Persistent Pulmonary Hypertension of the Newborn

Persistent Pulmonary Hypertension of the Newborn Nursing Grand Rounds Kendra Smith, MD 4/2/2020 425-785-7353 [email protected] } Site PI for IV Sildenafil and IV/SQ Remodulin study trials; Research funding provided to SCH

} Liquid ventilation study for infants with Congenital Diaphragmatic Hernia on extracorporeal life support (ECLS); Funding to the SCH Foundation from the Ladybug Foundation

} No personal financial support

} I will be talking about Remodulin, Sildenafil and other medications to treat adult pulmonary hypertension that are being used in neonates, as well as liquid ventilation; none are FDA approved for neonates } I am very honored to have been invited to speak for the Nursing Grand Rounds today (Thank you, Hai-Yen!!!)

} I want to acknowledge Drs. Satyan Lakshminrusimha, Steve Abman, and Robin Steinhorn for sharing their slides

} I want to thank the parents who have welcomed me into their lives while taking care of their baby

} I want to thank all of you! Call me after the presentation at 425-785-7353 or send me an e-mail with your question ([email protected])

} Definition of persistent pulmonary hypertension of the newborn (PPHN)

} Normal pulmonary circulation

} Pathophysiological changes in PPHN

} Clinical assessment/ echocardiography

} Effect of therapeutic modalities

} Situations where iNO is contraindicated

} Elevated pulmonary vascular resistance relative to systemic vascular resistance from either vasoconstriction or structural remodeling of the pulmonary vasculature Normal transition Fetal blood flow: 2/3 of IVC flow is 1/3 of IVC flow directed toward the mixes with foramen ovale (FO) by blood from the the eustachian valve SVC and enters and septum primum the RV then the and enters the left Pulmonary atrium artery

Normally at birth: • Air enters the lungs and improves oxygenation of the pulmonary vascular bed • Pulmonary blood flow increases • Pulmonary vascular resistance (PVR) decreases to ½ of systemic resistance • Left Atrial pressure increases and Foramen Ovale closes • Systemic vascular resistance (SVR) increases due to removal of placenta • PDA flow reverses from R->L to L->R • PDA closes in response to increased oxygen tension and with postnatal circulatory pattern

Courtesy of Satyan Lakshminrusimha Fetal Circulation Ratio of blood entering the pulmonary arteries to the ductus arteriosus is determined by the fetal Physiologic pulmonary pulmonary vascular hypertension resistance (PVR) and can vary with fetal Oxygen induced oxygenation status and vasodilation and lung gestation expansion decrease PVR to ~1/2 of SVR

Normal transition: Abnormal transition: Physiologic pulmonary Persistent Pulmonary Hypertension/HRF. hypertension resolved PDA flows R-> L or bidirectional Courtesy of Satyan Lakshminrusimha Diseases and 2 Pathophysiology of Hypoxic Respiratory Idiopathic (“Black lung” PPHN) Failure

Meconium aspiration at PDA syndrome, Respiratory distress syndrome, Pneumonia *** 1 4 Congenital diaphragmatic hernia, RV LV oligohydramnios Ï Alveolar or vascular hypoplasia LA

2 R‰L shunt at PFO MAS, RDS, RA Pneumonia, TTNB, Atelectasis ***

Asphyxia, sepsis, CDH Courtesy of Satyan Lakshminrusimha

30 , Frequency 8, Amplitude 55, FiO2 1.0

© Distributive/cardiogenic shock: NS (70 mL/K), dopa 20, dobut 20, epi 0.25, HC and Decadron ; not coagulopathic © At Seattle Children’s 7.09/49/31/-17; lactate 12 , preductal sat 90, post-ductal sat 80

Our case OI= 100 MAS/PPHN

• VV ECLS for 32 days • Partial liquid ventilation for 5 days MAP FiO • Off ECLS 4 days after treatment with liquid × 2 OI = ×100 • Off ventilation at 40 days of age (HFNC 8 LPM) PaO • IV sildenafil for 30 days 2 • iNO off 2 weeks after coming off ECLS

The PPHN quagmire

*MAS + Pneumonia can release inflammatory mediators that induce PPHN can occur due vasoconstriction to an abnormal pulmonary vascular bed despite absence 1 of alveolar hypoxia, hypercapnia and lung inflammation 4 2 7 9

3* 8 6

© Presence of meconium © Acidosis © Asphyxia at delivery © Maternal risk factors for infection • Prolonged rupture of membranes • Maternal fever • Positive group B streptococcus status © Postmaturity © Maternal aspirin or SSRI (selective serotonin reuptake inhibitors)

Persistent Pulmonary Hypertension

• Impaired pulmonary vascular adaptation during the early neonatal period • Affects ~10% of all neonates with respiratory failure • Mortality is 7-8% • 25% incidence of long-term neurodevelopmental impairment • Some genetic factors identified • Reversibility and impact on adult pulmonary disease poorly understood

Courtesy of Dr. Robin Steinhorn } Usually presents within first 24 hours of life with severe cyanosis, respiratory distress

} Labile hypoxemia: severe hypoxemia with wide swings in arterial PO2 without changes in vent settings (less effect on CO2 retention) } Hypoxemia out of proportion to the degree of parenchymal disease severity

} Single, loud S2, systolic murmur of tricuspid regurgitation

} Difference in arterial PO2 ≥ 10 to 20 mm Hg or oxygen sats ≥ 5 to 10%

Meconium aspiration – histology (decreased ventilation to perfusion)

Meconium

O2=40 CO2=45

CO2 45

Small rounded balls of meconium are in the alveoli O2=150mmHg CO 2=0

O2=100 CO 2=40 O2=40 O2=150 CO 2=45 CO =0 O2=40 2 CO 2=45 CO 2 =45 Normal V/Q Decreasing V/Q Increasing V/Q

