Kristi Watterberg - Academia.edu (original) (raw)
Papers by Kristi Watterberg
JAMA Network Open
ImportanceExtremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher ... more ImportanceExtremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.ObjectiveTo determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.Design, Setting, and ParticipantsThis secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at l...
Pediatric Research, 2018
BACKGROUND: Low birth weight in term-born individuals correlates with adverse cardiometabolic out... more BACKGROUND: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children. METHODS: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30′ later, evening). RESULTS: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01). CONCLUSION: Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).
JAMA, Oct 23, 2018
Previous studies of myo-inositol in preterm infants with respiratory distress found reduced sever... more Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then e...
Journal of Perinatology, 2017
Objective-To analyze reasons for low enrollment in an RCT of the effect of hydrocortisone for car... more Objective-To analyze reasons for low enrollment in an 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° 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. Result-257 of 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.
Pediatric research, Jan 18, 2017
Extremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the... more Extremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the U.S., yet these infants are focus of most published research. Moderately preterm neonates (MPT, 29-33(6/7) weeks), are an understudied group of high-risk infants. Objective: To determine the neonatal outcomes of MPT across the gestational age spectrum, and to compare these to EPT. A prospective observational cohort was formed in 18 Level 3-4 NICUs in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT admitted to NICUs, and all EPT born at sites between January 2012 and November 2013. Antenatal characteristics, and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses. MPT infants experienced morbidities similar to, although at lower rates, than EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. CNS injury occurred including intraventricu...
Pediatric Research, 2016
Articles Clinical Investigation nature publishing group Background: Preterm infants with respirat... more Articles Clinical Investigation nature publishing group Background: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. Methods: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. results: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. conclusion: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial. r etinopathy of prematurity (ROP) is a common problem worldwide among preterm infants, often leading to vision impairment or blindness (1). Hallman reported two trials of postnatal inositol treatment of preterms with RDS to support phosphatidylinositol in surfactant synthesis, and both trials demonstrated improved RDS and a lower incidence of death or BPD, and ROP (2,3). Inositol is an important component of surfactant, and essential intracellularly as phosphoinositides. Howlett concluded in a Cochrane metaanalysis of inositol in preterm infants, "that a multi-center, randomized controlled trial of appropriate size is warranted to confirm these findings" (4). We reported the pharmacokinetics (PK) of a single dose of i.v. inositol in preterm infants at doses of 60 or 120 mg/ kg, and found the half-life was 5.22 h, with large urine losses, particularly in the first 12 h after dosing (5). Our three goals were to identify a daily dose to achieve serum levels similar to those reported by Hallman, [170 mg/l (994 µmol/l) at 8-9 d for infants given 160 mg/kg/d, and an approximate mean value over the first week of life of 135 mg/l (750µmol/l) when receiving 80 mg/kg/d (2,6)]; to learn if divided doses would reduce urine losses; and to assure safety with up to 10 wk of treatment. We examined the safety and pharmacokinetics (PK) of inositol given at three dose levels compared with placebo for up to 10 wk, both i.v. and enteral (#NCT01030575). This time frame was chosen to support inositol levels throughout the postpreterm delivery period when most retinal vessel growth normally occurs within the high inositol, in-utero environment (7,8). RESULTS From January to October 2010, 125 infants ≤29 wk gestation were randomized and 122 received treatment during the time
BMC medical research methodology, Jan 12, 2006
The benefit-risk ratio has been proposed to measure the tradeoff between benefits and risks of tw... more The benefit-risk ratio has been proposed to measure the tradeoff between benefits and risks of two therapies for a single binary measure of efficacy and a single adverse event. The ratio is calculated from the difference in risk and difference in benefit between therapies. Small sample sizes or expected differences in benefit or risk can lead to no solution or problematic solutions for confidence intervals. Alternatively, using the joint distribution of benefit and risk, confidence regions for the differences in risk and benefit can be constructed in the benefit-risk plane. The information in the joint distribution can be summarized by choosing regions of interest in this plane. Using Bayesian methodology provides a very flexible framework for summarizing information in the joint distribution. Data from a National Institute of Child Health & Human Development trial of hydrocortisone illustrate the construction of confidence regions and regions of interest in the benefit-risk plane, ...
