Erika Fernandez

Relative adrenal insufficiency in the preterm and term infant

Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insufficiency occurs when a patients 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.

Prevalence of Low Cortisol Values in Term and Near-Term Infants with Vasopressor-Resistant Hypotension

OBJECTIVE:To determine the prevalence of low cortisol values and to evaluate clinical responses to hydrocortisone in ill term and near-term newborns.STUDY DESIGN:Retrospective cohort study including infants ≥35 weeks gestational age who were mechanically ventilated, received vasopressor therapy, and had a cortisol concentration obtained for evaluation of vasopressor-resistant hypotension. In those infants treated with hydrocortisone, physiologic responses were evaluated and correlated with cortisol values (<15 vs ≥15 μg/dl).RESULTS:A total of 32 infants had cortisol values obtained; 18 (56%) were <15 μg/dl. In all, 21 infants were treated with hydrocortisone of whom 13 had cortisol values <15 μg/dl. These 13 infants showed decreased heart rate, dopamine support and fluid bolus requirements after treatment, compared to infants with values ≥15 μg/dl (n=8).CONCLUSIONS:A significant number of hypotensive, mechanically ventilated infants have evidence of inadequate adrenal function. Hydrocortisone therapy resulted in hemodynamic stabilization in this population.

ACTH and cortisol response to critical illness in term and late preterm newborns

Objective:To determine cortisol and adrenocorticotropic hormone (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 to 75th percentile). Baseline cortisol values in critically ill infants (n=35) were 4.6 μg per 100 ml (3.0 to 16.2); 26 (74%) of these were <15 μg per 100 ml. ACTH-stimulated cortisol values were not significantly different from the comparison group (41 μg per 100 ml (30.3 to 51.8) vs 34.2 μg per 100 ml (25.2 to 43.3)). ACTH concentrations in ill infants (n=10) were 12 pgml−1 (5.5 to 19.2). None of baseline cortisol, stimulated cortisol and ACTH increased significantly with increasing severity of illness. Of the ill infants, 71% 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.

DISTRIBUTION AND ORIGIN OF NEUROPEPTIDE Y-IMMUNOREACTIVE FIBERS IN THE PENIS OF THE RAT

SummaryThe present study investigated the distribution of neuropeptide Y-immunoreactive fibers to the penis of the rat. In the corpora cavernosa penis, a dense plexus of fibers was asociated with arteries, intrinsic cavernosal muscle, and veins including the deep dorsal vein. In the corpus spongiosum, immunoreactive fibers were present around vascular smooth muscle and at the periphery of the acini of the paraurethral glands. Immunohistochemistry of penile neurons identified by retrograde tracer injection into the penis indicates that about 5% of the penile neurons in the pelvic plexus contained the neuropeptide while larger percentages of penile neurons in the sympathetic chains were immunoreactive for neuropeptide Y. Chemical and surgical sympathectomy greatly reduced the neuropeptide Y- and catecholamine-containing fibers in the erectile tissue but had no clear effect on the neuropeptide Y fibers around the paraurethral glands; a tissue that is not innervated by adrenergic fibers. It is concluded that (1) the widespread distribution of neuropeptide Y indicates that it may function in the control of penile blood flow, (2) with the possible exception of the paraurethral glands, the sympathetic chain is the most likely source of neuropeptide Y fibers in both erectile bodies of the penis, and (3) this peptide may play a role in the secretory functions of the paraurethral glands.

Adrenal Function in Newborns Undergoing Surgery

Objective:To measure cortisol, adrenocorticotropic hormone (ACTH)-stimulated cortisol and ACTH values in the newborn intensive care unit-admitted newborn infants within 48 h before surgery and to describe the relationship of these values to measures of clinical illness before and after surgery.Study Design:In this prospective observational study, we measured baseline and ACTH-stimulated cortisol concentrations within 48 h before surgery in newborn infants <44 weeks postmenstrual age and examined the relationship of these values to measures of illness severity both before and after surgery, including the score for neonatal acute physiology (SNAP) and use of vasopressors. ACTH concentrations were measured in a subset of the infants.Result:Twenty-five infants were enrolled and had median (25th to 75th percentile) baseline and ACTH-stimulated cortisol values of 7.1 (3.5 to 11.1) and 40.4 mcg per 100 ml (22.6 to 50.6). Preterm infants had significantly lower ACTH-stimulated cortisol values (median 21.6 vs 44.7 mcg per 100 ml). There was no correlation between any of these values and either the presurgical or postsurgical measures of illness severity, nor the increase in SNAP after surgery. Infants receiving vasopressors perioperatively had lower median ACTH-stimulated cortisol values (22.6 vs 44.7 mcg per 100 ml).Conclusion:Presurgical cortisol values do not predict clinical response to surgical stress as measured by severity of illness scores but lower values were associated with vasopressor therapy. Further investigation would be required to determine how cortisol values are related to outcome and whether perioperative glucocorticoid supplementation would be beneficial in this population.

Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants

OBJECTIVE The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions. STUDY DESIGN Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP) < GA; (2) MAP < GA + signs of inadequate perfusion; (3) any therapy for CVI; or (4) inotropic therapy. Short-term outcomes included death, days on ventilation, oxygen, and to full feedings and discharge. RESULTS Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes, and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotropic therapy was associated with increased mortality (11.1 vs. 1.3%; p < 0.05). CONCLUSION More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants

Objective:To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study Design:The original study was a multicenter RCT. Eligibility: ⩾34 weeks’ gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.Results:Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.Conclusion:Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Definitions of Cardiovascular Insufficiency and Relation to Outcomes in Critically Ill Newborn Infants

BACKGROUND We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. OBJECTIVE This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. STUDY DESIGN The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. RESULTS All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. CONCLUSIONS The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age

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.