Persistent Pulmonary Hypertension of the newborn (PPHN)

Persistent Fetal Circulation (PFC)

Jen-Tien Wung, M.D.,FCCM

Neonatal IntensivistDivision of Neonatology

Columbia University Medical Center

P P H NA complex syndrome with multiple causesFailure to initiate, or to sustain, the transition from fetal circulation to neonatal circulation normally occurs after birthCharacterised by remodelling of the pulmonary vasculature Elevated pulmonary vascular resistance and a variable degree of right-to-left shunting of venous blood across the fetal channels (PFO, PDA.)

P P H N

• Incidence of 0.43 – 6.8/1,000 live births

•Hypoxemia, respiratory distress•Fails to treat will lead to death or

deleterious hypertrophic changes in the right ventricle

•Mortality of 10 -20 %

Persistence of fetal circulation

PPHN Potential Mechanisms

• Failure to release of endogenous vasodilators :NO, PGI2, EDHF, Adenosine

• Increased production of vasoconstrictors:Et-1 , Thromboxane, LT, PAF

• Altered Vascular SMC responsiveness:Decrease sGC, cGMP Kinase & Increase PDE

• Structural modeling :SMC hyperplasia

PPHN - Causes•Perinatal asphyxia, MAS•Congenital heart diseases•Pulmonary hypoplasia, CDH, Oligohydramion•RDS•GBS or other sepsis•Premature ductal closure secondary to maternal drug

therapy (NSAIDs)•Maternal use of selective serotonin-reuptake inhibitor

(SSRI, fluoxetine) in late pregnancy•Alveolar capillary dysplasia (Misaligment of PVs)•Iatrogenic•Idiopathic

• Endothelin-1 (ET-1) causes vasoconstriction in the pulmonary arteries by activation of Endothelin-A (ETA) receptors. ET-1 has been found to be elevated in neonates with pulmonary hypertension and is considered a marker of disease severity. ET-1 is felt to play a role in the pathogenesis of PPHN caused by hypoxia or meconium aspiration,

• Thromboxane appears to mediate pulmonary hypertension caused by Group B Streptococcal (GBS) sepsis.

Analysis of NSAIDs in meconium and its relation to PPHN.

• In infants with PPHN, 88% showed at least one NSAIDs in meconium versus 25% in the control group (p=0.001)

MECONIUM FINDINGS POSITIVE FOR:

MATERNAL HISTORY REPORTED USE:

ASPIRIN 40% 1%IBUPROFEN 23% 13%NAPROXEN 19% 12%INDOMETHACIN 8% 2%

Pediatrics 2001;107:519-23 , Alano MA et al

PPHNClassification

1. Maladaptation2. Excessive muscularization3. Underdevelopment4. Flow obstruction

PPHN Classification1. Maladaptation• Pulmonary vessels have undergone normal

structural development, but there is a failure of transition from fetal to neonatal circulation or acute increase of pulmonary vascular resistance.

• Acute pulmonary vasoconstriction as under conditions of acute stress in MAS, asphyxia & iatrogenic stress

• Hypoxia and/or acidemia due to conditions such as airway obstruction, atelectasis, alveolar hypoventilation

• Alveolar over-inflation as in hyperventilation• Release of vasoactive substances as seen in

sepsis or tissue injury.

PPHNClassification

2. Excessive muscularizationInfants whose prenatal disturbances have resulted in increased medial wall thickness of muscular intra-acinar arteries and extension of muscularization of the medial smooth muscle layer into usually non-muscular peripheral pulmonary arterioles which interfere with normal postnatal pulmonary vasodilatation.1. Chronic intrauterine stress and hypoxia;2. Prenatal pulmonary hypertension

a) Antenatal constriction of the ductus arteriosus due to prenatal use of NSAIDS such as aspirin or indocin.

b) Fetal systemic hypertension 3. Idiopathic.