Pediatrics, 2008
OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to... more OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes.METHODS. Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile.RESULTS. Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at...
Pediatrics, 2004
Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response ... more Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%).Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, de...
Pediatrics, 2010
OBJECTIVE:This report presents data from the Eunice Kennedy Shriver National Institute of Child H... more OBJECTIVE:This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).METHODS:Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.RESULTS:Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respirato...
Pediatrics, 2007
BACKGROUND. Low cortisol concentrations in premature infants have been correlated with increased ... more BACKGROUND. Low cortisol concentrations in premature infants have been correlated with increased severity of illness, hypotension, mortality, and development of bronchopulmonary dysplasia. A total of 360 mechanically ventilated infants with a birth weight of 500 to 999 g were enrolled in a randomized, multicenter trial of prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia. Mortality and bronchopulmonary dysplasia were decreased in the hydrocortisone-treated patients exposed to chorioamnionitis. We now report outcomes at 18 to 22 months' corrected age.PATIENTS AND METHODS. Surviving infants were evaluated with standardized neurologic examination and Bayley Scales of Infant Development-II. Neurodevelopmental impairment was defined as a Mental Developmental Index or Psychomotor Developmental Index of <70, cerebral palsy, blindness or deafness.RESULTS. A total of 252 (87%) of 291 survivors were evaluated. Cerebral palsy was diagnosed in 13% of hydroc...
Pediatric Research, 2001
Premature infants have higher cortisol precursor concentrations than term infants; however, many ... more Premature infants have higher cortisol precursor concentrations than term infants; however, many sick preterm infants have surprisingly low cortisol concentrations. Those who develop chronic lung disease (CLD) have lower cortisol values than those who recover. We hypothesized that some infants have a decreased ability to synthesize cortisol, leading to physiologic disruptions including amplified inflammatory responses, thereby resulting in CLD. We measured cortisol, 11-deoxycortisol, 17hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone sulfate, and ACTH in 40 extremely low birth weight infants enrolled in a study of low-dose hydrocortisone therapy to prevent CLD. Thirty-four infants survived and 15 developed CLD. Hydrocortisone therapy did not suppress ACTH or any measured steroid value. Before study (Ͻ48 h of life), 17-OH progesterone was higher in CLD infants, as was the ratio of 17-OH progesterone to 11-deoxycortisol. On d 15-19 (Ն72 h after end of therapy), basal and stimulated cortisol concentrations were lower in CLD infants. In contrast, the basal ratio of 11-deoxycortisol to cortisol was higher in CLD infants, as were stimulated values of 17-OH progesterone and stimulated ratios of 17-OH progesterone to 11-deoxycortisol and 11-deoxycortisol to cortisol. Thus, infants who developed CLD had lower basal and stimulated cortisol values, but elevated cortisol precursors and precursor to product ratios, compared with infants who recovered. These data support the hypothesis that these immature infants have a decreased capacity to synthesize cortisol, which may lead to a relative adrenal insufficiency in the face of significant illness.
Journal of Perinatology, 2010
Objective: To measure cortisol, adrenocorticotropic hormone (ACTH)stimulated cortisol and ACTH va... more 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.
Journal of Perinatology, 2009
Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insuffi... more 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.
Journal of Perinatology, 2008
Objective-To determine cortisol and adrenocorticotropin (ACTH) responses to critical illness in t... more 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 [25 th-75 th 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. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Journal of Perinatology, 2009
Objective: Both excess and insufficient levels of glucocorticoid in extremely low birth weight (E... more Objective: Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment. Study Design: As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile. Result: Median cortisol value was 16.0 mg per 100 ml at baseline for all infants, and 13.1 mg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia. Conclusion: Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone.
