Pulmonary hypertension in the newborn- etiology and pathogenesis - PubMed (original) (raw)

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Pulmonary hypertension in the newborn- etiology and pathogenesis

Deepika Sankaran et al. Semin Fetal Neonatal Med. 2022 Aug.

Abstract

A disruption in the well-orchestrated fetal-to-neonatal cardiopulmonary transition at birth results in the clinical conundrum of severe hypoxemic respiratory failure associated with elevated pulmonary vascular resistance (PVR), referred to as persistent pulmonary hypertension of the newborn (PPHN). In the past three decades, the advent of surfactant, newer modalities of ventilation, inhaled nitric oxide, other pulmonary vasodilators, and finally extracorporeal membrane oxygenation (ECMO) have made giant strides in improving the outcomes of infants with PPHN. However, death or the need for ECMO occurs in 10-20% of term infants with PPHN. Better understanding of the etiopathogenesis of PPHN can lead to physiology-driven management strategies. This manuscript reviews the fetal circulation, cardiopulmonary transition at birth, etiology, and pathophysiology of PPHN.

Keywords: Fetal circulation; Hypoxia; Hypoxic respiratory failure; Newborn; Oxygen; Pathophysiology of pulmonary hypertension; Pulmonary hypertension.

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Conflict of interest statement

Declaration of competing interest The authors have no conflicts of interest to disclose.

Figures

Fig. 1.

Cardiopulmonary physiology in the fetus (1A), during transition at birth (1B), and in persistent pulmonary hypertension of the newborn (PPHN) after meconium aspiration (1C). A: Oxygenated blood entering the umbilical vein from the placenta passes via the inferior vena cava (IVC) and is streamed preferentially across the patent foramen ovale (PFO) to the left atrium to enter the systemic circulation ensuring maximal oxygen delivery to the coronary and cerebral circulations. Due to prevailing high pulmonary vascular resistance (PVR) in the fetus, the deoxygenated blood entering the right atrium from the IVC is preferentially streamed to the right ventricle, then right to left across the patent ductus arteriosus (PDA) to the aorta, bypassing the high resistance pulmonary circulation. Due to fluid filled lungs with high PVR and low pulmonary blood flow (QP), there is high pulmonary artery pressure (PAP) and low alveolar oxygen tension (PAO2), and low pulmonary venous return to the left atrium. PCWP: pulmonary capillary wedge pressure. Copyright Satyan Lakshminrusimha B: With the first breath, air enters the lungs increasing the alveolar oxygen tension (PAO2), that in turn causes pulmonary vasodilation with consequent decrease in PVR and increase in QP. This results in reduction in PAP. Cord clamping removes the low resistance placental circulation thus increasing the systemic vascular resistance, changing the direction of shunt across the PDA and PFO to left-to-right, and then closing the PDA and PFO with time. The left-to-right shunt across the PDA and PFO increases PO2 in the pulmonary artery contributing to pulmonary vasodilation. The lungs take over as the organ of gas exchange, and oxygenated blood is delivered by the systemic circulation to the coronary, cerebral and general circulation. Copyright Satyan Lakshminrusimha C: Following meconium aspiration, the alveoli are collapsed (complete obstruction) and hyperinflated (partial obstruction and ball-valve effect). This leads to poor gas exchange in the lungs. Poor alveolar inflation and decreased alveolar tension of oxygen (PAO2) results in persistently elevated PVR and decreased QP. When meconium aspiration occurs in-utero, the pulmonary artery remains constricted and undergoes remodeling. Due to lack of drop in PVR, the shunt across the PFO and PDA remain right-to-left, resulting in deoxygenated blood being delivered to the coronary and cerebral circulations (deoxygenated blood shunted across the PDA and PFO, and minimal oxygenated blood through the decreased pulmonary venous return). Owing to increased workload on the right ventricle (RV) that pumps against a high PVR (increased right ventricular afterload), RV undergoes hypertrophy. Copyright Satyan Lakshminrusimha.

Fig. 2.. Mediators affecting pulmonary vascular resistance.

In the cyclic AMP pathway, cyclooxygenase and PGI synthase actions lead to synthesis of PGI2 (prostacyclin) that acts on its receptor (IP) to activate adenylate cyclase. Adenylate cyclase catalyzes synthesis of cAMP. In the endothelin (ET) pathway, ET-1 acts on the ET-A receptor mediating vasoconstriction. Similarly, calcium ions act through activation of the Rho-kinase pathway and cause vasoconstriction of pulmonary artery smooth muscle cell (PASMC). In the endothelial cell, endogenous nitric oxide synthase is activated by ET effect on ET-B receptor and increases nitric oxide (NO) production. NO activated soluble guanylyl cyclase thus increasing cGMP production. cAMP and cGMP decrease intracellular calcium thus resulting in vasodilation. Phosphodiesterases 3 (PDE 3) and 5 (PDE 5) breakdown aAMP and cGMP to AMP and GMP, respectively. Thus PDE-3 and PDE-5 inhibitors (milrinone and sildenafil, respectively) are used in the management of PPHN. Nitric oxide may oxidize heme iron into ferric form resulting in methhemoglobin formation (MHb), thus decreasing oxygen carrying capacity of hemoglobin. Copyright Satyan Lakshminrusimha.

Fig. 3.. Pathophysiology of PPHN.

Based on pathophysiology, PPHN is classified into primary and secondary PPHN, and secondary is further classified into maladaptation, maldevelopment, underdevelopment (pulmonary hypoplasia) and intravascular obstruction. This illustration lists the various causes in each category. Copyright Satyan Lakshminrusimha.

Fig. 4.

A: Oxygen saturation and arterial oxygen tension in normothermia and hypothermia, adapted from Bushra et al [65] and Rios et al [64]. For the desired target PaO2 of 50–70 mmHg, newborn infants have a preductal SpO2 of 92–95% when they are normothermic, and 95–98% when they are hypothermic. Hypothermia shifts the oxygen dissociation curve to the left. 4B: Effect of asphyxia and therapeutic hypothermia on the pulmonary and systemic circulations. Asphyxia is associated with left and right ventricular dysfunction, pulmonary hypertension with persistent elevation in PVR, and systemic hypotension. Asphyxia-induced acute kidney injury leads to decreased renal clearance of milrinone that may result in further systemic hypotension. Severely asphyxiated newborn infants may have pressure-passive cerebral blood flow. Fluctuations in PaCO2 and blood pressure can cause fluctuations in cerebral blood flow. Therapeutic hypothermia is associated with increased viscosity that can also cause PPHN by intravascular obstruction. Copyright Satyan Lakshminrusimha.

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Pulmonary hypertension in the newborn- etiology and pathogenesis - PubMed (original) (raw)