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Pulmonary hypertension in newborns, iNO therapy & other alternative treatments

Dr. Samir Sheikh
Wednesday, April 19, 2017, 08:00 Hrs  [IST]

Anything which interrupts either the change of fetal circulation to normal adult circulation (postnatal adaptation) or prevents fall in pulmonary pressures leads to pulmonary hypertension. It is a syndrome characterized by common pathophysiologic features including sustained elevation of pulmonary pressures; decreased perfusion of the lungs; and continued fetal circulation and shunting of blood away from lungs through the fetal channels (foramen ovale and ductus arteriosus).

These perturbations happen with injury to lungs, problems of oxygenation or development of lung parenchyma or vessels. The risk factors are divided into maternal and fetal categories. Maternal risk factors are: diabetes mellitus, hypertension and severe anemia.

Fetal risk factors are: perinatal asphyxia, meconium aspiration syndrome, hyaline membrane disease, infant of diabetic mother, pulmonary hypoplasia, diaphragmatic hernia, post-term babies, pneumonia, sepsis, certain syndromic association.

Despite extensive search for risk factor or causes, reason remains unknown in approximately 15 per cent babies.

In the antenatal period, mother does the job of oxygenation and the fetal lungs undergo development but do not take part in oxygenation of blood. Hence, the blood, which is destined to go in lungs after birth, gets shunted before it reaches lungs through PDA (patent ductus arteriosus)               because of very high pressure in pulmonary blood vessels, goes to the mother and gets oxygenated. This is normal circulation in fetus which gets interrupted after birth because of fall in pulmonary blood pressure. Everyone undergoes this change at birth. If baby continues to have fetal circulation because of high pulmonary pressure, baby develops pulmonary hypertension. Every baby born is at risk of it but approximately moderate or severe pulmonary hypertension affects up to 2 to 6 per 1000 live births, and complicates the course of 10-20 per cent of all newborns admitted to neonatal intensive care. It is also responsible for an 8 per cent to 10 per cent risk of death and approximately 25 per cent risk of long-term neuro-development morbidity. PDA is a heart problem that occurs soon after birth in some babies. The cause of PDA is not known, but genetics might play a role. PDA is more common in premature babies and it affects twice as many girls as boys.

Pulmonary hypertension is normal phenomenon in intrauterine period. To continue the life, pulmonary pressure has to fall down and the baby has to shift to adult circulation from persistent fetal circulation. Pulmonary hypertension is completely curable. Untreated cases become incompatible with life. Certain childhood pulmonary morbidities are found to be common with babies who suffered from pulmonary hypertension in neonatal period but generally child outgrows these morbidities.

Nitric oxide (NO) is the gas molecule produced by the body by the conversion of arginine to citrulline by the enzyme nitric oxide synthase (NOS). The NOS present in the inner most lining of pulmonary blood vessels (endothelial NOS) is regarded as the most important regulator of nitric oxide production. The generated nitric oxide readily diffuses into adjacent vascular smooth muscle cells and mediates the vasodilatory pathway. With increasing gestation, capacity to generate endogenous nitric oxide increases to make fetus ready for postnatal adaptation.

Inhaled nitric oxide (iNO)
For a drug to be effective for pulmonary hypertension, it has to be as selective as possible for pulmonary blood vessels. Inhaled nitric oxide (iNO) has many features of an ideal pulmonary vasodilator, including rapid onset of action, typically within minutes. Since, the mechanism for synthesis of endogenous nitric oxide is dysfunctional in pulmonary hypertension, inhaled nitric oxide works as perfect replacement. It readily diffuses via pulmonary endothelium in to smooth muscles of pulmonary blood vessels because of its lipophilic nature. Once in the bloodstream, nitric oxide binds avidly to hemoglobin, which is subsequently reduced by methemoglobin reductase and excreted.

The safety and efficacy of inhaled nitric oxide for pulmonary hypertension have been well studied through large placebo-controlled trials. In most of these, the use of extracorporeal life support (ECMO) or death served as a primary endpoint. Approximately 60-70 per cent of the inhaled nitric oxide treated infants had improvement in PaO2 (PaO2 is the partial pressure of oxygen dissolved in the blood) in comparison to controls. It also significantly decreased the oxygenation index. The incidence of death or need for ECMO was significantly reduced by treatment with inhaled nitric oxide (relative risk 0.71 compared to controls) with the majority of the improvement seen in the reduction in the need for ECMO. Approximately 20-25 per cent babies do not respond to inhaled nitric oxide.

Therapies to treat pulmonary hypertension
The primary aim of therapy in pulmonary hypertension is selective pulmonary vasodilatation. In all cases, the importance of supportive care cannot be undermined. It includes optimization of lung function and oxygen delivery, and support of cardiac function. Optimal lung inflation NS recruitment of alveoli is essential because pulmonary vascular resistance increases with either under expansion or over expansion of lungs independent of lung disease. The use of lung recruitment strategies, such as high frequency ventilation and surfactant administration, is important in babies with lung parenchymal disease. Correction of acidosis and avoidance of hypoxemia are important because both stimuli promote pulmonary vasoconstriction. Maintaining a normal hematocrit is also important to ensure adequate oxygen delivery to tissues. Other drugs used for pulmonary hypertension are sildenafil, magnesium sulfate, bosentan, prostacycline and milrinone.

Initial trials using inhaled nitric oxide was started in early 1990s and there were lot of many trials on it but failed to show reduction in mortality. Results started becoming better with incorporation of advanced ventilatory techniques like high frequency ventilation and use of surfactant. Understanding of pulmonary pathophysiology has played a major role in improving the outcomes with inhaled nitric oxide. In India, it has been used since early years of this millennium.

Side effect of inhaled nitric oxide therapy
Nitric oxide is a free radical and gets converted to nitrogen dioxide on combining with oxygen. The same reaction takes place in environment and in blood. Nitric oxide avidly binds to hemoglobin in blood which results in the production of methaemoglobin. This is not in itself toxic, but methaemoglobin is not able to carry oxygen. Therefore, high levels of methaemoglobin will reduce the oxygen carrying capacity of the blood.

(Author is consultant, neonatology, Wockhardt Hospital)


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