Persistent Pulmonary Hypertension of Newborn(PPHN):Strategy for Diagnosis & Treatment Dr. Nargis Ara Begum Consultant Neonatology United Hospital
Overview • Background • Fetal and transitional neonatal circulation • Pathophysiology of PPHN • Risk factors &Conditions associated with PPHN • Clinical Presentation • Diagnosis • Management • Outcome,Prognosis & Follow-up • Outcome in our center
Background New born with persistent pulmonary hypertension is a medical emergency with very high morbidity and mortality. It is therefore, essential to understand the etiopathogenesis, methods of diagnosis, monitoring and available treatment modalities to ensure better outcome of this critical problem.
History of PPHN 1628 : 1 st describe by Willim Harvey as : UNRIPE BIRTH OF MANKIND 1969: Gersony et al - as persistent fetal circulation Current name : Persistent pulmonary hypertension in newborn
What is PPHN ? Persistent pulmonary hypertension of the newborn (PPHN) is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left shunting of blood.
Epidemiology • Incidence 1-6/1000 live birth • Most common in term and near term • Mortality nearly 40%(in absence of ECMO), 10-20 %(ECMO) • Imp morbidity severe handicap , ICH, deafness(>20%) Source: M.T.R.Roofthooft et al, pulmonary medicine, 2011.
Fetal Circulation
Normal Pulmonary Vascular Transition In utero: – Pulmonary pressures are equivalent to systemic pressures due to elevated pulmonary vascular resistance (PVR). – Only 5% to 10% of cardiac output goes through the lungs.
In utero high pulm vascular tone Compression of pulm arterioles by fluid filled alveoli. Presence of alveol & arteriolar oxygen tensions. Relative lack of vasodilators (NO, PGI2). Elevated level of vasoconstrictor endothelin-1 & thromboxane.
No Pathway Ligand (ATP,VEGF) Oxygen, estrogen Receptor Endothelium eNOS L-Citrulline L-Arginine NO Smooth Muscle GTP Guan Cyclase GMP cGMP Phosphodiesterases
Prostacyclin Pathway Ligand (ATP etc) Oxygen Receptor Lung distension Endothelium COX, PGI2 synthase Prostaglandins Arachidonoic acid PGI2 Smooth Muscle ATP Aden Cyclase AMP cAMP Phosphodiesterases
What happens at birth? • The change from fetal to postnatal circulation happens very quickly • Changes are initiated by baby’s first breath • Pulmonary arterial pressure decrease 50% of systemic pressure • Pulmonary blood flow increased to 10 folds pulm vascular tone –maintained by(distens of the lung and rising PO2 , and oxygenation simulates the activity of eNOS and COX-1 directly.)
TRANSITIONAL CIRCULATION: AT BIRTH Lung expansion causes establishment of adequate alveolar • ventilation and oxygenation, and successful clearance of fetal lung fluid Rapid fall in PVR • Removal of the placenta, the catechol surge , cold env Increase in SVR Shunt through DA reverses & becomes L to R.
FACTORS AFFECTING PVR Lower PVR: Increase PVR: • Oxygen, nitric oxide • Hypoxia • Prostacyclin, PG E1, D2 • Acidosis • Adenosine • Endothelin-1 • Magnesium • Eukotrienes, thromboxanes • Bradykinins • Platelet activating factors • Atrial natriuretic factor • Prostaglandin F2- alpha • Alkalosis • Alpha-adrenergic stimulation • Histamine • Calcium channel activation • Acetylcholine • Beta-adrenergic stimulation • Potassium channel activation
Pathophysiology
Risk Factors • Male gender • African or Asian maternal race • Pre-conception maternal overweight • Maternal diabetes, Maternal asthma • Chorioamnionitis • Antenatal exposure to SSRIs, NSAIDs • Infection(mainly GroupB Streptococcus) • Hypothermia • Hypocalcemia • Polycythemia • Late preterm and large for gestational age • IUGR
Classification 1. Parenchymal lung disease (meconium aspiration syndrome, respiratory distress syndrome, sepsis)- Maladaptation 2. Idiopathic (or "black-lung") /Maldevelopment 3. Pulmonary hypoplasia (as seen in congenital diaphragmatic hernia)-Underdevelopment.