Diseased Vasoconstriction of alveolus pulmonary vasculature bed

V/Q < 1 V/Q > 1 Under ventilated and Normally ventilated and normally perfused OR under-perfused OR normally ventilated but verventilated and over perfused normally perfused } When pulmonary and systemic arterial pressures are similar, small alterations in the ratio of the two can produce large changes in extrapulmonary shunting: ◦ When SVR > PVR, Normal blood flow Blood flow in PPHN there is no R Ï L shunt ◦ When PVR is close to or exceeds SVR, variable R Ï L shunting at the PFO and PDA results in labile hypoxemia

Clinical features • If a ductus is present and there is no major atrial/ventricular shunting,

– preductal O2 sat > postductal O2 sat (=differential cyanosis)

10-20 point difference between pre-vs. postductal arterial PO X 2 Or 5-10% difference X between pre- vs. postductal sats KS1 Clinical features • Absence of a difference in oxygen tension does not exclude PPHN because shunting at the atrial level produces no ductal gradient and is probably the most common site of shunting – preductal and postductal sats will be equal ≠ Slide 32

KS1 ?? Kendra Smith, 2/1/2020

} Hyperoxia test: ◦ Obtaining an arterial gas at baseline in room air and after 15 minutes of exposure to 100% oxygen and/or hyperoxia- hyperventilation (hyperoxia and alkalosis to induce pulmonary vasodilation and

improve PaO2) is no longer practiced due to known adverse effects of hyperoxia and alkalosis.

Lakshminrusimha S, Kumar V. Pediatric Critical Care Fifth Edition. Ed Fuhrman and Zimmerman. Chapter 56, Diseases of Pulmonary Circulation. Elsevier, 2017 } Lability usually indicates PPHN

} History of meconium at birth or suspected chorioamnionitis in the mother may help

} B-naturiuretic peptide (BNP) (used for Sildenafil and Remodulin studies); used monthly to follow BPD patients

} Some patients may need to be transported on both iNO and PGE Ductal Atrial Diagnosis Management shunt shunt

RÏLRÏL PPHN Oxygenation/iNO, lung recruitment

LÏRLÏR Parenchymal lung disease Lung recruitment, and V/Q mismatch specific therapy, iNO may be beneficial RÏLLÏR PPHN with LV dysfunction Milrinone with some pulmonary venous hypertension (common in CDH, asphyxia, sepsis) LÏRRÏL Tricuspid atresia/stenosis PGE1 and surgery or pulmonic atresia/stenosis RÏL RÏL TAPVR (total anomalous Surgery (Large Small LA/ no pulmonary venous return) tricuspid PA) regurg Differential diagnosis of hypoxemia and treatment • RÏL shunting at the PDA and PFO: due to PPHN • optimize lung inflation, treat with oxygen and iNO Differential diagnosis of hypoxemia and treatment • LÏR shunting at the PDA and PFO with marked hypoxemia suggests parenchymal lung disease with predominantly intrapulmonary shunting (V/Q mismatch) • optimize lung inflation, iNO may help Differential diagnosis of hypoxemia and treatment • RÏL shunting at the PDA with L ÏR shunting at atrial level suggests PPHN with LV dysfunction with some pulmonary venous hypertension (common in CDH, asphyxia and sepsis) • Treat with milrinone

X Differential diagnosis of hypoxemia and treatment • LÏR shunting at the PDA with RÏL shunting at atrial level • Diagnosis Tricuspid atresia/stenosis or pulmonic atresia/stenosis-> PGE and surgery Differential diagnosis of hypoxemia and treatment • RÏL shunting at the PDA with a large pulmonary artery and R ÏL shunting at atrial level with a small left atrium and no tricuspid regurgitation • Diagnosis TAPVR-> to surgery

1 2

PPHN may result in • Eventual cardiac failure

Causes of hypotension

7 6

Premature babies develop PPHN Kumar et al, J Perinatal 2007

Single center retrospective study

2% incidence of early pulmonary hypertension for infants <33 weeks (24/1202)

Aikio et al, J Pediatr 2012

2.2% incidence of early PH for infants <32 weeks (17/765)

Both studies showed risk factors of PPROM, oligohydramnios Epidemiology of PPHN APPROACH: • Case-control epidemiologic study of antenatal and perinatal risk factors for PPHN • Enrolled and interviewed 377 mothers with PPHN babies and 836 matched controls. RESULTS: • Pre-pregnancy conditions: maternal diabetes, asthma, high BMI • SSRI use after 20th week (6-fold increase)* (disputed )** • NSAID use may be associated with in utero PDA closure*** • Block prostaglandin which maintain ductal patency in utero and are important mediators of pulmonary vasodilation in response to ventilation at birth**** * Chambers CD, et al. N Engl J Med . • C-section delivery (7-fold increase) 2006;354: 579-587 ** Wilson KL, et al. Am J Perinatol . • Near term (34-37 weeks) (2-fold increase) 2011;28:19-24 *** Talati AJ, et al. Am J • Post-term (> 41 weeks) Perinatol .2000;17(2):69-71 **** Alano MA, et al. Pediatrics. • Large for gestational age (BW > 90th %ile) 2001;107(3):519-23 Courtesy of Satyan Lakshminrusimha

Normal Fetus Ratio of the blood entering the pulmonary arteries to the ductus is determined by the fetal PVR and can vary with fetal oxygenation status and gestation. Maintaining a high PVR in utero is important because gas exchange is done by the placenta.

