Persistent Pulmonary Hypertension in the Newborn Katherine Wang, MD Avera McKennan NICU Clinical Associate Professor, USD Medical School

Case Study MHx: 35 y/o G3P1 woman with medical history significant for Hashimoto’s thyroiditis, asthma, and atopic dermatitis One prior miscarriage at 10 wks GA and one prior delivery by C-section at 36wks GA This pregnancy was uncomplicated Presented on evening prior to delivery at 38-4/7 wks GA with decreased fetal movement

Non-stress test was non-reactive, BPP was 4/8 Mom was taken for repeat C-section Meconium stained fluid noted at delivery Infant noted to have nuchal cord x3 which were easily reduced APGAR 8 and 9 at 1 and 5 minutes At ~4 mins. of life infant noted to be hypoxic to 56% in room air

Improved with BBO2 Then transferred to NICU for further care of hypoxia

Physiology Persistent pulmonary hypertension is a result of failure of the normal circulatory transition at birth Incidence in the US is estimated at 2 per 1000 live term births Complicates the course of ~10% of all neonates with respiratory failure Mortality ranges from 5-10%

In Utero Placenta is the organ of gas exchange Less than 10% of fetal ventricular output is circulated through the pulmonary vascular bed Pulmonary vascular resistance (PVR) is naturally high PVR continues to increase with gestational age Is high at birth, such that PVR=SVR (systemic vascular resistance)

Birth Transition to the outside world is triggered by clearance of lung fluid, reduction in PVR, and increase in pulmonary blood flow The most important trigger seams to be ventilation of the lungs and increase in oxygen tension Vasoactive mediators produced by vascular endothelium are key to this transition These mediators act on the smooth muscle cells which control vasodilation/constriction - The first cries are key!

- Vasoconstriction is the enemy primary mediator

Main players Vasoconstriction Vasodilation Main mediator is Endothelin (ET-1) Vasodilation Main mediators are nitric oxide (NO) and prostacyclin (PGI2)

What goes wrong? Failure in decrease of PVR PDA remains open and blood continues to bypass the lungs There is also V/Q mismatch Clinical Picture Differential cyanosis: Post-ductal SaO2 is >5-10% lower than pre-ductal Labile hypoxemia: large change in SaO2 with minimal or no change in ventilator settings or FiO2 - Blood always takes the path of least resistance

Reminder that there are two places to measure pre-ductal SaO2 There is an increased difference because there is increased shunting via the PDA

Case Study Shortly after admission, infant’s FiO2 increased to 65% He was intubated and given surfactant Initial ECHO shows PPHN With persistently elevated FiO2, iNO is started

Causes

Constricted pulmonary vessels Abnormally constricted pulmonary vasculature due to parenchymal disease Meconium Aspiration Syndrome (MAS) – most common cause Respiratory Distress Syndrome (RDS) Hypoxic/Ischemic injury Sepsis, pneumonia

Normal lung, abnormal vessels In utero NSAID exposure in third trimester PDA constriction  Pulmonary vessel remodeling Maternal SSRI use in second half of pregnancy Serotonin increases fetal PVR 6 fold increase in prevalence of PPHN Malignant transient tachypnea of the newborn Often after elective C-section Giving high FiO2 without positive pressuree

Alveolar Capillary Dysplasia misalignment of lung vessels Typically present with cyanosis, respiratory failure refractory to all therapies Universally lethal Can only diagnose with lung biopsy Very rare, about 10% have familial association

Hypoplastic lungs Congenital Diaphragmatic Hernia Developmental defect in the diaphragm Occurs in 1 in 3000 live births 20-30% mortality PPHN due to lung hypoplasia and subsequent fewer pulmonary artery branches There is also abnormal medial muscular hypertrophy Major determinant of survival is degree of pulmonary hypoplasia and subsequent pulmonary hypertension

PPROM The earlier the gestational age at ROM, the worse the prognosis for pulmonary function Oligohydramnios leads to pulmonary hypoplasia Worst prognosis is for infants whose ROM is <20wks

Case Study Etiology of PPHN was thought to be secondary to meconium aspiration No signs of infection and blood culture was negative after 48hrs Also concern for fetal distress secondary to nuchal cord as mom initially presented for decreased fetal movement Cord blood gases were within normal parameters

Diagnosis It is important to differentiate PPHN from congenital heart disease PPHN is suggested by hypoxemia disproportionate to severity of parenchymal disease on CXR Look for differences in pre- and post-ductal saturations or PaO2 Fixed split S2 on cardiac exam Gold standard is ECHO Look at the direction of the ductal shunt and PFO shunt Flattening/bowing of interventricular septum Tricuspid regurgitation velocity

Epidemiology Primarily in late preterm and term infants More recent evidence suggests that it can present in some preterm infants with RDS This is separate entity from pulmonary artery hypertension complicating BPD Chronic process which is likely secondary to reduced pulmonary capillary bed due to the simplified lung of BPD

Treatments

Supportive therapy Optimization of temperature and nutritional support Minimization of stress – use of analgesia and sedation as needed Try to avoid paralysis if possible; associated with increased mortality Treatment of underlying disease (ie, sepsis, pneumonia) This may be all that is needed for mild cases

Goal is to maintain pH>7.25 Alkali infusion is no longer recommended – associated with increased use of ECMO and need for oxygen at 28 days Want to maintain pCO2 as close to 40 as possible All efforts are to keep pulmonary pressures low and maintain normal systemic pressures May need help of pressors

