Objective To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. Study design A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. Results At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). Conclusions In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. Trial registration ClinicalTrials.gov: NCT01958320.

Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insufficiency occurs when a patient's cortisol response is inadequate for the degree of illness or stress. Numerous studies have documented the existence of relative adrenal insufficiency in critically ill adults, and its association with increased morbidity and mortality. There is increasing evidence that relative adrenal insufficiency may be an etiology for hemodynamic instability and hypotension in the critically ill newborn, but compared with the adult population, there is still a paucity of data in this population. Randomized controlled trials are needed to evaluate the efficacy and safety of glucocorticoids for the treatment of cardiovascular insufficiency due to relative adrenal insufficiency in ill preterm and term newborn infants. Keywords: adrenocorticotropin; ACTH; adrenal insufficiency; corticotrophin-releasing hormone; cortisol; critically ill infants hypothalamic-pituitary-adrenal axis; newborns-full term Introduction Activation of the hypothalamic-pituitary-adrenal (HPA) axis and ultimate release of cortisol are critical in maintaining homeostasis in response to stress. Relative adrenal insufficiency occurs when the HPA axis produces insufficient cortisol for the degree of illness or stress. In some critically ill adult populations, relative adrenal insufficiency is prevalent, 1-4 and is associated with increased morbidity and mortality. 2,3,5 Some studies of glucocorticoid treatment in critically ill adults have shown benefit, with faster reversal of shock and reduction in mortality. 3,[5][6][7][8] Recently, increasing evidence supports the existence of relative adrenal insufficiency in ill newborns, but, similar to other ill populations, there remains no general consensus on which patients should be tested, which tests to use and how to interpret them, which patients should be treated or how they should be treated. 9 The following discussion is an overview of corticosteroid physiology, relative adrenal insufficiency in critically ill populations and evidence of its existence in newborn infants, with proposed underlying

Objective To determine cortisol and adrenocorticotropin (ACTH) responses to critical illness in term and late preterm newborns and examine the relationship of these values to measures of clinical illness, including markers of cardiovascular dysfunction. Study Design In this prospective observational study, we measured ACTH, baseline cortisol, and ACTH-stimulated cortisol concentrations in mechanically ventilated infants ≥ 34 weeks gestational age and <5 postnatal days. ACTH-stimulated cortisol concentrations were also measured in a comparison group of non-critically ill, non mechanically-ventilated infants. The relationship of these values to measures of severity of illness including SNAP (score for neonatal acute physiology) scores, blood pressure and vasopressor initiation was examined. Result Concentrations are presented as median [25th -75th percentile]. Baseline cortisol values in critically ill infants (n=35) were 4.6 mcg/dl [3.0-16.2]; 26 (74%) of these were <15 mcg/dl. ACTH-stimulated cortisol values were not significantly different from the comparison group (41 mcg/dl [30.3-51.8] vs.34.2 mcg/dl [25.2-43.3]). ACTH concentrations in ill infants (n=10) were 12 pg/ml [5.5-19.2]. Neither baseline cortisol, stimulated cortisol nor ACTH increased significantly with increasing severity of illness. 71% of the ill infants received vasopressor therapy for hypotension. Cortisol concentrations in these infants were similar to those infants who did not receive vasopressor therapy. Conclusion The majority of these critically ill newborns had very low cortisol and ACTH values without the expected increase in response to critical illness; however, their response to exogenous ACTH was normal. These results demonstrate that the inadequate response to critical illness in these newborns does not result from adrenal dysfunction. We therefore hypothesize that this is a secondary insufficiency arising from inadequate stimulation of the adrenal gland.

A significant number of hypotensive, mechanically ventilated infants have evidence of inadequate adrenal function. Hydrocortisone therapy resulted in hemodynamic stabilization in this population.