Case 1: A premature infant with apneic spells

A female infant was born at 25 weeks, three days’ gestational age with a birth weight of 820 g. The issues encountered during her stay at a tertiary-level neonatal intensive care unit (NICU) included prematurity, respiratory distress syndrome, chronic lung disease (CLD), patent ductus arteriosis, a single course of treatment with indomethacin, hypoglycemia, two red blood cell infusions, grade 1 intraventricular hemorrhage, mild periventricular leukomalacia and retinopathy of prematurity. Her respiratory history included three doses of surfactant, high-frequency oscillation and eventual extubation on day 7 of life to nasal prong continuous positive airway pressure. No systemic steroids were administered for extubation. On day 9 of life, the patient was started on inhaled nebulized budesonide 500 μg twice daily. She was initially on high-flow oxygen, and was then maintained on low-flow oxygen and, eventually, room air. On day 59 of life, the patient was transferred from the tertiary-level NICU to a secondary-level NICU (level 2C). Budesonide was weaned over a seven-day period. During this period, she became unwell, with increasing signs of respiratory distress, apneic spells and a urine sample obtained by catheterization positive for Enterococcus species and Escherichia coli. Urosepsis was suspected and treatment with intravenous fluids and intravenous antibiotics was commenced. The infant received 25 mL/min supplementary oxygen for 48 h and was then transitioned to room air. Fluid boluses for hypotension were not required, and the infant eventually recovered from the acute episode. Blood and cerebrospinal fluid cultures were negative for bacterial growth. A laboratory test was conducted due to clinical suspicion and revealed the underlying diagnosis. Morning serum cortisol level was measured at 08:00 and was found to be undetectable. Repeat measurements in samples obtained on the afternoon of the same day were only minimally increased and were below the laboratory reference range (33 nmol/L, reference range 85 nmol/L to 360 nmol/L). Importantly, there were no clinical signs of adrenal suppression or excess exogenous corticosteroid use. The morning serum cortisol level was sufficiently low that an adrenocorticotropic hormone (ACTH) stimulation test was not performed. The infant was treated with stress-dose hydrocortisone for significant sepsis, consisting of three times the maintenance dose required (calculated in dose/m2). Steroid therapy was discontinued following the acute episode and a repeat morning serum cortisol measurement at three months of age was found to be within normal limits (156 nmol/L). The child was diagnosed with neonatal hypothalamic-pituitary-adrenal suppression secondary to inhaled corticosteroid administration. The parents were provided with a written action plan for stress-dose steroids. Postnatal corticosteroids have been used for the prevention and treatment of neonatal CLD (also known as bronchopulmonary dysplasia), a significant cause of morbidity and mortality in preterm infants. Due to concerns regarding poor neurodevelop-mental outcome, use of early postnatal dexamethasone for preventing CLD in very low-birth-weight infants is not recommended. After seven days of life, dexamethasone has been shown to decrease the rate of CLD at 36 weeks’ postmenstrual age with less impact on neurodevelopmental outcome. However, no studies have examined whether the benefits of corticosteroids in infants at risk for CLD outweigh the potential adverse systemic effects. Inhaled corticosteroids may be an alternative to dexamethasone for treating infants with severe CLD due to their potential for fewer adverse effects. Despite this advantage, the literature has not demonstrated the effectiveness of inhaled steroids for the treatment or prevention of CLD (1). Moreover, a recent position statement from the Canadian Paediatric Society indicates that clinicians should be aware of the possibility of adrenal suppression in infants who are treated with corticosteroids (1). Level 2 NICUs should be aware of this possibility when accepting transfer of care from tertiary NICUs that use corticosteroids for any reason. Current recommendations for the monitoring of adrenal suppression include measuring morning serum cortisol levels in infants being treated with high-dose corticosteroids. Characterization of high, medium or low doses of inhaled corticosteroids in children younger than five years of age is not described in the Canadian guidelines. However, the Global Initiative for Asthma states that a high dose is >1000 μg/day of inhaled budesonide. Findings of low morning serum cortisol levels should be followed by a low-dose (1 μg) ACTH stimulation test, a dynamic test of hypothalamic-pituitary-adrenal axis function. Should the ACTH stimulation test fail to show a significant response in cortisol levels, an action plan that includes the use of stress-dose steroids at times of illness and surgery is required. Importantly, evidence of suppression is not uncommon, and recent studies have shown concern for hypothalamic-pituitary-adrenal axis suppression with low- and medium-dose inhaled corticosteroids (2). Most secondary-level NICUs are not involved in initiating treatment with steroids for CLD. However, many of these centres would receive infants in reverse transfer. Although this infant was treated with inhaled corticosteroids, any infant with a prolonged treatment strategy involving any form of corticosteroid may experience suppression of the hypothalamic-pituitary-adrenal axis. The implication is that, when under physiological stress as part of an intercurrent illness, the severity of the clinical presentation may be explained by a failure to mount a cortisol response. In extreme situations, such presentations (including sepsis, necrotizing enterocolitis or apnea) can lead to adrenal crisis, and possibly coma and death. Therefore, in infants with evidence of suppression, administration of stress-dose and possibly maintenance-dose steroids should be considered. Furthermore, it is important to provide follow-up for these families, including a written action plan while in the level 2 NICU and on discharge home. This action plan should continue for three to six months unless laboratory evidence is obtained indicating that the infant is no longer suppressed. Inhaled corticosteroids can cause adrenal suppression. Consider adrenal suppression in any infant in the NICU who has been exposed to long-term corticosteroids. Have a written action plan, both in the NICU and for home use, for infants who have been on long-term corticosteroids.

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