Normal Lung(left) vs PPHN Lung (right)

There is smooth muscle hypertrophy of the pulmonary arteriole (PA) and narrowing of the arteriolar lumen in PPHN

PPHNClassification

3. UnderdevelopmentInfants who have a decrease in the total number of pulmonary vessels.1. Space occupying lesions in chest such as in CDH, lung cysts, CCAM, pleural effusion, etc.2. Hypoplasia of lung as in Potter's syndrome or

oligohydramnio syndrome3. Interference in vessel growth, possibly due to drugs or intrauterine environment

Bil. Chylothoraces -> Bil. Hypoplastic lungs

Potter’s Syndrome

P P H NClassification

4. Flow obstruction

• Increase of blood viscosity: polycythemia, IUGR

• TAPVR, triatriatrum, misalignment of pulmonary vessels

Misaligment of pulmonary Vessels

PPHNManagement at CNMC

“Full Artillery” Approach1. FiO2 100%2. IMV 50 – 100/min.

PIP 25 – 45 cm H2O to achieve PaCO2 < 25 mmHg3. Muscle relaxant4. Tolazoline5. Dopamine 2-20 µg/kg/min

Dobutamine 5-30 µg/kg/minto achieve mean BP 45 – 50 mmHg

6. NaHCO3 1 meg/kg/hr to keep pH > 7.55

Oxyhemoglobin Dissociation Curve

Management of PPHNColumbia Approach

• Treating the underlying disease• Continuously monitoring of pre- & post-ductal O2

saturation• Mechanical Ventilation: 1. IMV or SIMV 2.

SIMV+PS or A/C 3. HFPPV 4. HFV (HFO)• No hyperventilation, induction of alkalosis or

neuromuscular blockade• Pulmonary vasodilator-- INO (for pre-ductal oxygen

saturation < 90%). If no response, inhaled iloprost or I.V. sidenalfil (watch for HPV) may be added.

• ECMO as last resort

MAP: MAP at referral hospital, MAP1: baseline MAP following admission and before INO therapy, MAP2:MAP within 24 hours of INO therapyJournal of Perinatology 2002; 22: 435

10

15

20

MAP MAPI MAP2

MEAN AIRWAY PRESSURE

CM

H2O

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*

*p<0.01

0

20

40

60

O I - A O I - B

oxyg

enat

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inde

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Oxygenation index before (OI-A),and after starting INO therapy (OI-B)

Journal of Perinatology 2002; 22: 435

*p<0.001

CHONY Kinsella NINOS Davidson Clark

N 112 107 114 114 126

Gestation (wks) 40 (med) >34 >34 >37 >34

Baseline O.I. 50.7 ± 2.6 49.3 ± 3.4 43.0 ± 17.6 24 ± 9 37+24 PaO2 (mm Hg) 32.7 ± 1.3 40.3 ± 1.7 46.8 ± 15.5 59 ± 16 72+64

PH 7.26 ± 0.2 7.41 ± 0.02 NA 7.50 ± 0.11 7.45+0.1

PaCO2 (mm Hg) 51.9 ± 2.2 35.5 ± 1.3 NA 30 ± 9 35+13

INO (hours) 45 (med) 75.5 ± 1.1 40 (med) 58 ± <96

Ventilator days 6.69 ± 0.3 9 ± 1 11.6 ± 7 9.2 ± 7.4 11+7

Nonresponders (ECMO+deaths)

25% 30-60% 46% 29.8% 40%

ECMO 17.9% 39% 38%

Mortality 8% 15% 14% 8% 8%

Settings for Conventional Technique• Flow Rate 5-7 LPM• FiO2 to keep PaO2 50-70 mmHg• IMV rate

–Usually started at 20-40/min–Avoid excessive labored breathing–Maintain PaCO2 40-60 mm Hg

• Inspiration time (Ti) - 0.5 seconds• Peak inspiratory pressure (PIP)

–Adequate chest excursions–Usually started at 20 cmH2O for term infant

• PEEP 5 cm H2O

Setting of High Frequency Positive Pressure Ventilation (HFPPV)

• IMV 100/min.• Ti 0.3 sec. (Te 0.3 sec)• Flow rate above 10 LPM• PIP is usually the same as conventional

settings • PEEP 0

High Frequency Ventilation

HFOVHFJV

MUSCLE

RELAXANT

Fig. 4. A 3900 gram infant had MAS and PPHN, transferred to CHONY for ECMO

IMV Ti PIP PEEP FiO2 PH PaCO PaO2

Before transfer

80 0.4 35 5 1.0 7.41 44 33

At CHONY 40 0.6 30 5 1.0 7.30 55 31

After reversal* 25 0.6 30 5 1.0 7.34 53 68

*TcPO2 started to rise (arrow) when the infant began to breathe spontaneously after reversal of pavulon.