Pulm blood flow – Placenta 25% in human fetus

1. Konduri GG, et al. Am J 1. Kiserud et al. Physiology of the Physiol . 1997;272:H2377- fetal circulation, Seminars in H2384 Fetal & Neonatal Medicine. 2. Lakshminrusimha S. Clin 2005 Perinatol . 2012;39:655-683. 2. Gao Y, Raj JU. Regulation of 3. Diseases of Pulmonary Courtesy of Satyan pulmonary circulation in fetus Circulation, Page 707 Lakshminrusimha and newborn, Physiol Rev. 2010 Fetal pulmonary circulation: first stage of transition (fetus is in state of physiologic pulmonary hypertension)

Pulmonary

venous PO 2 Pulmonary 17-19 mmHg Characterized by high pressure and arterial PO 2 low flow because of both passive and 17-19 mmHg active elevation of PVR

Fluid in • Passive resistance due to alveoli compression of pulmonary capillaries by fetal lung fluid

• Active vasomotor tone resulting Constricted blood from various mediators and vessels (high PVR hypoxic stimuli

• PVR > SVR Low alveolar oxygen ‹ R-L flow at PFO and PDA (17 mmHg)

1. Kiserud et al Physiology of the fetal circulation, Seminars in Fetal & Neonatal Med 2005 2. Gao Y, Raj JU, Regulation of pulmonary circulation in fetus and newborn, Physiol Rev 2010 Courtesy of Satyan Lakshminrusimha Histology Endothelin pathway in utero promotes vasoconstriction

ET-1 (Synthesized by vascular Pulmonary endothelial cells) vasodilators •Potent vasoconstrictor mediated by Ca •Vasodilator mediated by NO

•Two SMC receptor subtypes:

•ET A receptor plays a role in vasoconstriction in utero

increases •ET B receptor plays a role in vasodilation; may be less active in fetal life. •Mediated by endothelium- derived nitric oxide •May decrease PVR at birth NO pathway in utero promotes vasodilation

• ET B on the endothelial cell stimulates NO release and vasodilation. • eNOS produces NO, which diffuses from the endothelium to the SMC and • stimulates sGC to produce cGMP which Soluble guanylate cyclase is broken down by PDE5 to increases • GMP Stages of lung development

Pseudo- Terminal sac glandular 6-16 weeks Canalicular 16-26 weeks

Terminal sac Respiratory 26-36 weeks bronchiole

Alveolar 36 weeks-3 years Terminal bronchiole Alveoli

Increase in cross-sectional area of pulmonary vascular bed. Pulmonary vessels become more sensitive to vasoconstrictive mediators, such as endothelin and relative hypoxemia, resulting in active pulmonary vasoconstriction and an increase in the PVR Variations in conformation of the lung during development affects PVR

Alveolar, after birth, and over the first few weeks, PVR decreases Canalicular Saccular Alveolar, before birth

High PVR is caused The broad Despite rapid After birth lung by low density of intersaccular increase in the liquid is absorbed the vasculature septae contain the number of small and an air-liquid double capillary pulmonary interphase is network and, with arteries, high PVR established with increasing vascular is maintained by juxtaposition of density, the PVR active capillaries and decreases vasoconstriction alveolar epithelium to promote effective gas exchange. Lakshminrusimha, S. Clin Perinatol 2012; 39:655 -683 PPHN: Failure of postnatal adaptation-usually associated with perinatal hypoxia

Pulmonary vascular resistance PPHN (hypoxic pulmonary vasocontriction)

• Stretch (lung expansion)

• Increased O 2 (arterial + alveolar) • Ventilation • Increase in pH • Blood flow through the lung • Vasodilators Normal

Birth Time Fetus Neonate Takes weeks to months for the PAP to fall to adult levels In utero vasoconstrictors Increased PVR: Decreased Vasoconstriction PVR: Vasodilation

Cause high vascular tone in the fetal lung: • Low oxygen tension • Compression of pulmonary capillaries by fetal lung liquid Contribute to vascular tone: • Arachidonic acid metabolites: 1) Cyclooxygenase pathway • Prostaglandin F 2 alpha

• Thrmoboxane A 2 • 2) 5-lipoxygenase pathway • Leukotrienes • Endothelins (ET-1, ET-2, ET-3): response is tone-dependent (i.e. ET-1 and ET-2 dilate the fetal pulmonary vasculature and constrict the bed when the tone is reduced by ventilation What happens at birth? Second stage Dilated blood vessels 4 (reduced PVR) 1 Entry of air into the alveoli 2 3 Clearance of Increased lung fluid alveolar oxygen (100-150 mmHg)

Drop in PVR is accompanied by production of prostacyclin Within 5 minutes after birth, oxygen- (PGI ) and NO synthesized by induced vasodilation and lung 2 endothelial cells causing expansion decrease PVR to ~ half of relaxation of the smooth SVR muscle cells Pulmonary vascular changes: 3rd stage In 12-24 hours Rapid structural remodeling of the entire pulmonary bed from the main pulmonary artery to the capillaries further decreases PVR

Changes in shape and geometric orientation of endothelial and smooth muscle cells cause luminal enlargement

Courtesy of Satyan Lakshminrusimha Changes in small PA during transition

Fetal PA-near Neonatal PA-24 term gestation hrs after birth

Courtesy of Satyan Lakshminrusimha Birth-Related Stimuli:

Role of O2 along with ventilation and shear stress

L-Arginine Endothelial Nitric Cell Oxide L-Citrulline NO Synthase

O2 Guanylate Cyclase

Smooth GTP Muscle cGMP 5’GMP Cell

PDE5 VASODILATION Courtesy of Dr. Robin Steinhorn Because pulmonary vasodilation at birth is a vital step in establishing postnatal life, there are sufficient redundant vasodilators to compensate for failure or inadequacy of any single pathway. Important mediator to Dilation of fetal NO pathway dilates SMC pulmonary decrease PVR at birth circulation is caused by an Fetal pulmonary vasodilators increase in stimulate endothelial NO oxygen tension production mediated by eNOS BNP: B-type natriuretic peptides dilate fetal pulmonary vasculature Ì cGMP

activates

Diminished eNOS 2) Soluble guanylate expression may ** Cyclic guanosine cyclase contribute to both activated monophosphate cGMP induces relaxation (2 nd messanger) abnormal of SMC through activation vasoreactivity + of cGMP-dependent excessive protein kinase that muscularinization produces a lowering of 3) activates cytosolic ionic Ca, in part 4)Lowered via through activation of K activation of 5) Relaxation of channels K channel

