Clinical trial NCT01954056
Conditions: Infant, Newborn, Diseases Cardiovascular Insufficiency
Keywords: NICHD Neonatal Research Network Mechanical ventilation Intubation Neurodevelopmental impairment
Sponsor: NICHD Neonatal Research Network
Start date: 2014-06-19; Completion date: 2018-03-20
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will evaluate the effects of a 7-day course of hydrocortisone therapy on short-term morbidity, cardiovascular function, long-term neurodevelopment, and mortality in critically ill, term and late preterm infants diagnosed with cardiovascular insufficiency as defined by a need for inotrope therapy in the first 72 hours of age.

Detailed description:
Cardiovascular insufficiency is common and potentially life-threatening in critically ill term and late preterm newborns admitted to the newborn intensive care unit (NICU) in the first few days of age.

This study proposes to conduct a multicenter, randomized, masked, placebo-controlled trial within the Neonatal Research Network (NRN). This trial will evaluate the effects of a 7-day course of hydrocortisone therapy on short-term morbidity, cardiovascular function, long-term neurodevelopment, and mortality in critically ill, term and late preterm infants diagnosed with cardiovascular insufficiency as defined by a need for inotrope therapy in the first 72 hours of age.

Arms: arm 1: hydrocortisone (hydrocortisone sodium succinate, plain; will not have benzyl alcohol) given through intravenous line or by intramuscular injection if no intravenous line arm 2: Saline placebo
Interventions: intervention 1: Hydrocortisone intervention 2: Placebo
Intervention descriptions: intervention 1: • 7 day course of hydrocortisone (hydrocortisone sodium succinate, plain; will not have benzyl alcohol) given through intravenous line or by intramuscular injection if no intravenous line).

1 mg/kg loading dose x 1; 0.5 mg/kg q 6 hours x 12 doses; 0.5 mg/kg q 12 hours x 4 doses; 0.5 mg/kg q day x 1 dose intervention 2: 7 days of intravenous or intramuscular placebo (normal saline in equal volume)

1 mg/kg loading dose x 1; 0.5 mg/kg q 6 hours x 12 doses; 0.5 mg/kg q 12 hours x 4 doses; 0.5 mg/kg q day x 1 dose

Protocol documents:
Prot_SAP_000.pdf: 
Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
1 of  24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hydrocortisone treatment of cardiovascular insufficiency in term  
and late preterm infants:  
A randomized controlled trial 
 
 
Short Title:   Hydrocortisone for Cardiovascular Insufficiency 
Clinical trials.gov: NCT01954056 
 
 
 
 
 
Subcommittee: 
Erika F. Fernandez MD (PI) 
Kristi L. Watterberg, MD  
Michele Walsh, MD  
William Truog, MD 
Barbara Stoll, MD 
Gregory Sokol, MD 
Maky Fraga, MD 
Conra Lacy, RN 
 
 
 
 
 
 
 
 
 
 
 
Cheri Gauldin, RN 
Sandra Beauman, MSN,RN 
Andrea Duncan, MD 
William Buss, Pharm.D. 
Doug Kendrick, M.Stat 
Abhik Das, PhD  
Rosemary D. Higgins, MD 
 
 
 
 
 
 
 
Version 1.1 
February 24, 2014 
Revised April 2, 2014 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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PROTOCOL REVIEW CHECKLIST 
 
Protocol: _________________________________________________________ 
 
PI: ______________________________________________________________ 
 
Center/Institution: _______________________________ 
 
Date: ___________________ 
 
1.  Abstract/synopsis 
 
2.  Statement of Problem 
 
3.  Hypothesis 
 
4.  Specific Aims 
 
5.  Rationale/justification 
 
6.  Background/Previous studies 
 
7.  Methods/procedures 
 Description of study design (masked, randomized, etc.) 
 
 Definition of study population 
 
 Description of study intervention 
 
 Precise definition of primary/secondary outcomes 
 
 Sample size estimate with some statistical support (including 
estimate of compliance and consent rates) based upon primary 
outcome 
 