Pathogenesis of PPHN Intrauterine Injury Hemodynamic Stress Chronic Stress Inflammation Other (genetic) Developing Lung Circulation Chronic IU hypoxia Idiopathic PPHN Altered Vascular Structure Vascular Growth ↑ SMC Proliferation ↓ Angiogenesis Altered Extracellular Matrix ↓ Alveolarization ? Adventitial thickening Abnormal Vascular Reactivity Pulmonary hypoplasia ↓ Vasodilators (NO, PGI2, Adenosine) CDH ↑ Vasoconstrictors (ET1, LT, TBX, PAF) Enhanced Myogenic Tone RDS, MAS, GBS
Idiopathic PPHN • Idiopathic (or "black lung") PPHN is most common in term and near-term newborns. Remodeling of the pulmonary vasculature- vessel wall thickening and smooth muscle hyperplasia. • constriction of the fetal DA in utero from exposure to NSAIDs, Exposure to SSRI • reactive oxygen species (ROS) ,Thrx, endothelin - the vasoconstriction and vascular remodeling. • genetic susceptibility, Down Syndrome
Meconium Aspiration Syndrome • Mechanism of respiratory distress leading to PPHN include – blockage of the airway – inactivation of surfactant – direct damage to the lung parenchyma – atelectasis & V-Q mismatch
Perinatal Asphyxia • In response to asphyxia in utero-fetus directs blood flow to vital organs(heart, brain, adrenals). This leads to vasoconstriction of non vital vascular bed including pulm bed. • Surfactant inactivation • Cardiac dysfunction
Respiratory Distress Syndrome (RDS) • Surfactant deficiency •VQ mismatch
Congenital Diaphragmatic Hernia (CDH) • Pulmonary hypoplasia and abnormal vascular development with – Decreased bronchial and pulmonary arterial branching – Pulmonary arterial muscle hyperplasia leading to PPHN
Clinical Presentation • Most present within 1st 24 hours of life with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis, low apgar scores • There may be meconium staining of skin and nails, which may be indicative of intrauterine stress. • Differential cyanosis may appear in severe cases (with a pink upper body and a cyanotic lower body)
Clinical Findings • A prominent RV impulse and a single and loud S2 • Occasional gallop rhythm (from myocardial dysfunction) and a harsh regurgitant systolic murmur of TR may be audible. • Breath sounds may be normal (If pneumonia or meconium staining exists, crackles or wheezes may be present) • Severe cases of myocardial dysfunction may manifest with systemic hypotension.
Pulse Oximetry • A difference >10% between the pre- and postductal (right thumb and either great toe) oxygen saturation (d/t R L shunt through PDA) • However, absence of a pre- and postductal gradient in oxygenation does not exclude the diagnosis of PPHN, since right-to-left shunting can occur predominantly through the foramen ovale rather than the PDA.
Investigation • ABG, Hyperoxia test-Obsolate • BNP • CXR • Echo
Arterial Blood Gas Arterial blood gas- PaO2 gradient of > 20 mmHg between pre-ductal (upper extremity or head) and post-ductal (lower extremity or abdomen) ABGs
Hyperoxia Test To distinguish PPHN & CHD, from parenchymal lung disease Give 100% O2 x 10-15 min. PPHN or CHD = PaO2 < 100 mmHg Parenchymal = PaO2 >100 mmHg ( CHD more or less ruled out )
Diagnosis • Consider PPHN when hypoxemia is out of proportion to the degree of parenchymal lung disease and there is no evidence of cyanotic CHD. • Echo- diagnostic
Echocardiogram • Gold standard Level & direction of shunt Estimation of PAP
Assessment of severity of PPHN using oxygenation index(OI) Oxygen Index(OI)used to assess the severity of hypoxemia in PPHN and to guide the timing of interventions such as iNO administration or ECMO support. • OI = [mean airway pressure x FiO2 ÷ PaO2] x 100 • OI>25-iNO • OI>40-ECMO ( high OI indicates severe hypoxemic respiratory failure)
Severity of PPHN • Patients with OI ≥ 25 should receive care in a center where high-frequency oscillatory ventilation (HFOV), iNO, and ECMO are readily available • In patients with OI <25, general supportive care is typically adequate and no further invasive intervention is usually required
MANAGEMENT
Aims of Management The treatment strategy for PPHN aimed at- Lower pulmonary vascular resistance. Maintain systemic blood pressure Reverse right-to-left shunting. Improve arteriolar oxygen saturation and oxygen delivery to the tissues. Minimize barotrauma & Ensure adequate sedation and pain relief.
General Management • Minimum handling/stimulation of the newborn. • Minimal use of invasive procedures. • Continuous monitoring of oxygenation, blood pressure & perfusion. • Maintaining of normal body temperature. • Nutritional support. • Correction of electrolytes & glucose abnormalities. • Correction of metabolic acidosis.
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