Premies have low arterial sGC, a likely reason for their poor response to iNO Important in maintaining Prostaglandin pathway dilates SMC ductal patency Potent pulmonary vasodilator in fetus

PPHN seen in cyclooxygenase enzyme Arachidonic mothers taking Prostacyclin acid aspirin or receptor metabolite,

NSAIDS that stimulates prostacyclin inhibit COX (PGI2), activity and relaxes cause prenatal Broken down by smooth constriction of SR muscle by the ductus or by producing

decreasing PGI 2 cAMP synthesis at (PGI2 analogs birth are (association Remodulin, called into Flolan, question) Iloprost)

Transition Increased PVR: Decreased Vasoconstriction PVR: Vasodilation

• Hypoxia/low pH/Pulmonary problems

• Thromboxane A 2 (via COX; hypoxia induced) • Acetylcholine • Prostaglandin F 2α (via COX pathway) Stim • Bradykinin • Seratonin production • Histamine of NO • Endothelin-1 (hypoxia induced) • Lung inflation** • NO • Leukotrienes C 4 and D 4 • Structural changes • PGI , PGE , PGE ,PGD • HETEs (attenuate pulm myogenic response) 2 1 2 2 in endothelial cells • ATP • Rho/Rho kinase • Oxygen • Adenosine natriuretic • Low production of vasodilators (PGI + NO) 2 • Changes in peptides (ANP, BNP, • Overinflation/Underinflation interstitial CNP) • Excessive muscularization fluid and pressure • Arachidonic acid • Altered mechanical properties • Shear stress metabolites of smooth muscle • Atrial natriuretic • Fetal vasculature opposing vasodilation factor • Hypothermia (pulmonary venous • EETs constriction) • Magnesium • Polycythemia

Critical Windows of Vascular Development

Failed Transition

Transitional PA Pressure PA

Zone from Irreversibility Normal

Transitional Zone to Normal

Courtesy of Dr. Robin Steinhorn Age Modified from Aschner JL et, 2011 Excessive muscularization

• Thickening of media and adventitia • Increased matrix protein in pulmonary vessel walls • Does not necessarily imply hypercontractile tendencies, rather impaired dilation

Courtesy of Dr. Steve Abman. PPHN. NeoPrep 2014 Bancalari E, Keszler M, Davis P. The Newborn Lung. 3 rd Edition. 2019. Chapter 3 Normal versus abnormally muscularized arteries

• Fully • Increase in muscularized vascular thick-walled smooth preacinar muscle arteries extend ------resulting from to level of peripheral terminal ------extension into bronchioles vessels not normally • Intra-acinar nonmuscular containing arteries, muscle layers accompanying respiratory • Can occur bronchioles, prenatally or are partially postnatally muscular or nonmuscular * In utero ductal ligation 1-2 weeks before delivery can result in distal extension of the vascular smooth muscle in lambs Wild LM, Nickerson PA, Morin FC. Pediatr Res 1989;25:251 Excessive muscularization • Impaired dilation 1) Changes in relaxant properties of pulmonary vascular smooth muscle cell • Decreased pulmonary vascular content of myosin chain phosphatase (key enzyme responsible for muscle relaxation in pulmonary vasculature) 2) Dysfunctional endothelial cell function • Failure to produce dilators, overproduction of constrictors, failure to metabolize and remove constrictors

• Belik J, Majumdar R, et al. Pediatr Res 1998: 43:57 • McQuestron JA, Kinsella JP, et al. Am J Physiol 1995; 268:H288

} Transient tachypnea of the newborn (TTN) } Aspiration syndromes - meconium or blood } Congenital Diaphragmatic Hernia (CDH) } HYaline membrane disease (RDS) } PNEumonia/Sepsis } Air leaks/ Asphyxia Pneumothorax

Courtesy of Satyan Lakshminrusimha

1) PPHN Mechanism Parenchymal lung diseases: cause acute alveolar hypoxia leading to acute pulmonary vasoconstriction

MAS GBS pneumonia RDS

PPHN can result from alveolar hypoxia, inflammatory mediators, or abnormal pulmonary vascular muscularization 2) PPHN mechanism Remodeled vasculature: cause maladaptation of pulmonary circulation

CDH Chronic Intrauterine intrauterine closure of the hypoxia PDA 3) PPHN mechanisms Pulmonary hypoplasia: cause maladaptation of pulmonary circulation

CDH CPAM Hypoplasia congenital pulmonary (oligohydramnios adenomatoid due to renal malformation disease, chronic (intrathoracic space- amniotic fluid leak) occupying lesion) Congenital diaphragmatic hernia Bowel, part of liver, stomach, and spleen through diaphragmatic defect

Keller RL. 2007. Bancalari E, Keszler M, Davis P. The Newborn Lung. 3 rd Edition. 2019. Chapter 3 Angiograms in CDH show pruning of vascular tree

contralateral ipsilateral

Right lung of an Right and left lungs of infant with infant without CDH who died at 79 days of age. CDH who died There is significant “pruning” of the from other causes distal pulmonary vascular tree. while on ECLS Keller RL. 2007. 4) PPHN mechanisms: Malformations of alveolar and vascular development

Alveolar Acinar capillary dysplasia dysplasia Acinar dysplasia: Lung arrest at pseudoglandular stage Secondary to hyperviscosity often due to polycythemia BPD Preterms with fetal growth restriction and born after prolonged rupture of membranes