 Analytical Plan 
 
 Available population/compatibility with other ongoing protocols 
 
 Estimate of projected recruitment time 
 
8.  Risks/benefits 
 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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1. Abstract 
This study proposes to conduct a multicenter, randomized, masked, placebo-controlled trial 
within the Neonatal Research Network (NRN). This trial will evaluate the effects of a 7-day 
course of hydrocortisone therapy on short-term morbidity, cardiovascular function, long-term 
neurodevelopment, and mortality in critically ill, term and late preterm infants diagnosed with 
cardiovascular insufficiency as defined by a need for inotrope therapy in the first 72 hours of 
age.  
2. Statement of the Problem 
Cardiovascular insufficiency is common and potentially life-threatening in critically ill term and 
late preterm newborns admitted to the newborn intensive care unit (NICU) in the first few days 
of age. Cardiovascular insufficiency occurs when there is inadequate blood flow to meet the 
needs of metabolism and often presents as low blood pressure, poor capillary refill, low urine 
output, or metabolic acidosis. Critically ill infants with these signs often receive fluid boluses or 
inotropes and, increasingly, steroids to improve systemic blood flow. Yet, for the majority of 
infants, the etiology of cardiovascular insufficiency in the first few days of life is unclear. 
Emerging evidence suggests that a frequent etiology of cardiovascular instability or insufficiency 
in ill adult and some pediatric populations may be relative adrenal insufficiency, an inadequate 
cortisol response to acute stress or illness.1-4 Glucocorticoid treatment in some critically ill 
populations results in decreased mortality and morbidity in some studies.4-8 
Small studies have documented inappropriately low cortisol values in conjunction with 
cardiovascular dysfunction in critically ill term and late preterm newborn infants.9-11,12-14 In 
addition, we have shown that such infants have low endogenous concentrations of 
adrenocorticotropic hormone (ACTH) and have normal responses to exogenous ACTH.12 
Although small case series and retrospective studies have documented improved cardiovascular 
stability following glucocorticoid treatment in hypotensive term infants,13-17 no randomized 
controlled trials (RCTs) have evaluated the effects of glucocorticoids on cardiovascular function, 
short-term outcomes, or long-term neurodevelopment in critically ill term or late preterm infants 
with cardiovascular insufficiency. It is urgent that research is advanced in this area because, 
despite the lack of well-designed studies, there is an increasing use of glucocorticoid therapy for 
hypotension in this population. This study aims to determine, through optimal study design, the 
efficacy and consequences of glucocorticoid therapy in critically ill term and late preterm infants.  
3. Hypothesis 
We hypothesize that therapy with hydrocortisone will ameliorate the clinical syndrome of 
cardiovascular insufficiency syndrome seen in many critically ill term and late preterm infants, 
thereby decreasing short- and long-term morbidity and mortality.  
4. Specific Aims 
Goal of study. Although short term use of hydrocortisone is believed to be safe (see Table 1), 
evidence is limited to support its use in treating hypotension in the critically ill term and late 
preterm infant. Despite this paucity of data, many infants are increasingly receiving 
glucocorticoids for cardiovascular insufficiency—13.1% of intubated and mechanically 
ventilated infants in our own preliminary observational NRN data and 13.5% in a recent report of 
infants with meconium aspiration syndrome.18 We propose to perform a RCT of 
hydrocortisone for the treatment of cardiovascular insufficiency in critically ill, term and late 
preterm newborn infants who are mechanically ventilated in their first 72 postnatal hours. Our 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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goal is to determine if hydrocortisone treatment improves cardiovascular function, ameliorates 
other short-term outcomes, and increases survival without neurodevelopmental impairment.  
Specific aims of this multicenter, randomized, masked, placebo-controlled trial within the NRN 
are: 
a. Compare the incidence of death or neurodevelopmental impairment at 22-26 months in 
critically ill, mechanically ventilated, term and late preterm newborn infants receiving 
inotropes for cardiovascular insufficiency in the first 72 hours of age treated with 7 days 
of hydrocortisone vs. placebo. We hypothesize that hydrocortisone will decrease the 
incidence of death or neurodevelopmental impairment in these infants compared to 
placebo. 
b. Compare short-term outcomes between infants treated with hydrocortisone vs. placebo 
including duration of mechanical ventilation and oxygen therapy, days to full feeding, and 
length of hospital stay. We hypothesize that infants who receive hydrocortisone will 
spend fewer days on mechanical ventilation and oxygen, will take fewer days to reach 
full enteral feeds, and will have shorter stays in the hospital.  
c. Compare adverse events (defined below) between infants treated with hydrocortisone 
vs. placebo. We hypothesize that adverse events will not occur at a higher rate in those 
receiving hydrocortisone compared to placebo. 
d. Compare measures of cardiovascular sufficiency between those infants on 
hydrocortisone vs. placebo as measured by pre- and post-study drug differences in 
blood pressure, the duration and dose of inotropes received, and the presence of 
metabolic acidosis and oliguria. We hypothesize that infants treated with hydrocortisone 
vs. placebo will have higher blood pressures, receive a lower total dose of inotropes, 
and/or receive inotropes for a shorter period of time and have less metabolic acidosis 
and oliguria. 
Table 1. Hydrocortisone dosing 
Author 
Year 
N= 
Population 
Gestational 
Age 
Study 
Design 
Entry 
Criteria 
Hydrocortisone 
Dose and 
Duration Used 
Results 
Adverse 
Events 
Seri47 
2001 
N=21 
Mean: 
26.9 wks 
Retro- 
spective 
Dopa ≥22 
mcg/k/min 
2 mg/kg/day div  
q12h for 1-3 days 
OR: 3-6 mg/kg/day
div q12h 
OR: QID for 2-3 
days 
Increased blood 
pressure (BP), 
decreased fluid & 
pressor 
requirements 
No events 
reported 
Ng 
2006 
N=48 
<32 weeks 
RCT 
Dopa ≥10 
plus saline 
≥30 cc/kg 
3 mg/kg/day  
div q8h  
for 5 days 
Increased BP, 
weaned off 
pressors faster, 
decreased fluid & 
pressor 
requirement 
More glycosuria 
but no change in 
serum sugar. No 
change in rates of 
infection, 
necrotizing 
enterocolitis 
(NEC), SIP, 
duration of 
hospital stay or 
mortality. 
Noori 
2006 
N=15 
5 term, 
15 preterm Observation Dopa ≥15 
2 mg/kg once,  
then 2mg/kg/day  
div q12h  
Increased BP, no 
change in stroke 
vol or cardiac 
No change in 
middle cerebral 
or renal artery 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
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Author 
Year 
N= 
Population 
Gestational 
Age 
Study 
Design 
Entry 
Criteria 
Hydrocortisone 
Dose and 
Duration Used 
Results 
Adverse 
Events 
for 2 days 
output, decreased 
pressor need. 
flow. 
Baker 
2008 
N=117 
Mean: 
35 weeks 
Observation 
Inotrope >20 
& cortisol <5 
mcg/dl 
3.3 mg/kg/day div 
q6h for 2 days, 
then 1.1 mg/kg/day 
div q6h, then 
weaned over 
median of 6 days 
Increased BP, 
decreased pressor 
requirement & less 
oliguria 
No difference 
intraventricular 
hemorrhage 
(IVH), 
periventricular 
leukomalacia 
(PVL), infection, 
SIP compared to 
controls. No 
correlation of 
cortisol to 
response to 
treatment. 
Bourchier
1997 
N=40 
Preterm 
RCT: 
hydrocortis 
one vs dopa
MAP <25 or 
35 
depending 
on weight 
2.5mg/kg/ dose  
q6h for 2 days, 
then 1.25 mg/kg  
q6h for 2 days, 
then 0.625mg/kg 
for  
2 days or dopa 
No difference 
between dopa or 
hydrocortisone 
No difference in 
mortality, IVH, 
retinopathy of 
prematurity, CLD, 
NEC, serum 
sugar, or sepsis. 
 