Journal of Perinatology, 2011
Objective: For infants born with extremely low birth weight (ELBW), we examined the (1) correlati... more Objective: For infants born with extremely low birth weight (ELBW), we examined the (1) correlation between results on the Ages and Stages Questionnaire (ASQ) and the Bayley Scales of Infant Development-II (BSID-II) at 18 to 22 months corrected age; (2) degree to which earlier ASQ assessments predict later BSID-II results; (3) impact of ASQ use on follow-up study return rates. Study Design: ASQ data were collected at 4, 8, 12 and 18 to 22 months corrected age. The BSID-II was completed at 18 to 22 months corrected age. ASQ and BSID-II 18 to 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses. Result: ASQ sensitivity and specificity at 18 to 22 months were 73 and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results. Conclusion: For extremely low birth weight infant assessment, the ASQ cannot substitute for the BSID-II, but seems to improve tracking success.
The Journal of Pediatrics, 2012
Objective-To assess the feasibility of a randomized placebo controlled trial (RCT) of blood press... more Objective-To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants. Study design-This was a prospective pilot RCT of infants 23 0/7-26 6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
The Journal of Pediatrics, 2012
Objective-To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequen... more Objective-To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants. Study design-This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). Results-136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08-0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes. Conclusions-Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
The Journal of Clinical Endocrinology & Metabolism, 2005
Context: Various cosyntropin doses are used to test adrenal function in premature infants, withou... more Context: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. Objective: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. Design: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. Setting: The setting was nine newborn intensive care units. Patients: The patients included infants with 500-999 g birth weight. Intervention: The drug used was cosyntropin, at 1.0 or 0.1 g/kg, given between 18 and 28 d of birth. Main Outcome Measure: We measured the cortisol response to cosyntropin. Results: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 g/kg, yielded higher cortisol values (P Ͻ 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P ϭ 0.02), infants receiving enteral nutrition vs. not (P Ͻ 0.001), infants exposed to chorioamnionitis vs. not (P ϭ 0.04), and those receiving mechanical ventilation vs. not (P ϭ 0.02), as well as a positive correlation with fetal growth (P ϭ 0.03). A response curve for the 1.0-g/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 g/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. Conclusions: A cosyntropin dose of 0.1 g/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 g/kg cosyntropin to test adrenal function in these infants.
JAMA Network Open
ImportanceExtremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher ... more ImportanceExtremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.ObjectiveTo determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.Design, Setting, and ParticipantsThis secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at l...
Pediatric Research, 2018
BACKGROUND: Low birth weight in term-born individuals correlates with adverse cardiometabolic out... more BACKGROUND: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children. METHODS: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30′ later, evening). RESULTS: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01). CONCLUSION: Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).
JAMA, Oct 23, 2018
Previous studies of myo-inositol in preterm infants with respiratory distress found reduced sever... more Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then e...
Journal of Perinatology, 2017
Objective-To analyze reasons for low enrollment in an RCT of the effect of hydrocortisone for car... more Objective-To analyze reasons for low enrollment in an 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° 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. Result-257 of 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.
Pediatric research, Jan 18, 2017
Extremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the... more Extremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the U.S., yet these infants are focus of most published research. Moderately preterm neonates (MPT, 29-33(6/7) weeks), are an understudied group of high-risk infants. Objective: To determine the neonatal outcomes of MPT across the gestational age spectrum, and to compare these to EPT. A prospective observational cohort was formed in 18 Level 3-4 NICUs in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT admitted to NICUs, and all EPT born at sites between January 2012 and November 2013. Antenatal characteristics, and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses. MPT infants experienced morbidities similar to, although at lower rates, than EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. CNS injury occurred including intraventricu...