HYPER-

VENTILATION

Hyperventilation• Overventilation impedes venous return,

decreases pulmonary blood flow, oxygenation, cardiac output and blood pressure

• Increases pulmonary vascular resistance. The capillaries are stretched and their caliber is reduced

• Increases lung injury (barotrauma, volutrauma, and biotrauma).

• Shifts O2-hemoglobin dissociation curve to the left due to alkalosis

• Decreases cerebral blood flow.• Causes hearing loss.

P P H NMild sedation PRN

Phenobarbital:5 – 10 mg/kg I.V. p.r.n for agitation of infant on tolazoline

Midazolam (Versed):0.05 – 0.1mg/kg i.v. PRN

P P H NDopamine

• 2.5ug/kg/min for oliguria• Up to 10ug/kg/min for poor cardiac

contractility. Dobutamine is added if needed.

• >10 ug/kg/min is not used, because of the danger of alpha-adrenergic effect, which causes pulmonary vasoconstriction

P P H NVasodilator Therapy

• tolazoline (priscoline)• epinephrine (0.1 ug/kg/min)• prostaglandin E1 (0.1 ug/kg/min)•magnesium sulfate• inhaled nitric oxide (after 5/1994)• Inhaled iloprost• Sidenafil, P.O., or I.V.

P P H Ntolazoline (priscoline)

• Nonspecific vasodilator• May cause hypotension• May decrease urine output• Causes cutaneous flushing• Increase gastric secretion• May cause posturing and CNS irritability

P P H Ntolazoline (priscoline)

• Infuse into upper extremity or scalp vein• Test dose: 1 mg/kg• Maintenance: 1mg/kg/hr

PPHN MgSO4

Loaded with 200 mg/kg over 30 min, followed by continuous infusion at 50-150 mg/kg/hourto attain a serum magnesium level of 5-7 mmol/L

Boo, Singapore Med J, 2010

1992

Schematic of NO uptake and mechanism for pulmonary vasodilatation

PPHN PPHN + INO

PPHN + Nipride PPHN + INO

Inhaled Nitric Oxide

•Specific pulmonary vasodilator

•The gold standard therapy for PPHN

INOmaxTM

Dosage

• The recommended initial dose is 20 ppm.

• Dose reduced as tolerated to 5 ppm after a sustained improvement in oxygenation (24 to 48 hours).

• Duration is usually 2 to 6 days

Methemoglobin Concentration-Time ProfilesNeonates Inhaling 0, 5, 20 or 80 ppm INOmaxTM

Methemoglobin Concentration - Time Profile

Davidson et al. Pediatrics 1998;101:325-334

Inspired NO2 level - Time Profile

Davidson et al. Pediatrics 1998;101:325-334

INOmaxTM

Administration

• INOventTM system or other systems• Precise monitoring of inspired NO and

NO2 should be instituted• Monitoring for PaO2 and pre- & post-

ductal O2 saturation • Monitoring MetHb (baseline, 6 hours

and then every 12 hours).

INOmaxtm DS Transport System

INO max DS

INOblender

INO max DS

Setup for I-NO Therapy via Infant Respirator with constant flow

Desired NO dose × (Respirator flowrate + NO

flowrate) = NO concentration in the tank × NO flowrate

Calculation of Required NO FlowrateDesired NO dose × (Respirator flowrate + NO flowrate)

= NO concentration in the tank × NO flowrate

Example:If: Respirator flowrate is 8 LPM (8000 ml/min)

Desired NO dose is 20 PPMNO concentration in the tank is 800 PPMNO flowrate is X ml/min

Then: 20 × (8000 + X) = 800 × X20 × 8000 + 20 X = 800 X160000 = 780 XX = 205 ml/min (approx.. 200ml/min)

INOmaxTM

Weaning

20ppm 15ppm 10 ppm 5 ppm ( 4 --->3 -->2 -->1 ) 0

INOmaxTM

Discontinuation

• INOmaxTM discontinued when the infant is stable on 5 ppm, and FiO2 <60%

• About half of patients require an increase of FiO2 (20 - 40%) for a few hours after weaning off INOmaxTM

Discontinuation of INO (1)

Note the stability of mean blood pressure, heart rate, and SPO2 with the same FiO2 as INO is withdrawn.