5. Rationale/Justification 
There has never been a randomized controlled trial of hydrocortisone for the treatment of 
cardiovascular insufficiency in term and late preterm newborn infants in the first few 
days of life. No studies have examined the long-term effects of hydrocortisone given for the 
purposes of improving cardiovascular stability. This RCT is urgently needed because the use of 
steroids is rapidly increasing in hypotensive critically ill term and late preterm infants without 
evaluation of efficacy or safety (see also section 6b, Preliminary Studies, below).18,19 
Investigators at the University of New Mexico Health Sciences Center have been performing 
investigations in the area of adrenal function and cardiovascular dysfunction in the critically ill 
term and late preterm infant since 2002 and most recently, within the multicenter NRN. The 
proposed study can only be conducted through a multicenter collaboration. The NRN is a well-
established network of academic neonatal centers that has systems in place and extensive 
experience in conducting large trials. We have instituted a database for this particular targeted 
study population within the NRN and the investigators have experience in formulating, 
managing, and editing this database. In addition, the NRN has an established follow-up program 
with successful tracking of patients and high follow-up rates, standardized assessments 
conducted by certified examiners, and comprehensive data management. 
6a. Background/Previous Studies 
Incidence of cardiovascular insufficiency. Cardiovascular insufficiency is a frequent 
occurrence in the critically ill term and late preterm infant admitted to the NICU. Previous studies 
on cardiovascular insufficiency have used hypotension as a proxy measure of insufficiency, 
rather than other signs of cardiovascular insufficiency.16,20-23 This may not be the most 
appropriate measure as many neonatal clinicians do not use blood pressure to determine 
initiation of therapy (see section 6b, Preliminary Studies, below). If hypotension is defined 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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pragmatically as the receipt of therapy for the diagnosis, one retrospective study of 1011 
mechanically ventilated, ≥34 week neonates admitted to a NICU reported that 60% received 
volume expanders and 35% received vasopressors.24  
Consequences of cardiovascular insufficiency. The consequences of cardiovascular 
insufficiency are the result of end organ injury or damage. In extremely preterm infants, 
hypotension has been associated with intraventricular hemorrhage (IVH), periventricular 
leukomalacia (PVL), cerebral palsy, hearing loss, and neurodevelopmental impairment.25-27 It is 
difficult to differentiate the consequences of hypotension itself from the treatment, as treated 
blood pressure vs. untreated low blood pressure may be associated with adverse outcomes in 
retrospective, multiple regression analyses.28,29  
Although less is known about the critically ill term or late preterm infant, there are reports of 
increased neurological events (seizures, brain atrophy, intracranial hemorrhage, or stroke) and 
chronic lung disease in association with the use of vasopressors (inotropes).24 Other studies 
have reported a higher incidence of death in ill newborn infants who received vasopressors 
compared to those who did not (68.2% vs. 15.7%).18 These adverse outcomes may have been 
due to the underlying disease, inadequate perfusion, vasopressor (inotrope) therapy, or other 
factors. It will remain difficult to sort out the contributions of these factors; however, a 
randomized, placebo-controlled trial is the best strategy to determine the efficacy and 
consequences of therapies given to maintain cardiovascular stability.  
Adrenal insufficiency as etiology of cardiovascular insufficiency. The etiology of 
hypotension or cardiovascular insufficiency in the acutely ill newborn is, in most cases, unknown 
at the time of treatment. Proposed mechanisms include hypovolemia, myocardial dysfunction, 
abnormal regulation of peripheral vascular tone, pulmonary hypertension with resultant 
decreased left ventricular preload, and maladaptation to transition after birth.30 Recently, studies 
have suggested relative adrenal insufficiency as an etiology of hypotension in other critically ill 
populations of adults and children.2,31-34 Adrenal insufficiency occurs when there is insufficient 
cortisol release from the adrenal cortex, especially in response to severe illness and stress. The 
adrenal gland releases cortisol in response to ACTH. ACTH is produced in the pituitary gland, 
which is stimulated by corticotrophin-releasing hormone (CRH) that is made in the 
hypothalamus. The integrity and activation of the hypothalamic-pituitary-adrenal (HPA) axis is 
essential to general adaptation to illness and stress. The HPA axis is responsible for the 
maintenance of cellular and organ homeostasis. In response to acute stress or critical illness, 
cortisol concentrations should increase substantially. Recent guidelines for adults with critical 
illness have suggested that random cortisol values <10 mcg/dl or delta cortisol values <9 mcg/dl 
after cosyntropin is associated with cardiovascular insufficiency and mortality and should be 
considered evidence of relative adrenal insufficiency.4-6,8,33,35  
There is no consensus on the definition of relative adrenal insufficiency in the acutely ill 
newborn infant because data regarding adrenal function in the ill newborn are sparse. Term 
newborns have demonstrated the ability to adapt quickly to postnatal changes and can show a 
response to stress by the end of the first postnatal week.36 However, small studies, including our 
work,12 have documented inappropriately low cortisol concentrations in sick, hypotensive term 
newborns during this first week.11,16,37 In addition, one of these studies reported low cortisol 
responses to ACTH and a high mortality rate in such infants.11 These studies suggest that 
insufficient adrenal function in the face of illness may play a role in the etiology of hypotension 
or cardiovascular insufficiency in the term and late preterm critically ill newborn infant.  
We postulate that the newborn is uniquely susceptible to adrenal insufficiency due to shifts 
in hormone production during transition to extra-uterine life. CRH is produced in increasing 
concentrations by the placenta through gestation, resulting in maternal and fetal serum CRH 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
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concentrations at term that are much higher than at any other time in life.38 Placental CRH 
stimulates cortisol production in the fetal adrenal gland. At birth, the very high concentration of 
CRH from the placenta is suddenly withdrawn. We hypothesize that the pituitary gland of the 
newborn infant—who has previously been exposed to such high concentrations of CRH—is 
transiently refractory to the lower concentrations of CRH produced by the hypothalamus, and 
may not be able to increase ACTH to stimulate the adrenal gland for several days after delivery. 
If the newborn is well, this brief refractory period is well tolerated; however, if the infant is 
seriously ill, a state of relative adrenal insufficiency and cardiovascular compromise, including 
hypotension, may ensue. Our preliminary investigations have documented low cortisol and 
ACTH values in ill hypotensive newborns, but normal responses to exogenous ACTH, 
consistent with adrenal insufficiency secondary to HPA axis dysfunction upstream from the 
adrenal gland and poor adaptation to extra-uterine life.12  
Glucocorticoid therapy for cardiovascular insufficiency. If relative adrenal insufficiency 
underlies the hypotension or cardiovascular insufficiency seen in many critically ill newborn 
infants, the appropriate therapy for this condition is not symptomatic treatment with volume 
expansion and inotropes, but glucocorticoid therapy in doses designed to mimic serum 
concentrations seen in critical illness. This approach is different than the goal of anti-
inflammatory dosing of steroids (hydrocortisone or dexamethasone) used in preterm infants for 
the prevention of bronchopulmonary dysplasia. Glucocorticoids for the purpose of physiologic 
replacement in shock has shown to improve outcomes in adult critically ill patients, including a 
reduction in the duration of inotrope administration and, in some studies, reduced mortality.4,8 
Although no long-term outcomes have been studied, randomized controlled trials of 
glucocorticoids for the prevention and treatment of hypotension in preterm infants have shown 
an improvement in blood pressure.20,21 Glucocorticoid administration for hypotension has not 
been associated with any adverse events in the small cohort or case studies in the term 
newborn population14-16 and has not been shown to be an independent risk factor for adverse 
neurodevelopmental outcomes.39 
Hydrocortisone dosing. High-dose corticosteroid administration has shown no benefit and 
possible harm in critically ill adult patients with acute lung injury, acute respiratory distress 
syndrome (ARDS), and septic shock.40 Instead, prolonged, low-dose corticosteroid therapy has 
shown a beneficial effect on short-term mortality, ventilation-free days, length of intensive care 
unit stay, multiple organ dysfunction syndrome scores, lung injury scores, and shock reversal 
without increasing significant adverse events.5,6,40 Relative adrenal insufficiency in ill adults—or 
more recently deemed “critical illness-related corticosteroid insufficiency”—is defined by 
catecholamine refractory shock (norepinephrine or equivalent dose of inotrope >0.05 to 0.1 
mcg/kg/min) or having persistent ARDS for >48 hours. In these adult patients, a course of 
hydrocortisone at a dose of 200–350 mg/day (stress doses) is recommended, which is 
equivalent to at least 3 mg/k/day. The duration should be for at least 7 days because rapid 
steroid tapers (2–6 days) have been associated with rebound inflammation, increased 
inflammatory mediators, and a need to reintroduce vasopressor agents and mechanical 
ventilation.41,42 The definition of relative adrenal insufficiency in adults is a random cortisol level 
below 10 or 15 mcg/dl in acutely ill patients. To achieve cortisol levels of 15–20 mcg/l, a dose of 
about 0.6 mg/kg/dose q 6 hours (~2.4 mg/kg/day) would need to be given.43 
Hydrocortisone dosing in infants. Pharmacokinetic data in term and late preterm infants are 
limited. In 1962, Reynolds, et al, reported pharmacokinetics in five term infants after a bolus of 5 
mg/kg hydrocortisone.44 Serum concentrations were evaluated with two assay methods (Porter-
Silber chromogen values and chromatography with isotope dilution), which showed similar 
results. Mean peak serum concentration (30–80 minutes after dose) was 557 mcg/dl, and mean 
serum half-life was just under 4 hours (range 2.4–7.1 hours). This half-life is much longer than in 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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adults, where elimination half-life has been reported to be 2  0.3 hours.45 Extrapolating, a dose 
of 0.5 mg/kg would give a peak cortisol level of approximately 50 mcg/dl or a level of about 18 
mcg/dl after 6 hours. 
Doses as low as 1 mg/kg/day in preterm infants have been shown to significantly increase blood 
pressure.46 Studies of vasopressor-dependent, critically ill term and preterm newborn infants 
have used variable dosing (2–3 mg/kg/day), and all have shown an increase in blood pressure, 
a decrease in volume and inotrope requirement, and a decrease in heart rate without increases 
in adverse events (see Table 1). 
Considering the likely longer T1/2 for newborn infants and the biological effect, a dose of 1 
mg/kg/dose load followed by 0.5 mg/kg q 6 hours is a reasonable initial dosing strategy.  
6b. Preliminary Studies   
We have been performing investigations in the area of adrenal function and cardiovascular 
dysfunction in the critically ill term and late preterm infant at the University of New Mexico 
Health Sciences Center since 2002 and most recently, within the multicenter NRN.  
To determine the incidence of low cortisol values in infants receiving vasopressors, as evidence 
of cardiovascular insufficiency, we performed a retrospective cohort study of infants ≥35 
weeks gestational age (GA) and who were mechanically ventilated, received vasopressor 
therapy, and had a cortisol concentration obtained for evaluation of vasopressor-resistant 
hypotension. We found that a significant number (56%) of hypotensive critically ill infants 
had cortisol values <15 mcg/dl, a value considered to be suggestive of relative adrenal 
insufficiency.35 Treatment with hydrocortisone in this population resulted in improved 
hemodynamic function, as evidenced by decreased heart rate, decreased dopamine support, 
and fewer fluid boluses.   
In a subsequent prospective observational study, we enrolled a cohort of mechanically 
ventilated infants ≥35 weeks gestation and <6 days old. Twenty-six of the 35 ill infants (74%) 
had cortisol levels <15 mcg/dl. However, all ACTH-stimulated cortisol values were >18 mcg/dl. 
We performed ACTH measurements in 10 infants; the median ACTH concentration was 12 
pg/ml. There was no correlation between severity of illness scores and any cortisol value 
(baseline, stimulated, or rise). The results confirmed that the majority of critically ill newborns 
had an inadequate cortisol response to acute illness. Cortisol values did not increase 
with severity of illness, again suggesting relative adrenal insufficiency. However, these 
infants did respond appropriately to ACTH stimulation, despite having lower ACTH 
values than expected for the degree of illness.11,47 This suggests that their inadequate 
response to acute illness was not due to inadequate adrenal capacity to produce and secrete 
cortisol, but to dysfunction of a different component of the HPA axis.  
To determine the best design for an RCT that examines the benefits and safety of 
hydrocortisone in this population, we first needed to better characterize the study population. 
In 2009, we conducted a time-limited, prospective, multicenter (16 centers), observational 
study to determine the incidence, management, and short-term outcomes of newborn 
infants who were intubated and mechanically ventilated at less than 72 hours postnatal age, 
≥34 weeks gestation, and admitted to NRN Centers. A total of 816 infants were studied. The 
incidence of cardiovascular insufficiency was determined by using four different definitions as 
outlined in Table 2 below.   
 


