase pulmonary edema)
Significant methemoglobinemia

54. Severe pulmonary hypertension with hypoxemia despite iNO: what next?
Other supportive measures optimal?
Volume status
Systemic blood pressure
Lung volume appropriate?
Is the patient an ECMO candidate?
Is there a role for other pulmonary vasodilators?

57. Role of ECMO in pulmonary hypertension
Oxygenation index (OI) >=40
OI = Paw x %O2/PaO2
Gestational age >=35 weeks
Weight >= 2 kg
Ventilation < 10 (14) days
Absence of significant CNS bleed
Reversible lung disease

58. Gentle Ventilation
Surfactant
HFV
iNO

59. ELSO database: Neonatal Respiratory Cases

60. Cumulative Survival in Neonatal Respiratory Support

61. Neonatal Diagnoses and Survival

62. Systemic vs. inhaled pulmonary vasodilators

63. Possible adjuncts and/or alternatives for pulmonary hypertension
Sildenafil: phosphodiesterase inhibitor (PDE5)
Dipyridamole: PDE inhibitor – anecdotal reports of augmentation of the effect of NO
Prostacyclin (PGI2): increases cAMP
PGE1: pulmonary and systemic dilator, PDA
Nitroprusside
Adenosine
Arginine
Milrinone: PDE3 inhibitor (cAMP), systemic effects

64. Sildenafil Phosphodiesterase (converts cGMP to GMP) inhibitor type 5
Causes pulmonary vasodilation
Neonatal animal models, limited human data
iNO with sildenafil cause systemic vasodilation and worse oxygenation in animal model
Human adults with primary and secondary pulmonary hypertension

65. Sildenafil pilot randomized trial
Inclusion criteria: oxygenation index (OI) >= 40
7 treatment and 6 control
Starting dose 1 mg/kg q 6 hr, increase to 2 mg/kg if no response
Results: Sildenafil group showed a significant and sustained drop in OI and increase in SPO2 from baseline and as compared to placebo.
6/7 treatment vs. 1/7 placebo patients survived (p<0.02)
Baquero H, Sola A, et al. Pediatrics 2006;117:

66. FIGURE 1 Oral sildenafil produced significant changes in OI
Baquero, H. et al. Pediatrics 2006;117:
Copyright ©2006 American Academy of Pediatrics

67. FIGURE 2 SpO2 improved after oral sildenafil
Baquero, H. et al. Pediatrics 2006;117:
Copyright ©2006 American Academy of Pediatrics

68. Cautions regarding sildenafil
Large randomized study needed to prove safety and efficacy
Unlike iNO, sildenafil’s effects are not localized:
Uncertain effects in the developing animal or human, especially CNS
Uncertain risk re: ROP in prematures
Potential to slow gastric emptying
Risk of systemic hypotension

69. FDA warning on sildenafil (8/30/12)
FDA notified healthcare professionals…Revatio (sildenafil) should not be prescribed to children (ages 1 through 17) for pulmonary arterial hypertension… based on a recent long-term clinical pediatric trial showing that: (1) children taking a high dose of Revatio had a higher risk of death than children taking a low dose and (2) the low doses of Revatio are not effective in improving exercise ability.

70. Implications of FDA warning on pediatric use of sildenafil
Sildenafil should be used in neonates/infants only with fully informed consent (documented in writing) and/or as part of a study
Patients on long term sildenafil should be closely monitored by a cardiologist
Need for short/long term efficacy and safety studies of sildenafil

71. Prostacyclin (PGI2)
Stimulates adenylyl cyclase in smooth muscle, increases cAMP, smooth muscle relaxation
T½ 2-3 minutes, IV infusion vs. aerosol
Pediatric and adult patients with pulmonary hypertension by IV continuous infusion, home therapy programs for chronic use
Neonates: case reports only
IV and aerosolized, alone and in combination with iNO
Caution: can cause systemic hypotension

72. Iloprost Stable synthetic analog of prostacyclin (PGI2)
Increases cAMP
Aerosolized, IV
Case reports and small series
Limited experience in neonates
Aerosolized iloprost improves oxygenation in pulmonary hypertension in prematures, term, CHD
May have a role as adjunct therapy or to wean off of iNO