Treatment modalities Lung recruitment

• Positive airway pressure strategies and O 2. If need • Lung volume PIP 28 or V T > 6 mL/kg ÏHigh frequency Surfactant* • pH 7.3-7.4 (>7.25), PaCO 2 • pH, paO2, paCO2 40-60, PaO 2 55-80 (sats low to mid 90’s) • iNO 20 ppm (5-20) PULMONARY • Hydrocortisone *** VASODILATORS, Anti- • DOPA, Epi, Vasopressin inflammatory agent, • Intravenous vasodilators Inotropes Patients are sensitive to • Sedation agitation/pain * Muscle relaxation Ï increased mortality * Hyperoxia Ï increases oxygen free radicals and reduces response to iNO *PPHN can occur due to an abnormal pulmonary vascular bed despite absence of alveolar hypoxia, Asphyxia and PPHN hypercapnia and lung inflammation

Hyperventilation can cause impaired cerebral perfusion and neurosensory deafness

*MAS + Pneumonia can release inflammatory mediators that induce vasoconstriction } PaCO2 reported at baby’s temp (not corrected to 37 degrees-alpha-stat method)

} Decreasing temp increases the solubility of CO2 in the blood and decreases PaCO2

} May have implications for PPHN management with potential of overventilation or underventilation Courtesy of Satyan Lakshminrusimha PVR is PVR is increased increased with with atelectasis: l oss overexpansion: of support for compression of extra-alveolar alveolar capillary vessels bed

Hyperventilation should not be used due to decreasing cerebral perfusion and neurosensory deafness at extremes of respiratory alkalosis Effect of Ventilation: Pulmonary Vascular Resistance PVR) is minimal at FRC

Low lung volume Optimal lung volume High lung volume at FRC

FRC=functional residual capacity FRC

Functional residual capacity (FRC) or rest volume (<20% of total lung capacity) is the point at which collapsing and distending pressures balance out to zero pressure- is the gas that remains in the lung after a normal expiration. Importance of PEEP= Paw

Paw= Mean Make PEEP a priority Airway Pressure Model – PPHN with Remodeled Pulmonary Vasculature Increased Hysterotomy and fetal shear stress ductal ligation at 126 d gestation

Delivery 9 days later by C-section

Vascular remodeling with smooth muscle hypertrophy Term ~ 145 days Courtesy of Satyan Lakshminrusimha Severe Hypoxic Pulmonary Vasoconstriction in Lambs with PPHN; Change Point – Similar to Control Lambs

Change Point ~ 60 ± 7 mmHg

Recommendation for infants is to keep

saturations in the low to mid-90’s with PaO 2 levels between 55-80

Lakshminrusimha S et al, Pediatr Res. 2009 Nov;66(5):539-44 Hyperoxia accentuates vascular dysfunction

Brief exposure to 100% PPHN 100% O 2 oxygen in lambs resulted in increased contractility of pulmonary arteries Reactive ROS and reduced response to oxygen iNO* species Vascular remodeling eNOS expression PDE5 activity

Blunted cGMP and iNO response Vasoconstriction

Courtesy of Dr. Robin Steinhorn *Laksminrusimha, S, et al. J Appl Physiol.2011:111(5):1441-7

Histology of alveolus, smooth muscle and endothelial cells

Respiratory bronchiole

Alveoli

NO combines with hemoglobin to form methemoglobin and does not exert a vasodilator effect on the systemic circulation NeoReviews Nitric oxide signaling pathway Prostacyclin signaling pathway

Indocin can inhibit COX Arachidonic pathway -> ongoing Amino Acid acid ÌPVR generated by urea cycle

Oxygen + Oxygen + Sheer Prostacyclin Sheer stress stress

iNO

cGMP and cAMP indirectly Ó free cytosolic calcium leading to vascular dilation X X Prostacyclin Derivatives:

Inhibit PDE5: Remodulin, Methylxanthines function as PD inhibitors Inhibits Sildenafil, which play a key role in regulating PDE3: Flolan, intracellular levels of cAMP and cGMP Hydrocortisone Milrinone Iloprost Inhaled nitric oxide

No iNO iNO • Enters only ventilated alveoli and redirects pulmonary blood by dilating adjacent pulmonary arterioles so reduces V/Q mismatch • Works best with adequate lung recruitment, preferably with high- frequency ventilation (HFOV and HFJV) • Doses >20 ppm do not increase the efficacy and are associated with more adverse effects such as elevated methemoglobin and nitrogen dioxide (especially if the inspired oxygen is high) Courtesy of Ikaria Initiation of iNO 20-20-20 rule

When: OI of 20 Dose: 20 ppm Response: P/F ratio increases by > 20 mm Hg

Weaning iNO 60-60-60 rule

When: start 60 min after FiO 2 <60 and PaO 2 >60 SpO2 > 90% } Discontining abruptly can cause “rebound” pulmonary hypertension and hypoxemia due to down regulation of endogenous NO and elevations in free radicals and endothelin-1 caused by iNO therapy

} Continuing iNO in the absence of a response or not weaning iNO or extremely slow weaning can potentially lead to suppression of endogenous eNOS. } iNO is FDA approved for neonates >34 weeks but given the fact that premature infants can develop PPHN as well, it is beneficial in some cases

} Patients with preexisting LV dysfunction treated with iNO, even for short durations, are at risk for developing pulmonary edema (package insert, INOmax, 2009) Neonates who have LV dysfunction associated with high left atrial pressures and a

1) L Ï R shunt at the foramen oval 2) R ÏL shunt at the PDA X should NOT be treated with iNO because it can precipitate pulmonary edema. Milrinone may be a better choice.