Hydrocortisone treatment of cardiovascular insufficiency in term and late preterm infants:  A randomized controlled trial   
 
Eunice Kennedy Shriver NICHD Neonatal Research Network 
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Table 2.  Incidence of cardiovascular insufficiency as defined in four different ways among 
mechanically ventilated term and late preterm newborn infants in NRN Centers 
Definition of cardiovascular insufficiency 
Incidence 
% (n/all mechanically ventilated infants) 
2 consecutive mean blood pressures 
< postmenstrual age in weeks 
43%   (351/816) 
2 consecutive mean blood pressures 
< postmenstrual age in weeks plus sign of low systemic flow 
27%   (219/816) 
Receipt of volume, inotropes and/or steroids 
62%   (503/816) 
Receipt of inotropes 
27%   (221/816) 
Reasons for initiating therapy. Sixty-two percent of these mechanically ventilated infants 
received treatment for cardiovascular insufficiency. The trigger for receiving therapy included 
low blood pressures, but low blood pressure was not the only trigger. In fact, 42% of the infants 
who received therapy (fluid, inotropes, or steroids) did not have cardiovascular insufficiency as 
defined by two consecutive mean blood pressures < postmenstrual age (PMA) in weeks. Many 
infants had blood pressures within normal limits for age48 at the time therapy was initiated 
(Table 3). Of those who received fluid boluses, 60% did not have a low blood pressure as 
defined by a mean blood pressure less than PMA in weeks at the time of initiation of the bolus 
(Table 4). When examined for “reasons” that clinicians initiated fluid boluses, inotropes, or 
steroids, 42–77% received one of these therapies for low blood pressure while other reasons 
included poor perfusion or capillary refill >3 sec (29–49%), low urine output (9.7–14%), and 
metabolic acidosis (9.7–19.5%).  
Table 3.  Systolic, diastolic, and mean blood pressures at time of initiation of therapy. Mean (SD). 
 