Pediatric Research, 2016
Articles Clinical Investigation nature publishing group Background: Preterm infants with respirat... more Articles Clinical Investigation nature publishing group Background: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. Methods: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. results: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. conclusion: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial. r etinopathy of prematurity (ROP) is a common problem worldwide among preterm infants, often leading to vision impairment or blindness (1). Hallman reported two trials of postnatal inositol treatment of preterms with RDS to support phosphatidylinositol in surfactant synthesis, and both trials demonstrated improved RDS and a lower incidence of death or BPD, and ROP (2,3). Inositol is an important component of surfactant, and essential intracellularly as phosphoinositides. Howlett concluded in a Cochrane metaanalysis of inositol in preterm infants, "that a multi-center, randomized controlled trial of appropriate size is warranted to confirm these findings" (4). We reported the pharmacokinetics (PK) of a single dose of i.v. inositol in preterm infants at doses of 60 or 120 mg/ kg, and found the half-life was 5.22 h, with large urine losses, particularly in the first 12 h after dosing (5). Our three goals were to identify a daily dose to achieve serum levels similar to those reported by Hallman, [170 mg/l (994 µmol/l) at 8-9 d for infants given 160 mg/kg/d, and an approximate mean value over the first week of life of 135 mg/l (750µmol/l) when receiving 80 mg/kg/d (2,6)]; to learn if divided doses would reduce urine losses; and to assure safety with up to 10 wk of treatment. We examined the safety and pharmacokinetics (PK) of inositol given at three dose levels compared with placebo for up to 10 wk, both i.v. and enteral (#NCT01030575). This time frame was chosen to support inositol levels throughout the postpreterm delivery period when most retinal vessel growth normally occurs within the high inositol, in-utero environment (7,8). RESULTS From January to October 2010, 125 infants ≤29 wk gestation were randomized and 122 received treatment during the time
BMC medical research methodology, Jan 12, 2006
The benefit-risk ratio has been proposed to measure the tradeoff between benefits and risks of tw... more The benefit-risk ratio has been proposed to measure the tradeoff between benefits and risks of two therapies for a single binary measure of efficacy and a single adverse event. The ratio is calculated from the difference in risk and difference in benefit between therapies. Small sample sizes or expected differences in benefit or risk can lead to no solution or problematic solutions for confidence intervals. Alternatively, using the joint distribution of benefit and risk, confidence regions for the differences in risk and benefit can be constructed in the benefit-risk plane. The information in the joint distribution can be summarized by choosing regions of interest in this plane. Using Bayesian methodology provides a very flexible framework for summarizing information in the joint distribution. Data from a National Institute of Child Health & Human Development trial of hydrocortisone illustrate the construction of confidence regions and regions of interest in the benefit-risk plane, ...
Pediatrics, 2008
OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to... more OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes.METHODS. Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile.RESULTS. Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at...
Pediatrics, 2004
Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response ... more Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%).Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, de...
Pediatrics, 2010
OBJECTIVE:This report presents data from the Eunice Kennedy Shriver National Institute of Child H... more OBJECTIVE:This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).METHODS:Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.RESULTS:Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respirato...
Pediatrics, 2007
BACKGROUND. Low cortisol concentrations in premature infants have been correlated with increased ... more BACKGROUND. Low cortisol concentrations in premature infants have been correlated with increased severity of illness, hypotension, mortality, and development of bronchopulmonary dysplasia. A total of 360 mechanically ventilated infants with a birth weight of 500 to 999 g were enrolled in a randomized, multicenter trial of prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia. Mortality and bronchopulmonary dysplasia were decreased in the hydrocortisone-treated patients exposed to chorioamnionitis. We now report outcomes at 18 to 22 months' corrected age.PATIENTS AND METHODS. Surviving infants were evaluated with standardized neurologic examination and Bayley Scales of Infant Development-II. Neurodevelopmental impairment was defined as a Mental Developmental Index or Psychomotor Developmental Index of <70, cerebral palsy, blindness or deafness.RESULTS. A total of 252 (87%) of 291 survivors were evaluated. Cerebral palsy was diagnosed in 13% of hydroc...