Mechanical ventilation Expansion of lungs is as important as oxygenation Under/over-expansion will lead to increased PVR Optimal recruitment = 8-9 ribs expansion on CXR Often high frequency ventilation is utilized to help provide gentle ventilation Study showed improved oxygenation with combo of high frequency ventilation and iNO when PPHN associated with parenchymal lung disease

Oxygen therapy - revisited Traditional theory: high oxygen supplementation Higher PaO2 helped maintain pulmonary vasodilation Rise of the reactive oxygen species (ROS) Produced by normal metabolism but also from oxygen Bench studies show ROS promote vascular smooth muscle cells proliferations in PPHN When combined with NO can actually cause vasoconstriction These are inactivated by superoxide dismutase (SOD)

This maybe more relevant in patients with CDH Recent study in animal model showed 100% oxygen increased pulmonary artery contractility and reduced response to iNO Some experts starting to recommend lower goal SaO2 – 90-95% vs traditional goal of >95% Alternately goal PaO2 55-80 vs traditional PaO2>60-70 This maybe more relevant in patients with CDH

Surfactant Early surfactant therapy and lung recruitment is association with decreased risk of ECMO or death Intrinsic surfactant often inactivated in pneumonia, MAS, and RDS It is less clear if surfactant therapy is beneficial in infants with CDH In some centers, only administer 50% of the typical dose due to pulmonary hypoplasia

Pulmonary Vasodilators After optimization of lung recruitment Typically after surfactant therapy If continue to have difficulty with oxygenation, consider vasodilator therapy Type of vasodilator depends on systemic blood pressure and ventricular function on ECHO

- Vasoconstriction is the enemy primary mediator

1) Inhaled Nitric Oxide iNO is most commonly used Selective vasodilator without significant decrease in systemic blood pressure It is preferentially distributed to ventilated lung segments thus improving V/Q mismatch Large study showed iNO therapy decreased the need for ECMO in term infants with hypoxemic respiratory failure Only FDA approved treatment for PPHN in term and near-term infants (>34 wks GA)

Recommended dose of 20ppm Higher doses are not recommended due to association with increased level of nitrogen dioxide and methemoglobin Complete response is defined as increase in PaO2/FiO2 ratio of 20mmHg or more Clinically we typically look for a 10-20% drop in FiO2 within 1 hour Methemoglobin levels are checked at initiation and then once daily Methemoglobin level of <2% is low

When infant is improving, generally FiO2<60%, weaning of iNO must be gradual Abrupt withdrawal will lead to rebound vasoconstriction Long term continuance of iNO in infants who are unresponsive or failure to wean can lead to prolonged dependence due to suppression of endogenous production

2) Phosphodiesterase 5 (PDE) inhibitors (Sildenafil) Use if blood pressure is stable Helpful in the presence of right-to-left shunt at PFO or PDA level with good ventricular function Oral or IV preparations available IV dose: load of 0.42mg/kg over 3 hours, continuous infusion of 0.07mg/kg per hour Oral dose: 1-2 mg/kg every 6 hours

Metabolized by the liver FDA pediatric warning in 2012 Severe hepatic dysfunction may impair metabolism FDA pediatric warning in 2012 Pediatric study identified increased mortality associated with increasing doses Concern for chronic use in kids (study participants were >1 year old)

3) Milrinone This is an inodilator Useful if blood pressure is normal but there is evidence of ventricular dysfunction iNO not ideal because it may precipitate pulmonary edema Inhibits phosphodiesterase and increases cAMP concentration in smooth muscle cells Dosing: loading dose of 50μg/kg over 30-60 minutes, maintenance dose starting at 0.33μg/kg/minute Skip loading dose if systemic hypotension

4) Aerosolized medications Prostaglandin E1 prostaglandin I2 These are continuous inhalants These are not FDA approved treatments There is some concern about unknown effect of alkaline pH on neonatal airway (pH = 10)

ECMO Cardiopulmonary bypass Use of ECMO peaked in the early 1990s and has declined since Starting ECMO criteria Oxygenation Index >40 or alverolar-arterial oxygen gradient >600 Maximization of medical management with hemodynamic instability

Outcomes Usually resolves spontaneously in most infants Not typically associated with genetic factors 25% of infants with moderate or severe PPHN will exhibit significant neurodevelopmental impairment at 12-24months Difficult to determine if this is secondary to underlying disease or PPHN itself

Case Study Infant did initially require dobutamine drip for pressor support Responded well to iNO and was able to wean off in 4 days Extubated on DOL 3 Required sedation with fentanyl and versed drip but weaned easily Able to be discharged home on DOL 10 Diagnosed with unilateral mild high frequency hearing loss at 18 months

References Lakshminrusimha S, Saugstad OD. The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy. J Perinatology. 2016; 36: S3-S11 Lakshminrusimha S, Keszler M. Persistent Pulmonary Hypertension of the Newborn. NeoReviews. 2015 Dec; 16(12): c680-c692. Steinhorn RH, Farro KN. Pulmonary Hypertension in the Neonate. NeoReviews. 2007 Jan; 8(1): c14-c21. Steinhorn, RH. Neonatal Pulmonary Hypertension. Pediatr Crit Care Med. 2010 March; 11(2 Supple): S79-S84.