First fluid bolus 
First vasopressor dose 
First steroid dose 
 
<37 wks GA 
N = 168 
≥37 wks GA 
N = 324 
<37 wks GA 
N = 66 
≥37 wks GA 
N = 149 
<37 wks GA 
N = 30 
≥37 wks GA 
N = 73 
Systolic BP 
53.3 (10.7) 
58.8 (14.3) 
47.9 (8.5) 
52.7 (12.5) 
49.2 (13.1) 
55.2 (13.0) 
Diastolic 
BP 
30.5 (13.0) 
43.2 (10.9) 
29.5 (15.1) 
31.4 (10.3) 
32.2 (10.8) 
36.1 (9.4) 
Mean BP 
38.4 (9.8) 
42.4 (11.8) 
35.6 (7.7) 
39.1 (10.1) 
39.1 (11.2) 
43.4 (10.3) 
Table 4.  Therapy received for cardiovascular insufficiency; timing, blood pressure at time of 
initiation and total days of therapy. Median (25th percentile, 75th percentile); % (n/N) 
 
All  
N = 502 
Volume expanders 
N = 488 
Inotropes 
N = 215 
Steroids 
N = 103 
Age at 1st dose 
(hours) 
4.0 (1.2, 15.1) 
3.5 (1.1, 14.8) 
12.633 (5.03, 24.7) 
26.2 (12.4, 43.5) 
Mean BP at 1st dose  
39 (33, 47) 
39 (33, 47) 
36 (31, 42) 
41 (35, 49) 
% with mean BP 
<PMA  
39.2% (131/334) 
39.8% (137/344) 
53.8%  
(93/173) 
32.6% 
(30/92) 
Total Days 
NA 
NA 
2.5 (1, 5) 
4 (2, 7) 
The timing of therapy is outlined above in Table 4. Most infants had therapy initiated for 
cardiovascular insufficiency within the first 24 hours of age.  


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Low blood pressure was not the only clinical measure used to initiate therapy for cardiovascular 
insufficiency and appears to be an unreliable measure. Therefore, the presence of inotropes 
was used to evaluate outcomes. The patient characteristics and outcomes are listed in Tables 5 
and 6. Outcomes were significantly worse in those who received inotropes vs. those who did 
not. 
Table 5.  Patient characteristics of infants who received inotropes vs. those who did not 
Table 6-1.  Outcomes in infants who received inotropes vs. those who did not 
Outcome 
All Infants 
N=783 
Inotropes  
N=212 
No inotropes  
N=571 
P-value 
Death, % 
6.8 (53/778) 
15.7 (33/210) 
3.5 (20/568) 
<.0001 
Died within 7 days, % 
3.0 (23/778) 
8.6 (18/210) 
0.9 (5/568) 
<.0001 
Age at time of death 
9.0 (3.0, 26.0) 
7.0 (3.0, 11.0) 
25.5 (8.0, 52.5) 
0.0054 
Days intubated and on vent 
3.0 (2.0, 8.0) 
8.0 (4.0, 13.0) 
2.0 (2.0, 5.0) 
<.0001 
Days on oxygen 
6.0 (2.0, 11.0) 
10.0 (6.0, 17.0) 
4.0 (2.0, 8.0) 
<.0001 
Day of life at time of full nipple 
feeding 
9.0 (6.0, 17.0) 
16.0 (10.0, 26.0) 
8.0 (5.0, 14.0) 
<.0001 
Days in NICU 
12.0 (8.0, 24.0) 
16.0 (10.0, 34.0) 
11.0 (8.0, 21.0) 
<.0001 
Table 6-2.  Outcomes in infants by gestational age who received inotropes vs. those who did not; 
excluding infants with CDH, HIE, receipt of whole body cooling, and omphalocele,  
 
Outcome 
All Infants 
 
Inotropes 
 
No Hypotension by 
any definition 
* signified p-value 
is <0.5 between 
groups 
GA < 37 weeks 
N = 277 
N = 42 
N = 115 
 
Death (%) 
3.2 
14.3 
0 (0/115) 
* 
Died within 7 days (%) 
1.4 
9.5 
0 (0/115) 
* 
Age at time of death4 
9 (4, 16) 
4 (3, 16) 
NA 
NA 
Days intubated and on ventilator 
2 (2, 5) 
7 (4, 11) 
2 (2, 4) 
* 
Days on oxygen 
5 (2, 9) 
10.5 (4, 16) 
4 (2, 8) 
* 
DoL at time of full nipple feeding 
9 (6, 17) 
20.5 (10, 27) 
8 (6, 14) 
* 
Days in NICU 
12 (8, 24.5) 
16 (10, 34) 
10 (6, 17) 
* 
Patient Characteristic 
All Infants 
N=783 
Inotrope 
N=212 
No inotropes 
N=571 
P-value 
Prenatal steroid use, % 
6.0 (47/778) 
4.8 (10/210) 
6.5 (37/568) 
0.4586 
Birth weight, g 
3001 (646) 
3145 (671) 
2948 (629) 
0.0001 
Gestational age, wks 
37.3 (2.1) 
37.8 (2.1) 
37.1 (2.1) 
<.0001 
Apgar score <3 at 5 min, % 
12.1 (93/771) 
18.8 (39/208) 
9.6 (54/563) 
0.0008 
Intubation in L & D, % 
39.8 (311/782) 
54.7 (116/212) 
34.2 (195/570) 
<.0001 
Cesarean section, % 
55.8 (437/783) 
56.1 (119/212) 
55.7 (318/571) 
1.0000 
Male, % 
60.7 (475/782) 
62.7 (133/212) 
60.0 (342/570) 
0.5392 
Outborn, % 
43.6 (341/782) 
30.7 (65/212) 
48.4 (276/570) 
<.0001 
Inhaled NO, % 
19.3 (151/781) 
54.7 (116/212) 
6.2 (35/569) 
<.0001 
Extra corporeal membrane 
oxygenation (ECMO), % 
4.7 (37/781) 
14.2 (30/212) 
1.2 (7/569) 
<.0001 
Surfactant use, % 
42.1 (329/781) 
52.4 (111/212) 
38.3 (218/569) 
0.0006 
Whole body cooling, % 
10.8 (84/781) 
22.2 (47/212) 
6.5 (37/569) 
<.0001 