73. Milrinone Increases cAMP, causing pulmonary and systemic vasodilation
Reports in adults, pediatric and neonatal patients, post op cardiac
May be useful as adjunct therapy or to help wean off iNO

74. References: milrinone
Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. Journal of critical care 2006; 21:
Neonatal persistent pulmonary hypertension treated with milrinone: Four case reports. Biology of the neonate 2006;89:1-5

75. Arginine: precursor to endogenous nitric oxide
Conversion of arginine to citrulline results in release of NO
Little or no neonatal data for its use in pulmonary hypertension
Probably not a limiting factor in NO production in vivo

76. Enzymes and Intermediates in the Urea Cycle and Nitric Oxide Pathway
Figure 1. Enzymes and Intermediates in the Urea Cycle and Nitric Oxide Pathway.
The mitochondrial enzymes are present only in the urea cycle in the liver. The cytoplasmic enzymes argininosuccinate synthase (AS) and argininosuccinate lyase (AL) are also present in endothelial cells, where they recycle citrulline into arginine for high-output nitric oxide synthesis.13 CPS denotes carbamoyl-phosphate synthetase, NOS nitric oxide synthase, and OTC ornithine transcarbamylase.
Pearson D et al. N Engl J Med 2001;344:

77. Old discarded therapies
Acetylcholine:
used to test pulmonary vascular reactivity
Tolazoline: (no longer available)
Alpha blocker, histamine effects
Associated with significant side effects
Fentanyl
Block hypoxia induced pulmonary vasoconstriction

79. Potential future therapies of pulmonary hypertension
Modulation of endothelin-1 (ET-1) receptors
ETA: ET-1 binding causes vasoconstriction
ETB: activation causes ET-1 clearance and induces production of NO and prostacyclin
Combined ETA and ETB receptor antagonists:
Bosentan: human adult studies showed benefit
Tezosentan: decreases pulmonary artery pressure in pig meconium aspiration model
O-nitrosoethanol (ENO):
increases endogenous S-nitrosothiols

80. Potential future therapies of pulmonary hypertension
Superoxide dismutase:
scavenger of reactive oxygen species
may augment responsiveness to inhaled nitric oxide
Platelet derived growth factor inhibitor: imatinib
Anecdotal reports in adults with PA HTN
Report of one patient with congenital diaphragmatic hernia
Adult phase III trial in progress
Magnesium sulfate, non-randomized clinical reports

81. Management of the patient with congenital diaphragmatic hernia
Supportive ventilation: HFOV, avoid over-distention and pneumothorax
Timing of surgical repair should be individualized: delayed repair typical
Unclear role for nitric oxide
No reduction in ECMO or mortality with iNO
iNO may play role in stabilization prior to ECMO

82. Management of the patient with HIE and pulmonary hypertension
Common underlying pathophysiology:
Placental insufficiency
In utero hypoxia, ischemia
Therapeutic hypothermia for HIE
May exacerbate pulmonary hypertension
Hypothermia may cause hypotension, dysrhythmias, coagulopathy

83. Underlying etiologies for severe long-term pulmonary hypertension
Lung hypoplasia
Congenital diaphragmatic hernia
Pulmonary vascular anomalies
Alveolar capillary dysplasia
Pulmonary vascular remodeling
Smooth muscle hyperplasia: chronic in utero hypoxia, chronic pulmonary vascular overload due to L to R shunt, multiple pulmonary emboli

84. Diagnostic approaches to severe persistent pulmonary hypertension
Cardiac catheterization
Lung biopsy: open vs. percutaneous
(autopsy)

85. References:
Abman SH. Pulmonary Vascular Disease and Bronchopulmonary Dysplasia: Evaluation and Treatment of Pulmonary Hypertension. NeoReviews 2011;12;e645
Baquero H, Sola A, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117:
Clark RH, et al for the Clinical Inhaled Nitric Oxide Research Group. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000;342:469-74

86. References:
Steinhorn RH, Farrow KN. Pulmonary hypertension in the neonate. NeoReviews 2007;8;e14
The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997;99:
The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336: