Management Practices During Perinatal Respiratory Transition of Very Premature Infants

Abstract

The present review considers some controversial management practices during extremely premature perinatal transition. We focus on perinatal prevention and treatment of respiratory distress syndrome (RDS) in immature infants. New concerns regarding antenatal corticosteroid management have been raised. Many fetuses are only exposed to potential adverse effects of the drug. Hence, the formulation and the dosage may need to be modified. Another challenge is to increase the fraction of the high-risk fetuses that benefit from the drug and to minimize the harmful effects of the drug. On the other hand, boosting anti-inflammatory and anti-microbial properties of surfactant requires further attention. Techniques of prophylactic surfactant administration to extremely immature infants at birth may be further refined. Also, new findings suggest that prophylactic treatment of patent ductus arteriosus (PDA) of a high-risk population rather than later selective closure of PDA may be preferred. The TREOCAPA trial (Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen) evaluates, whether early intravenous paracetamol decreases the serious cardiorespiratory consequences following extremely premature birth. Lastly, is inhaled nitric oxide (iNO) used in excess? According to current evidence, iNO treatment of uncomplicated RDS is not indicated. Considerably less than 10% of all very premature infants are affected by early persistence of pulmonary hypertension (PPHN). According to observational studies, effective ventilation combined with early iNO treatment are effective in management of this previously fatal disease. PPHN is associated with prolonged rupture of fetal membranes and birth asphyxia. The lipopolysaccharide (LPS)-induced immunotolerance and hypoxia-reperfusion-induced oxidant stress may inactivate NO-synthetases in pulmonary arterioles and terminal airways. Prospective trials on iNO in the management of PPHN are indicated. Other pulmonary vasodilators may be considered as comparison drugs or adjunctive drugs. The multidisciplinary challenge is to understand the regulation of pregnancy duration and the factors participating the onset of extremely premature preterm deliveries and respiratory adaptation. Basic research aims to identify deficiencies in maternal and fetal tissues that predispose to very preterm births and deteriorate the respiratory adaptation of immature infants. Better understanding on causes and prevention of extremely preterm births would eventually provide effective antenatal and neonatal management practices required for the intact survival.

Keywords: ductus arteriosus; inhaled nitric oxide; paracetamol; persistence of pulmonary hypertension; prenatal steroid; respiratory distress syndrome; spontaneous premature birth; surfactant therapy.

FIGURE 1

Measurements of plasma concentrations of cortisol and the synthetic steroids in non-pregnant female subjects. Cortisol concentrations are shown starting 24 h before the intramuscular (IM) injections of the following synthetic glucocorticoids: Dexamethasone phosphate (6 mg), Betamethasone acetate (3 mg) + Betamethasone phosphate (3 mg), or Betamethasone phosphate (6 mg). Betamethasone was only half of the single antenatal betamethasone dose. The limit of the synthetic steroid (∼1 ng/ml) known to suppress the endogenous cortisol synthesis is shown by dashed line. As a result of the slow release of intramuscular betamethasone acetate, its concentration in plasma exceeds 1 mg/ml even 4 days after the injection. This is likely to take place in pregnant mothers and since the synthetic steroid passes to the fetal blood, suppression of cortisol synthesis of the fetus and the newborn infant shortly after the birth is anticipated. The data shown is from the study by Jobe et al. (59, 141). Copyright from Springer Nature, and from Wiley Periodicals, Inc.

FIGURE 2

Proposed mechanisms of suppression of nitric oxide (NO) synthesis in the lung as a sketch depicting macrophage (above), endothelial cell (middle), and smooth muscle cell (below). The lack of NO synthesis is proposed to be due to (i) failure of iNOS synthesis due to immunotolerance, associated with inflammatory insults by prolonged rupture of fetal membranes and (ii) oxidant-induced inactivation of endothelial NO synthase (eNOS) involving glutathionylation, resulting in diversion of the NO synthetase (NOS)-catalyzed NO production to superoxide (O₂^∙−) production (uncoupling). Superoxide converts NO to toxic peroxynitrite (ONOO^–). Tetrahydrobiopterin (BH4), an essential co-factor of eNOS, may also be oxidized to BH2 upon inactivation of eNOS during ischemia-reperfusion injury. Phosphodiesterase-5 (PDE5) inhibitors (sildenafil), hydrocortisone (HC; inhibits PDE5 synthesis and the formation of superoxide), superoxide dismutase (SOD; breaks down superoxide), and N-acetylcysteine (NAC; source of cysteine and reduced glutathione) and L-arginine (substrate of NOS) are augmenting the formation and the activity of NO.