Postnatal steroid management in preterm infants with evolving bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting extremely preterm infants. Although mechanical ventilation and oxygen requirements in premature infants are identified as inciting mechanisms for inflammation and the development of BPD over time, data now support an array of perinatal events that may stimulate the inflammatory cascade prior to delivery. Corticosteroids, such as dexamethasone and hydrocortisone, have proven beneficial for the prevention and management of BPD postnatally due to their anti-inflammatory characteristics. This review aims to examine the pharmacologic properties of several corticosteroids, appraise the existing evidence for postnatal corticosteroid use in preterm infants, and assess steroid management strategies to ameliorate BPD. Finally, we aim to provide guidance based on clinical experience for managing adrenal suppression resulting from prolonged steroid exposure since this is an area less well-studied.

Fig. 1. Mechanism of corticosteroid effects.

After a glucocorticoid crosses the cell membrane it forms a glucocorticoid-glucocorticoid receptor (GR) complex. This complex is then able to enter the cell nucleus and exert genomic effects that either increase or decrease gene transcription. This complex may also have non-genomic effects by increasing synthesis of annexin A1 or interacting with cell membrane.

Fig. 2. Molecular structure of endogenous cortisol and other synthetic structural derivatives.

The basic structure of cortisol, the body’s endogenous corticosteroid, includes four basic rings (A–D) and several features important for both glucocorticoid and mineralocorticoid activity. The non-planar orientation of the various methyl (CH3) and hydroxyl (OH) groups account for the steroid’s biological activity [5]. Structural components that are critical for both glucocorticoid and mineralocorticoid activity include the 3-ketone group and the 4,5 double bond on ring A. The presence of the 17-hydroxyl group contributes to both the glucocorticoid function and potency. The 11-hydroxyl group is needed for glucocorticoid, but not mineralocorticoid activity.

Fig. 3. As a concept, any study trying to identify adverse associations of steroids needs to consider all steroids to which the infant has been exposed.

Often antenatal steroid exposure is not considered. BPD bronchopulmonary dysplasia, BP blood pressure.

Fig. 4. Hydrocortisone equivalence for protocolized systemic postnatal corticosteroids described in respective studies.

Linafelter has two different cumulative doses: 104 mg/kg represents the amount over 28 days as described by the protocol in the study; *245 mg/kg represents the actual reported median hydrocortisone equivalent used in the babies in that study (prednisolone cumulative dose of 61 mg/kg) [55]. The blue bars/starting dose uses the left vertical axis while the orange line/cumulative dose uses the right vertical axis.

Fig. 5. Hypothalamic-pituitary-adrenal axis.

Cortisol exerts negative feedback on both the hypothalamus and anterior pituitary, leading to decrease in both corticotropin releasing factor (CRF) and adrenocorticotropic hormone (ACTH) predominantly through action on the glucocorticoid receptor (GR). When cortisol levels drop or there is a physiologic need for cortisol release, CRF and ACTH levels rise, stimulating the secretion and production of cortisol by the adrenal gland. Mineralocorticoid receptors (MR) are expressed at low levels in the hypothalamus and anterior pituitary.