Clogged drain Inhaled nitric oxide at the alveolar-capillary membrane

Release of reactive Air O2 NO 2 oxygen species space such as superoxide Nitric oxide

Formation of reactive nitrogen Type I Type II species such as alveolar Alveolar peroxynitrite cell cell NO and O - Inactivation by 2 2 hemoglobin Formation of Red S-nitrosothiols Leukocyte cell methemoglobin + nitrate ferrous Hgb Plasma proteins Vascular space Endothelial cell

• Is toxic at higher concentrations • Reacts with superoxide anion to form peroxynitrite, which causes lipid peroxidation and other oxidative injury to cell membranes

• NO 2 is even more toxic • Use at 20 ppm is felt to be safe

Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. NEJM. 2005;353:2683-2695 } Congenital heart disease that is dependent on right-to-left shunting across ductus arteriosus ñ Critical Aortic Stenosis ñ Interrupted Aortic Arch ñ Hypoplastic Left Heart Syndrome

} May worsen pulmonary edema in patients with TAPVR due to the fixed venous obstruction } iNO is FDA approved for neonates >34 weeks

} Patients with preexisting LV dysfunction treated with iNO, even for short durations, are at risk for developing pulmonary edema (package insert, INOmax, 2009) iNO • Overall rate of neurodevelopmental handicap in infants treated with NO was 46%, with 25% mildly affected and 21% severely affected at 1 year FU

Lipkin PH, et al. Neuodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide . J Pediatr . 2002;140:306-310 • Mild neurodevelopmental handicaps in 14% and 12% had severe at 1 year • Senorineural hearing loss present in 6-19%

Rosenberg A A, et al. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for PPHN. J Pediatr. 1997;131:70-75 } Decreases PDE5 activity so cGMP increases which promotes vasodilation Inhibit PDE5: Hydrocortisone, } Attenuates reactive oxygen species Sildenafil production by induction of superoxide dismutase

} Stabilizes systemic blood pressure allowing improved oxygenation possibly secondary to hemodynamic stability

} Treats pulmonary interstitial glycogenosis } Start early! Perez M, et al. Hydrocortisone normalizes PDE5 activity in pulmonary artery smooth muscle cells from lambs with PPHN. Pulm Circ , 2014;4:71-81 Patchy Diffuse • Abnormal accumulation of glycogen in interstitium • Associated with lung disease (MAS, PPHN, pneumonia) • Diffuse infiltrates seen on CXR • Improves with steroids Remodulin Flolan Iloprost

} Potent, short-acting, cAMP-dependent vasodilator of the pulmonary and systemic circulations } Acutely relaxes vascular smooth muscle cell } Inhibits platelet aggregation } Ameliorates endothelial injury } Inhibits VSMC migration and proliferation } Reverses vascular remodeling } Reduces synthesis and improves clearance of ET-1

See end of presentation for more details • Phosphodiesterase-5 inhibitor • Facilitates nitric oxide-cyclic-GMP-induced vasodilatation in the lungs by inhibiting the degradation of cGMP • Used to prevent rebound PPHN in weaning patients off iNO • Used in oral form • IV international study started 2013; completed in December of 2018 } Inhibits phosphodiesterase (PDE3) and increases concentration of cAMP in pulmonary and systemic arterial smooth muscle and in cardiac muscle. } Acts additively with iNO } Believed to improve cardiac function by ◦ Positive inotropy (improved contraction). Increases cardiac output with reduction in filling pressures and systemic vascular resistance ◦ Positive lusitropy (improved relaxation). Causes peripheral vasodilation and improved relaxation of the myocardium during diastole ◦ Reduced ventricular afterload } Minimally affects heart rate } Anticipate a drop in BP!!!

} Systemic BPs should be maintained at a normal range for age and gestation, as an increased systemic resistance may decrease the degree of R Ï L shunting. } Increasing BP to supraphysiologic levels is not recommended. ◦ PDA acts as a pop-off valve, limiting RV preload and dysfunction. ◦ Increasing BP limits RÏL shunt across the PDA and may add to right ventricular strain. ◦ If PBF (pulmonary blood flow) is forced by elevating systemic pressure (+ limiting RÏL shunts) through the constricted pulmonary circuit, endothelial dysfunction due to increased shear stress can exacerbate PPHN Sharma V, et al. Maternal Health Neonatol Perinatol BMC . 2015 Age Systolic Diastolic Mean

6 to 18 h 80 ± 13 43 ± 10 57 ± 12

18 to 30 h 83 ± 12 46 ± 10 60 ± 11

3 d ± 6 h 84 ± 14 48 ± 13 60 ± 12

7 d ± 1 d 91 ± 15 52 ± 11 67 ± 13

} Gestational age goal is only at the 10 th % } Start hydrocortisone early! ◦ Optimal therapy for reduced PBF is selective pulmonary vasodilation (iNO) ◦ Dopamine at > 10 mcg/kg/min is not selective to the systemic vasculature and can increase pulmonary arterial pressure in PPHN* ◦ Norepinephrine and vasopressin are effective ◦ Caution not to use dobutamine which can cause peripheral vasodilation

Lakshminrusimha S. Clin Perinatol 2012;39:655-683 } Start hydrocortisone early!!!

} Treat hypotension due to hypovolemia aggressively with volume replacement (particularly important for septic shock) } Once euvolemic, use dopamine and epinephrine (norepinephrine, vasopressin). (Dobutamine can vasodilate) } Maintain at normal range for age and gestation ◦ Rationale: Increased systemic resistance with dopamine may decrease the degree of R Ï L shunting. } Evaluate ABG/CBG, gluc, CBC, iCa, lactate, coags

} Evaluate neuro status: Is patient a candidate for cooling?

