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

2. 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

3. 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

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

5. 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%

6. 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)

7. 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!

8. - Vasoconstriction is the enemy primary mediator

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

10. 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

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

12. 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

13. Causes

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Treatments

23. 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

25. 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

26. 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

27. 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)

28. 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 – % vs traditional goal of >95%
Alternately goal PaO vs traditional PaO2>60-70
This maybe more relevant in patients with CDH

29. 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

30. 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

31. - Vasoconstriction is the enemy primary mediator

32. 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)

33. 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

34. 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

35. 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

36. 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)

37. 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 minutes, maintenance dose starting at 0.33μg/kg/minute
Skip loading dose if systemic hypotension

38. 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)

39. 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

40. 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 months
Difficult to determine if this is secondary to underlying disease or PPHN itself

41. 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

44. 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 ; 36: S3-S11
Lakshminrusimha S, Keszler M. Persistent Pulmonary Hypertension of the Newborn. NeoReviews Dec; 16(12): c680-c692.
Steinhorn RH, Farro KN. Pulmonary Hypertension in the Neonate. NeoReviews Jan; 8(1): c14-c21.
Steinhorn, RH. Neonatal Pulmonary Hypertension. Pediatr Crit Care Med March; 11(2 Supple): S79-S84.