Persistent Pulmonary Hypertension of the Newborn Arthur E. D’Harlingue, M.D. Director of Neonatology Children’s Hospital & Research Center Oakland adharlingue@mail.cho.org

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.

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

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

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

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.

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

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

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

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

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

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.

Normal Heart

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

Pulmonary Hypertension Preductal Sp02 HIGH Postductal Sp02 LOW PA Ao

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

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

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.

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.

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

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;353:2683-2695

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

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

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

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

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

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

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

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

Disease Components Airway Alveolar Pulmonary Vascular Myocardial

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)

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

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.

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

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

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

Lung Volume and Vascular Resistance Pulmonary Vascular Resistance Lung Volume

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

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

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

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

Reduction in need for ECMO with surfactant

Reduction in need for ECMO with surfactant

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

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

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;353:2683-2695 47

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;353:2683-2695 48

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

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

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 15-25 improves oxygenation, but does not reduce death or need for ECMO

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

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

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?

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

Gentle Ventilation Surfactant HFV iNO

ELSO database: Neonatal Respiratory Cases

Cumulative Survival in Neonatal Respiratory Support

Neonatal Diagnoses and Survival

Systemic vs. inhaled pulmonary vasodilators

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

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

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;117:1077-1083

FIGURE 1 Oral sildenafil produced significant changes in OI Baquero, H. et al. Pediatrics 2006;117:1077-1083 Copyright ©2006 American Academy of Pediatrics

FIGURE 2 SpO2 improved after oral sildenafil Baquero, H. et al. Pediatrics 2006;117:1077-1083 Copyright ©2006 American Academy of Pediatrics

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

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.

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

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

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

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

References: milrinone Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. Journal of critical care 2006; 21:217-233 Neonatal persistent pulmonary hypertension treated with milrinone: Four case reports. Biology of the neonate 2006;89:1-5

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

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;344:1832-1838

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

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

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

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

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

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

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

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;117:1077-1083 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

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;99:838-845 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;336:597-604