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GA ≥ 37 weeks 
N = 370 
N = 93 
N = 113 
 
Death (%) 
4.3 
9.8 
2.7  
* 
Died within 7 days (%) 
1.4 
4.4 
0.0 
* 
Age at time of death 
12.5 (2, 45.5) 
12 (2, 18) 
48 (30, 60) 
 
Days intubated and on ventilator 
3 (2, 8) 
9.5 (4, 13) 
2 (1, 4) 
* 
Days on oxygen 
5 (2, 10) 
11 (8, 18.5) 
3 (1, 5) 
* 
DoL at time of full nipple feeding 
8 (5, 15) 
14 (10, 26) 
6 (3, 9) 
* 
Days in NICU 
12 (7, 21) 
17 (11, 35) 
8 (5, 15) 
* 
7.  Methods/Procedures 
a. Study Design 
The study will be a randomized, multicenter, double-blind, placebo-controlled trial. 
Patients will be enrolled and randomized in a variable block design, 1:1 ratio of 
hydrocortisone or placebo.  
b. Study Population 
Inclusion criteria: Eligible infants will be ≥34 weeks gestation who are—  
 
Intubated and mechanically ventilated for a minimum of 2 hours before 72 hours 
postnatal age   
 
Admitted to a NRN NICU before 48 hours postnatal age.   
Information will be collected on maternal and infant demographics including antenatal 
steroids. Data will also be collected on eligible infants who are not enrolled on the 
screening and eligibility form including gestational age, outborn/inborn status, and 
reason for not enrolling. 
The exclusion criteria include those infants with cardiovascular insufficiency which is 
likely not due to relative adrenal insufficiency. 
 Exclusion criteria: 
 
Attending physician refusal    
 
No parent/guardian consent 
 
Infants receiving extracorporeal membrane oxygenation (ECMO) 
 
Infants who are intubated for the sole purpose of an anticipated surgery or airway 
anomalies 
 
Infants for whom treatment will be limited based on poor prognosis  
 
Receiving dexamethasone or hydrocortisone 
 
Receiving ibuprofen or indomethacin 
 
Infants will be excluded if there is a known diagnosis at the time enrollment of—  
 
Congenital heart disease not including  
atrial septum defect, ventricular septal defect or patent ductus arteriosus 
 
Hypotension thought to result from specific, immediately remediable factors 
including placental hemorrhage, acute hemorrhage, or tension pneumothorax 
 
Pituitary hypoplasia or congenital adrenal hyperplasia 
 
Chromosomal disorder 
 
Hypertension in the absence of inotrope therapy as defined by a mean arterial 
blood pressure >95th percentile for postmenstrual age in weeks48  
 
Receipt of therapeutic hypothermia for hypoxic ischemic encephalopathy   
 
Severe brain structural abnormalities or periventricular leukomalacia, stroke or 
seizures 
 
Congenital diaphragmatic hernia 


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 
Abdominal wall defects, such as gastroschisis or omphalocele 
 
Major renal anomalies requiring dialysis. 
 
 Infants diagnosed with pituitary hypoplasia or congenital adrenal hyperplasia will be 
discontinued from study drug and withdrawn from study. All other infants in whom  study 
drug is discontinued, including those treated with ECMO after enrollment will remain in 
the analysis according to the intention –to- treat principle. 
Timing of consent. Parents/guardians of infants who meet inclusion criteria and who do 
not have any of the exclusion criteria may be approached for consent for enrollment into 
the study, regardless of any blood pressure values or therapies planned or given for 
cardiovascular insufficiency. Infants ideally would be enrolled and randomized to study 
drug within 24 hours of intubation and receipt of inotropes (up to max of 96 hours of 
age). For transported infants, parents will be contacted for consent by telephone. 
Enrolling infants as soon as possible will allow more time for discussion with parents, 
enrollment, randomization, and receipt of study drug. 
c. Study Intervention 
Randomization criterion. Decision of the clinical care team to treat with an inotrope 
(dopamine, dobutamine, epinephrine, or norepinephrine) within the first 72 hours of life, 
at a minimum dose of 5 mcg/kg/min (epinephrine 0.01 mcg/kg/min), will be the trigger for 
randomization to study drug. Blood pressure will not be a criterion for randomization. 
Low dose dopamine (<5mcg/kg/min) initiated for low urine output does not qualify for 
randomization. Low blood pressure did not correlate with interventions for cardiovascular 
insufficiency in our multicenter NRN observational study (see section 6b, Preliminary 
Studies, above). However, receipt of inotrope support was associated with significantly 
worse outcomes, including a mortality rate of almost 16% vs. 4%. Therefore, this is a 
reasonable clinical indicator of adverse outcomes.  
Randomization method. Randomization will be stratified by Network center using a 
randomly permuted block randomization algorithm devised by the NRN Data 
Coordinating Center at RTI. A centralized secure, password-protected web-based 
(Hatteras Clinical DMS) randomization process will be used to allocate infants to either 
hydrocortisone or placebo. The medication will be reconstituted by the pharmacist, and 
caregivers will remain blinded. Placebo will be normal saline and will be given in equal 
volume to a hydrocortisone dose and delivered at same rate. 
Study Drug. Enrolled infants who receive inotrope therapy before 72 hours postnatal 
age will be randomized to receive 7 days of hydrocortisone (hydrocortisone sodium 
succinate, plain; will not have benzyl alcohol) given through intravenous line, po if no line 
or by intramuscular injection (I.M.) (if no intravenous line and infant is NPO) or 7 days of 
intravenous, po or I.M. placebo (normal saline in equal volume). Hydrocortisone 
dosing will be 2.5 mg/kg/day on day 1, 2 mg/kg/day on days 2 and 3, 1 mg/k/day on 
days 4 and 5, then 0.5 mg/kg/day on days 6 and 7. 
 