} Assure appropriate lung inflation

} Anticipate shock (+ Ì lactate) even if the BP is normal; Tx hypovolemia aggressively with NS, start hydrocortisone and dopamine early, shoot for BPs for age (see table)

} HFV and iNO are helpful adjuncts but iNO can worsen an infant’s condition if there is LV dysfunction } Milrinone therapy is associated with hypotension and IVH and is not approved by the FDA in neonates (use cautiously)

} Anticipate DIC, get coags early

} Give Na Bicarb or Acetate only if CO2 is in the appropriate range } Avoid excessive noise and stress which can cause

the PO2 to plummet within minutes } Treat with narcotics for sedation (Fentanyl, morphine) and sedatives (Ativan, ie. Lorazepam) ◦ Avoid excessive narcotic use which can cause systemic hypotension and worsen R→L shunts. (Can also happen with milrinone, also)

} Avoid paralysis, if possible (associated with increased mortality) } Beta-type natriuretic peptide (BNP) can be an early indicator. Can serve as a biomarker to assess efficacy of treatment and to predict rebound PPHN (can be used in BPD patients to screen along with monthly echocardiograms)

} If patient requires a PIP > 28 cm H20 or tidal volume > 6 mL/kg to keep PaCO2 < 60 o conventional, switch to a high-frequency ventilator

Endothelin Receptor Antagonist Stimulates endothelial NO synthase Endothelin Superoxide (vasoconstrictor) dismutase Superoxide anions Diffuses to SMC

NO is a

Stimulates soluble guanylate cyclase free radical and Increasee can Ionic Ca combine with superoxide anions to Reduce form Stimulates ionic Ca peroxy- PDE3A nitrite, a potent vasoconstrictor. Therapeutic Targets in Pulmonary Arterial Hypertension

Endothelial NO PGI 2 ET-1 Cell

ET A ET B guanylate cyclase adenylate cyclase Smooth GTP ATP Muscle cGMP cAMP 5’GMP AMP Cell vasoconstriction PDE5 PDE3 vasodilation

Prostacyclin derivatives (Remodulin, Flolan, Iloprost) Endothelium-derived vasodilators: Prostacyclin (PGI 2) and Nitric oxide COX and PGIS are involved in the production of Prostacyclin cyclooxygenase

Prostacyclin synthase Remodulin* Flolan Iloprost

Soluble guanylate cyclase Alprostadil Adenylate cyclase (PGE1, Prostin): Used to maintain ductal patency to decrease RV Reduces afterload. ionic Ca Aerosolized form used in adults. IV PEG1 is used in CDH in combo with iNO to promote pulmonary vasodilation + reduce RV afterload . Endothelium-derived vasoconstrictor: Endothelin,Fig. 56.1 ET-1 Remodulin Prostacyclin (PGI 2) Flolan Iloprost • Potent, short-acting, cAMP-dependent vasodilator of the pulmonary and systemic circulations • Acutely relaxes vascular smooth muscle cell • Inhibits platelet aggregation • Ameliorates endothelial injury • Inhibits VSMC migration and proliferation • Reverses vascular remodeling • Reduces synthesis and improves clearance of ET-1 Remodulin/Tyvaso (treprostinil) • For Class II, III, IV PAH • Administer as continuous SQ or IV infusion • Half life: 4 hours • Metabolized by the liver • Causes vasodilation of pulmonary and systemic arteries

Adverse effects: inhibits effect on platelet aggregation so there is an increased risk of bleeding; caution in patients with impaired liver or renal function, hypotension, headache, dizziness, edema Remodulin. Prostacyclin (PGI 2)

• Continuous SQ or IV infusion • Dose 1.25 ng/k/min (or 0.625 ng/k/min if not tolerated) • Dose increase based on clinical response (increments of 1.25 ng/k/min per week for first 4 weeks of treatment, later 2.5 ng/k/min per week) Prostaglandin (PGE1)

• Alprostadil (Prostin VR 500, Pfizer, New York, NY, USA • Dose: aerosolized at delivered at 150-300 ng/k/min diluted in saline to provide 4 mL/hr via MiniHeart low-flow jet nebulizer (WestMed Inc., Tucson, Arizona, USA) • IV PGE1 has been used in CDH along with iNO to promote pulmonary vasodilation and maintain ductal patency and reduce right ventricular afterload Prostacyclin (PGI 2) Analogue Flolan™ (epoprostenol) • Stimulates membrane bound adenylate cyclase, increases cAMP • Acutely relaxes vascular smooth muscle • Inhibits pulmonary artery smooth muscle cell proliferation in vitro; inhibits platelet aggregation • ameliorates endothelial injury • Reverses vascular remodeling • Reduces synthesis and clears ET-1 • Exerts positive inotropic effects Prostacyclin (PGI 2) Analogue Flolan™ (epoprostenol) • Dose: 10-40 ng/k/min continuous inhalation or central line infusion • ½ life 3-5 minutes • Escalation of dosing is frequently required • Acute withdrawal can lead to fatal PH • May lower systemic vascular resistance, worsening ductal or atrial level R -> L shunt • May worsen intrapulmonary shunts by vasodilating non-ventilated areas of the lung Prostacyclin (PGI 2) Analogue Ventavis™ (Iloprost) • For Class III and IV PAH • IV – Dilates systemic and pulmonary arterial vascular beds • Inhaled (½ life: 20-25 minutes) – Selective pulmonary vasodilatation, increases cardiac output, improves venous and arterial oxygenation Inhaled Prostanoids

• Inhaled prostanoids - 40 Patient 1 Patient 2 experience largely Patient 3 Patient 4 30 confined to case reports OI • Iloprost or treprostinil – 20 newer generation

10 preparations specifically designed for inhalation 0 -10 0 10 20 30 40 • Longer t 1/2 Time (hours)

Kelly et al; J Pediatr 2002;141: 830 Therapeutic Targets in Pulmonary Arterial Hypertension

Endothelial NO PGI 2 ET-1 Cell

ET A ET B guanylate cyclase adenylate cyclase Smooth GTP ATP Muscle cGMP cAMP 5’GMP AMP Cell vasoconstriction PDE5 PDE3 vasodilation

SILDENAFIL Sildenafil

• Phosphodiesterase-5 inhibitor • Facilitates nitric oxide-cyclic-GMP-induced vasodilatation in the lungs by inhibiting the degradation of cGMP • Used to prevent rebound PPHN in weaning patients off iNO • Used in oral form • IV international study started 2013; completed in December of 2018 IV Sildenafil

• Load of 0.42 mg/kg over 3 hours (0.14 mg/kg/hr) followed by 1.6 mg/kg/day as a continuous maintenance infusion (0.07 mg/kg/hour) Sildenafil Stimulates endothelial NO synthase Endothelin Cyclooxygenase (vasoconstrictor)