Aly H, Sahni R, Wung JT

Arch Dis Child 1997;76:

Discontinuation of INO (2)

Acute deterioration of mean blood pressure, heart rate, and SPO2 with the same FiO2 followed the initial attempt at weaning. FiO2 was increased and the weaning was successful. Note how quickly FiO2 was reduced following successful weaning.Aly H, Sahni R, Wung JT Arch Dis Child 1997;76:

Changes in PaO2 30 minutes after discontinuing INO treatment gases

PPHN Case #8 (1)• 4250g B/M 40 wk. gestation• 35y.o. G5 P4 gestational D.M. on Insulin

Variable deceleration, vaginal delivery, cord around neck x 2

• In nursery - tachypnea & acrocyanosis• 2hrs - oxyhood FiO2 90% VBG 7.31/54/55• Endotracheal intubation• 28.5 hrs - arrived CHONY• 29.1hrs - INO 25 PPM started• 56hrs - INO discontinued• 3d - extubated, 7d - off CPAP

PPHN Case #8 (2)Hrs IMV P Ti FiO2 pH PCO2 PO2

8 40 25/5 0.35 100 7.44 31 150 9 7.50 27 127 12 7.48 21 150 17 7.32 39 57 19 60 35/5 0.48 100 7.45 25 81 19.1 7.44 28 58 21 86 22/3 0.25 7.49 26 81 24 80 24/4 0.35 7.37 37 52 28.5 Arrived at CHONY 29 100 25/0 0.3 100 7.21 56 16 29.1 INO 25 ppm started 30 100 22/0 0.3 65 7.45 33 99

PPHN 4250g IMV 100 P25/0 Ti 0.3

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0 10 20 30 40 50 60 70 80

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FiO2Pre-SO2

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

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FiO2Pre-SO2Post-SO2

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

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FiO2Pre-SO2Post-SO2SBP

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

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FiO2Pre-SO2Post-SO2SBPDBP

INO 25 INO 20

Fig. 8. BP and O2 saturation change after INO for a PPHN infant 4250g IMV 100 P25/0 Ti 0.3.

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FiO2Pre-SO2Post-SO2SBPDBPHR

INO 25 INO 20

Case #8 –(3), on IMV 100, P 25/0, Ti 0.3

O2 saturation and BP response to INO,

•Understand the nature of the disease

•Watch for trending

•Be patience

• 735 gm, 26 wks,PROM x7 days, oligohydramions• Stat c-section for preterm labor, variable deceleration,

breech presentation, cord prolapse,• Apgar score 7/1’, 8/5’• CPAP FiO240%, Deteriorated during transport from

TN to NICU, FiO260%,→ NTT FiO2100%,IMV rate 40, P 20/5, O2 sat. 50’sCurosurf O2 sat. transiently ↑to 90’s for 5 min. and then ↓to <20’s

• ECHO revealed PPHN• INO 20ppm started with slowly ↑ O2 sat. • INO x 3days, IMV x 4days, CPAP x 85 days,

Discharged at DOL#100

30% of PPHN fail to respond to iNO

It is not the single magic bullet for the complex pathophysiology of PPHN

Medical therapies have received regulatory approval worldwide that target three different pathways:

•the nitric oxide pathway, •the prostacyclin pathway and •the endothelin pathway

the nitric oxide pathway

• Inhaled nitric oxide• Sildenafil citrate, an oral phosphodiestrase type-5 inhibitor,

was approved in 2005 by the FDAselectively inhibit cGMP-specific

phosphodiesterases (type 5) augment the pulmonary vascular response

to endogenous or inhaled nitric oxide.