1 mg/kg loading dose x 1 
 
0.5 mg/kg q 6 hours x 12 doses   
 
0.5 mg/kg q 12 hours x 4 doses   
 
0.5 mg/kg q day x 1 dose   
We will continue hydrocortisone for 7 days, weaning after the first 3 days, to avoid possible 
rebound hypotension and in consideration of possible down-regulation of glucocorticoid 


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receptors by higher cortisol concentrations.40,49 Therapy with active drug or placebo 
should be instituted ideally within 12-24 hours of initiation of inotrope therapy. All other 
treatments will be at the discretion of the clinical care team. This real-world management 
design will increase generalizability of study results and improve compliance with study 
procedures. 
Rationale for hydrocortisone dosing: see section 6, Background, for rationale on dosing.   
Laboratory. One blood sample (1ml) for a cortisol level will be obtained within 4 hours 
prior to initiation of study drug for each enrolled patient. The sample of blood from each 
center will be labeled study patient ID and shipped to a central laboratory (The University 
of New Mexico CTSC Research Lab) in Albuquerque, New Mexico. The cortisol levels 
will be measured by the IMMULITE 1000 cortisol procedure (chemiluminescent system).  
Blood for cortisol levels is not mandatory for study if parents wish to decline blood draw 
for this timed study lab. Cortisol levels obtained by clinical team will be collected from 
medical chart. The relationship between cortisol concentrations and response to 
hydrocortisone, severity of illness and outcomes will be analyzed.    
The literature shows conflicting results on the value of cortisol concentrations in 
determining therapy. Infants often respond to glucocorticoids regardless of cortisol 
levels. While we found that infants with cortisol values <15 mcg/dl had positive 
responses to hydrocortisone in a small retrospective study,13 other studies were unable 
to use cortisol values to predict the severity of illness, need for cardiovascular support, 
or the response to treatment.10,14,50 
Echocardiograms. If an echocardiogram is ordered by the clinical team, the clinical 
report will be labeled with patient ID and will be sent to the NRN Data Coordinating 
Center at RTI. The following measurements will be collected if available: shortening 
fraction, ejection fraction presence of ductus and diameter, Left atrium to aortic ratio, 
presence of diastolic retrograde flow in descending aorta, velocity in left pulmonary 
artery, pressure gradient across PDA and shunt direction, tricuspid regurgitation, right 
ventricular function, evidence of pulmonary hypertension, atrial and ventricular 
dimensions, isovolumic relaxation and contraction times, presence of any defects and 
myocardial performance indices if available (some institutions do not have equipment to 
determine indices like wall stress).  
 
Concurrent medications. All concurrent medications just prior and during the course of 
study drug administration will be recorded including dopamine, dobutamine, epinephrine, 
norepinephrine, milrinone, vasopressin, sedatives (i.e. morphine, fentanyl, versed), any 
steroids, respiratory medications (i.e. inhaled nitric oxide, surfactant), neuromuscular 
blockers and prostaglandins. Inotrope duration and dosing (maximum drip doses) will be 
specifically collected for evaluation of study drug effect in addition to collecting total fluid 
volume received. Inotropes and volume expanders may be given as directed by clinical 
team. Once patients are enrolled in the study, they will not be allowed to receive 
dexamethasone or indomethacin/ibuprofen while on study drug. Dexamethasone is an 
extremely potent glucocorticoid, and risks of using the two steroids at the same time are 
unknown. The concurrent use of dexamethasone for airway edema will not be allowed. 
The combined use of a glucocorticoid and indomethacin is associated with spontaneous 
intestinal perforation in very preterm newborns. Although our study population should not 
be at risk of this complication, it seems prudent to avoid this combination therapy.  
Initiation of indomethacin or ibuprofen or any anti-hypertensive medication will result in 


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discontinuation of study drug. Data collection will continue and all analysis will be 
intention to treat. 
Open-label hydrocortisone will be discouraged. If the attending physician feels that it 
is necessary to administer open-label hydrocortisone for vasopressor (inotrope)-resistant 
hypotension, we will first encourage maximum vasopressor (inotrope) therapy, to include 
at least a dopamine dose of 10 mcg/kg/min and a second drug at a dose of at least 10 
mcg/kg/min of dobutamine or 0.1 mcg/kg/min of epinephrine. We will recommend dosing 
of hydrocortisone as outlined in this protocol. The max total daily dose that any infant 
would receive if open-label hydrocortisone were used would be 5 mg/kg/day. Some 
small studies have used up to 5-7 mg/kg/day without adverse events.15,51,52 Some 
providers obtain cortisol values to direct therapy but cortisol values obtained in this 
population have shown very little correlation to severity of illness or response to therapy 
we recommend, until more data is available, that cortisol values are not used to direct 
therapy. 10,14,51 Data collection will continue, and all analyses will be intention to treat. 
d.  Primary & Secondary Outcomes 
Primary Outcome. The primary outcome will be death or neurodevelopmental 
impairment at 22-26 months. Neurodevelopmental impairment will be defined as any of 
the following deficits: a cognitive, language or motor score less than 1 SD below the 
mean on the Bayley Scales of Infant Development III (BSID), gross motor functional 
(GMF) level ≥1, visual impairment or blindness in any eye, hearing impairment, or 
seizure disorder. The disability can be mild, moderate, or severe and will be defined as 
per the NRN standard definitions at the time of assessment (general definitions are listed 
in Table 7). Assessment will be performed by certified NRN examiners who will be 
blinded to treatment assignment group. From previous NRN trials, we anticipate a follow-
up rate of 90%. At the time of follow-up, a medical history will be obtained; growth 
parameters and a BSID-III neurological and vision examination will be performed. 
Table 7.  Disability definitions 
Disability Severity 
Exam Component 
Criteria 
Mild-to-moderate 
Bayley Scales 
(a) 
BSID cognitive score >1 SD below mean but not >2 SD 
BSID language score >1 SD below mean but not >2 SD 
BSID motor score >1 SD below mean but not >2 SD 
NF05 Impairment 
(b) 
GMF level of 1 or 2 
Any seizure disorder1 
Any hearing deficit 2 
Other impairment  
(c) 
 Visual impairment 3 
 
 
 
Severe 
Bayley Scales 
(A) 
BSID cognitive score >2 SD below mean 
BSID language score >2 SD below mean 
BSID motor score >2 SD below mean 
NF05 Impairment 
(B) 
GMF level 3 or greater 
Blindness4 
Profound hearing loss5 
1. Any active or history of seizure(s) or seizure disorder, as noted in history or by chart review.  
2. Hearing deficit where there is some amplification required (hearing aids or cochlear implants) in one or both ears as 
noted by history or chart review that does not reach level of profound hearing loss as defined in the severe 
category. 