Pediatric Research, 2001
Premature infants have higher cortisol precursor concentrations than term infants; however, many ... more Premature infants have higher cortisol precursor concentrations than term infants; however, many sick preterm infants have surprisingly low cortisol concentrations. Those who develop chronic lung disease (CLD) have lower cortisol values than those who recover. We hypothesized that some infants have a decreased ability to synthesize cortisol, leading to physiologic disruptions including amplified inflammatory responses, thereby resulting in CLD. We measured cortisol, 11-deoxycortisol, 17hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone sulfate, and ACTH in 40 extremely low birth weight infants enrolled in a study of low-dose hydrocortisone therapy to prevent CLD. Thirty-four infants survived and 15 developed CLD. Hydrocortisone therapy did not suppress ACTH or any measured steroid value. Before study (Ͻ48 h of life), 17-OH progesterone was higher in CLD infants, as was the ratio of 17-OH progesterone to 11-deoxycortisol. On d 15-19 (Ն72 h after end of therapy), basal and stimulated cortisol concentrations were lower in CLD infants. In contrast, the basal ratio of 11-deoxycortisol to cortisol was higher in CLD infants, as were stimulated values of 17-OH progesterone and stimulated ratios of 17-OH progesterone to 11-deoxycortisol and 11-deoxycortisol to cortisol. Thus, infants who developed CLD had lower basal and stimulated cortisol values, but elevated cortisol precursors and precursor to product ratios, compared with infants who recovered. These data support the hypothesis that these immature infants have a decreased capacity to synthesize cortisol, which may lead to a relative adrenal insufficiency in the face of significant illness.
Journal of Perinatology, 2010
Objective: To measure cortisol, adrenocorticotropic hormone (ACTH)stimulated cortisol and ACTH va... more 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.
Journal of Perinatology, 2009
Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insuffi... more 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.
Journal of Perinatology, 2008
Objective-To determine cortisol and adrenocorticotropin (ACTH) responses to critical illness in t... more 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 [25 th-75 th 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. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Journal of Perinatology, 2009
Objective: Both excess and insufficient levels of glucocorticoid in extremely low birth weight (E... more Objective: Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment. Study Design: As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile. Result: Median cortisol value was 16.0 mg per 100 ml at baseline for all infants, and 13.1 mg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia. Conclusion: Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone.
Journal of Perinatology, 2011
Objective: For infants born with extremely low birth weight (ELBW), we examined the (1) correlati... more Objective: For infants born with extremely low birth weight (ELBW), we examined the (1) correlation between results on the Ages and Stages Questionnaire (ASQ) and the Bayley Scales of Infant Development-II (BSID-II) at 18 to 22 months corrected age; (2) degree to which earlier ASQ assessments predict later BSID-II results; (3) impact of ASQ use on follow-up study return rates. Study Design: ASQ data were collected at 4, 8, 12 and 18 to 22 months corrected age. The BSID-II was completed at 18 to 22 months corrected age. ASQ and BSID-II 18 to 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses. Result: ASQ sensitivity and specificity at 18 to 22 months were 73 and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results. Conclusion: For extremely low birth weight infant assessment, the ASQ cannot substitute for the BSID-II, but seems to improve tracking success.
The Journal of Pediatrics, 2012
Objective-To assess the feasibility of a randomized placebo controlled trial (RCT) of blood press... more Objective-To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants. Study design-This was a prospective pilot RCT of infants 23 0/7-26 6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
The Journal of Pediatrics, 2012
Objective-To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequen... more Objective-To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants. Study design-This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). Results-136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08-0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes. Conclusions-Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
The Journal of Clinical Endocrinology & Metabolism, 2005
Context: Various cosyntropin doses are used to test adrenal function in premature infants, withou... more Context: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. Objective: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. Design: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. Setting: The setting was nine newborn intensive care units. Patients: The patients included infants with 500-999 g birth weight. Intervention: The drug used was cosyntropin, at 1.0 or 0.1 g/kg, given between 18 and 28 d of birth. Main Outcome Measure: We measured the cortisol response to cosyntropin. Results: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 g/kg, yielded higher cortisol values (P Ͻ 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P ϭ 0.02), infants receiving enteral nutrition vs. not (P Ͻ 0.001), infants exposed to chorioamnionitis vs. not (P ϭ 0.04), and those receiving mechanical ventilation vs. not (P ϭ 0.02), as well as a positive correlation with fetal growth (P ϭ 0.03). A response curve for the 1.0-g/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 g/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. Conclusions: A cosyntropin dose of 0.1 g/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 g/kg cosyntropin to test adrenal function in these infants.