Diffuses to SMC

Prostacyclin synthase

Prostaclyclin Stimulates soluble guanylate cyclase receptor Increasee Adenylate Ionic Ca cyclase Cyclic guanosine monophosphate Cyclic adenosine monophosphate Reduce ionic Ca Broken down by PDE3A Sildenafil Increased cAMP-> pulmonary and Inhibits systemic PDE5 and vasodilation and inotropy increases cGMP in SMC Therapeutic Targets in Pulmonary Arterial Hypertension

Endothelial NO PGI 2 ET-1 Cell

ET A ET B guanylate cyclase adenylate cyclase Smooth GTP ATP Muscle cGMP cAMP 5’GMP AMP Cell vasoconstriction PDE5 PDE3 vasodilation

MILRINONE inhibits PDE3 Milrinone

• Inhibits phosphodiesterase (PDE3) and increases concentration of cAMP in pulmonary and systemic arterial smooth muscle and in cardiac muscle. • Acts additively with iNO • Believed to improve cardiac function by – Positive inotropy (improved contraction). Increases cardiac output with reduction in filling pressures and systemic vascular resistance – Positive lusitropy (improved relaxation). Causes peripheral vasodilation and improved relaxation of the myocardium during diastole – Reduced ventricular afterload • Minimally affects heart rate Milrinone

• Loading dose: 50 mcg/kg over 30-60 minutes • Maintenance dose 0.33mcg/kg/min and escalated to 0.66 mcg/k/min and then to 1 mcg/kg/min based on response • Loading dose not recommended in the presence of systemic hypotension and in prematures • Have a NS fluid bolus ready in the event of hypotension • May be choice of pulmonary vasodilator in PPHN with left ventricular dysfunction • Potential adverse event may be intracranial hemorrhage Bassler Dr, et al. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate . 2006;89:1-5 Milrinone Endothelial NO synthase cyclooxygenase

Prostacyclin synthase

Diffuses to SMC

Soluble guanylate cyclase

Stimulates Adenylate cyclase

Milrinone : inhibits PDE 3A +increases Reduces cAMP levels in ionic Ca arterial SMC + Breaks down cAMP cardiac myocytes resulting in pulmonary (and systemic) vasodilation and inotropy. Therapeutic Targets in Pulmonary Arterial Hypertension

Endothelial NO PGI 2 ET-1 Cell

BOSENTAN ET A ET B guanylate cyclase adenylate cyclase Smooth GTP ATP Muscle cGMP cAMP 5’GMP AMP Cell vasoconstriction PDE5 PDE3 vasodilation Endothelin Receptor Antagonist Tacleer™ (bosentan) • (ET-1 is a potent vasoconstrictor and vascular smooth muscle cell mitogen whose concentrations in plasma and lung tissue are elevated in patients with PH). Bosentan is a nonselective inhibitor of both ET A and ET B. ET B is thought to release NO and mediate vasodilatation. • First oral drug approved for treatment of PAH in adults • Used for refractory PH in infants with CDH, BPD and CHD • NG: 1-2 mg/k twice daily • Did not show additive effect when combined with iNO* • May have a role in chronic pulmonary hypertension associated with BPD or CDH

*Stenhorn RH, et al. Bosentan as adjunctive therapy for PPHN: results of the FUTURE-4 study. Circulation. 2014;30:A13503 2 Endothelin Receptor Antagonist= Inhibits ET A and TE B (vasodilation) Stimulates endothelial NO synthase Endothelin acts on Endothelin ET-B stimulating Cyclooxygenase (vasoconstrictor) NO release + vasodilation

Diffuses to SMC

Prostacyclin synthase 1

Prostaclyclin Stimulates soluble guanylate cyclase Endothelin receptor acts on ET-A Increases receptors in SMC Adenylate Ionic Ca causing cyclase vasoconstriction by Cyclic guanosine monophosphate increasing ionic calcium Cyclic adenosine monophosphate Reduces ionic Ca Broken down by PDE3A Increased cAMP-> pulmonary and systemic vasodilation and inotropy • Lakshminrusimha S, Kumar V. Pediatric Critical Care Fifth Edition. Ed Fuhrman and Zimmerman. Chapter 56, Diseases of Pulmonary Circulation. Elsevier, 2017 • Mathew B, Lakshminrusimha S. Saunders Elsevier, The Newborn Lung, Neonatology Questions and Controversies.Third edition. Ed Bancalari E, Keszler M, Davis Peter G. Chapter 8. Elsevier, 2017 • Abman SH. Abnormal vasoreactivity in the pathophysiology of PPHN. Pediatr Rev. 1999: 20:e103 • Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. NEJM. 2005;353:2683-2695 • Kinsella JP, Abman SH. Inhaled NO and HFOV in PPHN. Eur J Pediatr. 1998;157:S28 • Konduri GG. New approaches for PPHN. Clin Perinatol . 2004;31:591-611 • Lotze A, Mitchell BR. Multicenter study of surfactant use in the treatment of term infants with severe respiratory failure. J Pediatr . 1998;132:40-47 • Neonatal Inhaled Nitric Oxide Study Group. Inhaled NO in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med . 1997;336:597-604 • NINOS. Inhaled NO and hypoxic respiratory failure in infants with CDH. Pediatrics . 1997:99-838. NINOS Neurodevelopmental follow up. Pediatrics . 2000;342:469 • Steinhorn RH, Farrow KN. Pulmonary hypertension in the neonate. NeoReviews. 2007;8(1):e14-e21. • Steinhorn RH, Kinsella JP, et al. IV Sildenafil in the treatment of neonates with PPHN. J Pediatr. 2009;155:841-847 • Van Meurs K, Congenitall Diaphragmatic Hernia StudyGroup. Is surfactant therapy beneficial in the treatment of the term newborn infant with CDH? J Pediatr . 2004;145:312-316