Persistent Pulmonary Hypertension of the Newborn (PPHN)

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by failure of normal pulmonary vascular transition at birth, leading to increased pulmonary vascular resistance, right-to-left shunting, and severe hypoxaemia despite adequate ventilation.

Types of persistent pulmonary hypertension of the newborn

Type of PPHN	Pathophysiology	Causes
Maladaptation	Reflex vasoconstriction of pulmonary arterioles	Perinatal asphyxia, meconium aspiration syndrome (30%), pneumonia, neonatal respiratory distress syndrome (20%), congenital diaphragmatic hernia, hypoxia, acidosis, hypocalcaemia, magnesium, hypothermia
Maldevelopment	Muscularization of pulmonary arterioles	Intrauterine growth restriction (chronic in-utero hypoxia), post-maturity, NSAIDs in pregnancy
Underdevelopment	Decreased pulmonary arterioles	Hypoplastic lungs, congenital diaphragmatic hernia, alveo-capillary dysplasia
Intravascular obstruction	Increased viscosity or obstruction	Polycythemia

Pathophysiology pathways of PPHN

Pathway	Effect	Drugs used to treat
Endothelin	Vasoconstriction	Bosentan
Nitric Oxide – cGMP	Vasodilation	iNO, sildenafil
Prostacyclin-cAMP	Vasodilation	Milrinone, prostaglandins

Risk factors
- Term or post-term baby
- Meconium aspiration syndrome (the most common cause)
- Birth asphyxia
- Sepsis
- Pneumonia
- Maternal diabetes
- NSAIDs or SSRIs during pregnancy
- Smoking
- Congenital diaphragmatic hernia
- Lung hypoplasia
Normal vascular transition at birth
- Lung expansion → reduced pulmonary vascular resistance (PVR)
- Cord clamping → increased systemic vascular resistance (SVR)
- Closure of the ductus areteriosus (DA) and the foramen ovale (PFO)
Pathophysiology
- Pulmonary vascular resistance (PVR) remains high
- Systemic vascular resistance (SVR) is relatively lower than PVR
- This leads to a persistent right-to-left shunt → reduced pulmonary blood flow → hypoxia
Patient History
- Term or post-term neonate
- Severe hypoxia with a relatively normal chest radiograph
Signs and symptoms
- Cyanosis refractory to oxygen
- Labile hypoxia
  - Desaturations occur with handling
- Tachypnoea
- Mild respiratory distress
- Preductal vs postductal SpO2 difference > 5 – 10%
  - Right hand = preductal
  - Foot = post-ductal
- Loud P2
- Tricuspid regurgitation murmur
Investigations
- Chest radiograph:
  - Normal lungs
  - Good lung volume
  - Right heart enlargment
  - May show the underlying disease, e.g., meconium aspiration syndrome or NRDS
- Echocardiography: gold standard. Confirms the diagnosis and excludes a congenital heart defect
  - R to L shunt across a patent ductus arteriosus (PDA) or patent foramen ovale (PFO)
  - Right ventricular dilation
  - Septal flattening
  - Tricuspid regurgitation jet – estimates pulmonary pressure
  - Tricuspid regurgitation and pulmonary regurgitation
- Oxygenation index (OI)
  - 15 = significant disease
  - 20 – 25 = severe disease
  - ≥ 40 = consider ECMO
Treatment
- Minimal handling
- Maintain temperature, glucose, and calcium
- Correct acidosis, hypotension, and anaemia (Hb 15 – 16 g/dL0
- CPAP or mechanical ventilation
- Optimize oxygenation
  - Target SpO2 92 – 97%
  - Target PaO2 50 – 80 mmHg
  - Avoid hyperoxia
- Pulmonary vasodilation
  - Inhaled nitric oxide (iNO) is first-line
  - Sildenafil (PDE-5 inhibitor)
  - Mildrinone (PDE-3 inhibitor)
  - Bosentan (endothelin antagonist)
  - Magnesium sulfate
  - Prostacycline
- Fluids and ionotropes to improve systemic pressure
  - MAP goals of 40 – 45 mmHg
  - This helps to reduce right-to-left shunting
- ECMO rescue therapy if OI ≥ 40 or if there is refractory hypoxia

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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