Mechanism of action of NO

GTP cGMP Relaxation

guanylyl cyclase

NO or NO donor

X Sildenafil(Type 5 phosphodiesterase inhibitor)

Ca++

Oral Sildenafil for Human PPHN

Baquero et al, Pediatrics, 2006

Oxy

gena

tion

Inde

x

**

Sildenafil as a treatment for pulmonary hypertension

• It relaxes pulmonary vascular smooth muscle by inhibiting cyclic guanosine monophosphate (cGMP) binding, cGMP specific phosphodiesterase (type 5, PDE5), which is concentrated in the lungs.

• 0.5 mg/kg q6h, P.O. → 2mg/kg 6 hourly• (T1/2 4 hours)

Intravenous Sildenafil for PPHNSteinhorn et al, J Pediatr, 2009

• Five centers enrolled 36 neonates with PPHN or hypoxemic respiratory failure in eight ‘step up’ treatment groups.– Demographic data for infants:39±2 weeks

gestation– 3.44 ±0.51 kg– 34±17 hours of age at enrollment

• Of the 36 infants, 29 were enrolled while already receiving inhaled NO.

Oxygenation Index Over TimeSteinhorn et al, J Pediatr, 2009

Response to Sildenafil Infusion without iNO Steinhorn et al, J Pediatr, 2009

Intravenous Sildenafil for PPHN

• Loading dose: 0.4mg/kg over 3 hours• Maitenance infusion: 1.6mg/kg/day

Steinhorn et al, J Pediatr, 2009

the prostacyclin pathwayproduced predominantly by endothelial cells and a

potent vasodilator of all vascular beds. most potent endogenous inhibitor of platelet

aggregation cytoprotective and antiproliferative activities. • I.V. epoprostenol -1995 The prostacyclin analogue, • Treprostinil- subcutaneous infusion in 2002, and

intravenous infusion in 2004• the inhaled prostacyclin analogue, Iloprost, was

approved in 2004.

cAMP pathway

cAMP Relaxation

PGI2

X milrinone(Type 3 phosphodiesterase inhibitor, PDE)

Adenylyl cyclase

Inhaled prostacyclin for term infants with PPHN refractory to iNO

Four infants with severe PPHN unresponsive to iNO show improvement with inhaled PGI2. The intravenous form of PGI2 was aerosolized in an alkaline solution through the respiratory circuit. Age at initiation of PGI2 ranged from 1 day to 16 days old and was preceded with iNO for at least 3 hours (range 3hr to 14 days). Within 1 hour of initiation of PGI2, mean PaO2 increased from 57 to 100 (p = 0.06) and within 2 hours, mean OI decreased from 29 to 19 (p<0.05). 3 MAS survived, 1 ACD with transient response and died 6 days later.

The journal of Pediatrics 2002;141:830-2, Kelly LK et. al.

iloprost (Ventavis) inhaled

1mcg → 2.5 mcg →5mcg(10 mcg/ml)

•Dilute with Glycine solution or normal saline to make total volume 2 ml

•Nebulization using Aeroneb (electronic micropump) for 15 min. q30’, 45’ or1hr

•(Half-life 20 – 30 min.)•Monitor vital signs and O2 saturations

MiniHeart Low Flow Nebulizer

Aeroneb electronic micropump

the endothelin pathwayEndothelin-1 (ET-1): ET A receptors- facilitates vasoconstriction and

proliferation of vascular smooth-muscle cells,ET B receptors- principally involved in the clearance of

endothelin, particularly in the vascular beds of the lung and kidney leading to vasodilation and nitric oxide release.

• bosentan, an endothelin ET A /ET B receptor antagonist -2001,

• ambrisentan, the oral ET A selective ERA-2007

• sitaxsentan the oral ET A selective ERA-2007 in the EU.

Endothelin receptor antagonists

• bosentan and sitaxsentanhave been reported to be effective in treating pulmonary hypertension. It remains to be seen if they are safer, more effective or even complementary to sildenafil.

Endothelin-A receptor blockage in porcine pulmonary hypertension

• The authors compared the effects of ET-A receptor blockade in piglets with either hypoxia-induced (FIO2 10%) or GBS-induced (infusion of heat-killed GBS bacteria) pulmonary hypertension.

• Both groups were also treated with iNO. • Pulmonary hypertension induced by hypoxia was

responsive to ETA-blockers while induced by GBS was unresponsive

Pediatric Research 2002; 52:913-921. Ambalavanan N, et. al