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3. Visual impairment in one or both eyes per NRN standard follow-up (wears or was prescribed corrective lenses or 
other abnormality or blind but some functional vision) from chart review or history that does not reach level of 
blindness as defined in the severe category. 
4. Blindness (no useful vision) per NRN standard follow-up as noted by history or chart review. 
5. Profound hearing loss per NRN standard follow-up (in any ear as noted by inability to understand commands or 
communicate with examiner with or without amplification) by history or chart review. 
 
Level of Disability 
Definition 
Normal 
None of either (a) or (b) or (c) 
Mild 
Any of (a) but none of (b) or (c), OR 
Any of (b) or (c) but none of (a) 
Moderate 
At least one from each of (a) and [(b) or (c)] 
Severe 
At least one of (A) or (B) 
Secondary Outcomes. Secondary outcomes will include measures of severity of illness 
using the oxygenation index and respiratory severity score (mean airway pressure X 
Fio2), 53 cardiovascular stability (Table 8) and short-term outcomes prior to discharge 
(Table 9). Measures of short term outcomes and cardiovascular stability will be 
compared between groups and in relation to each other.  
Table 8.  Cardiovascular measures 
Blood Pressure 
Blood pressure from before to after study drug administration (continuous) 
Heart Rate 
Heart rate from before to after study drug administration (continuous) 
Fluid (volume) 
Administration 
Presence and number of fluid boluses given prior to study drug and during the study 
drug administration.    
Inotrope Administration 
The presence of inotrope initiation & presence of inotrope exposure at days of life 3, 
5 & 7 (dichotomous) 
Inotrope Duration 
Number of total days (complete 24 hours=1 day) an infant remains on any inotrope 
(continuous)  
Inotrope Total Dose 
Peak dose in 24-hour periods for 10 days after initiation of study drug. 
Table 9.  Short-term outcomes 
Duration of mechanical 
ventilation 
Number of days of laryngeal intubation and mechanical ventilation 
Days to full feeds 
Day of age when enteral feeds ≥ 120 cc/kg/day (continuous) 
Need for gastrostomy tube 
Need for gastrostomy tube before discharge (dichotomous) 
Duration of O2 requirement 
Number of days on oxygen while in hospital (continuous) 
Need for home oxygen 
Infant was discharged to home on oxygen (dichotomous) 
Length of hospital stay 
Number of days from birth to date of first discharge (continuous) 
Renal insufficiency 
Presence of creatinine >2.0 in first 7 days of age (dichotomous) 
NEC 
Presence of NEC stage II or greater at any time prior to discharge (dichotomous) 
Death 
Presence of death before discharge (dichotomous) 
Head imaging 
Any result from head imaging performed by the clinical care team (head ultrasound, 
magnetic resonance imaging, CT scan); no abnormalities noted, IVH, PVL 
 ECMO therapy 
 ECMO administered at any time while in hospital 
 


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e. Sample Size Estimate 
Determining a sample size based on available data is limited by the available studies on 
long-term outcomes including neurodevelopmental impairments or death in term and late 
preterm infants who have cardiovascular instability and require cardiovascular support. 
This sample size is based on the best available data, which is closest to the population 
proposed to study. Based on previous data, the incidence of death or any 
neurodevelopmental impairment (permanent hearing loss, blindness, moderate or 
severe cerebral palsy or Bayley MDI or PDI scores <70) was 32% in a similar population 
of critically ill newborn infants with respiratory distress and in need of mechanical 
ventilation, but excluding congenital diaphragmatic hernia defects.39 Based on 4 
additional studies in similar populations of term and late preterm infants with respiratory 
failure, the average incidence of death or any neurodevelopmental impairment was 30%. 
54,55,56,57 If these studies had all included mild impairment the event rate would have been 
higher.  
 
The trial is powered at 80% to detect a reduction in the primary outcome of death or 
any neurodevelopment impairment at 22-26 months from 30% to 20%, for a relative risk 
reduction of 33%, and a relative risk of 0.67, using a two tailed test with 5% Type I error. 
Allowing for 10% attrition, the required sample size for this scenario is 646 (Table 10). 
This sample size will also provide >80% power to detect treatment differences in 
important secondary outcomes of days in the NICU, intubated and on a ventilator and 
hours on inotropes without adjusting for multiple comparisons (Table 11).”   
Table 10.  Enrollment/time/consent estimates  
 
 
 
 
 
Because of the lack of data on outcomes in this population with which to ascertain power 
calculations with high confidence, the overall event rate of any NDI or death in this 
population will be calculated either: 1 year after the first patient is evaluated at 22-26 
month follow-up or after 30% of a planned enrollment of 646; whichever occurs first. At 
this point, the number needed to achieve 80% power, to detect a difference of 10% with 
an alpha of 0.05 and a 2 sided t-tail test, will be recalculated. 
 
Table 11.  Secondary outcome effect sizes  
 
 
 
 
 
f. 
Analytical Plan 
 
All analysis will be conducted by intention-to-treat analysis. To ensure that 
randomization has achieved the desired balance, all demographics will be compared 
Reduction in death or 
neurodevelopment delay 
at 22-26 mo 
Total enrollment 
(including 10%loss) 
Months to complete 
enrollment if consent rate 
60% 
Months to complete 
enrollment if consent rate 
70% 
10% 
646 
48 
41 
 
Our previous baseline data 
Effect size 
Sample size per group 
Days in NICU 
17.3 
3 days 
310 
Days on ventilator 
8.4 
2 days 
140 
Hours on inotropes 
81.4 
24 hours 
179 


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using Fisher’s exact or chi-square tests for categorical factors and t tests or non-
parametric tests for continuous outcomes. Dichotomous outcomes including the primary 
outcome will be compared between the hydrocortisone-treated group and control groups 
while adjusting for NRN center differences using robust Poisson regression, so that 
adjusted relative risk estimates of the treatment effect can be obtained. For continuous 
outcomes, non-normally distributed data may be log-transformed prior to analysis. 
Secondary analyses may be performed adjusting for gestational age or other critical 
baseline covariates that may be imbalanced across the two treatment groups, in addition 
to center. Short-term continuous outcomes will be compared between those receiving 
hydrocortisone and those on placebo using linear regression adjusting for NRN center 
and other critical baseline covariates that may be imbalanced.  
 
g. Available Population 
With all NRN Centers enrolling into the observational study (which also excluded those 
with major congenital heart disease, acute hypotension resulting directly from known 
acute maternal and/or fetal hemorrhage within 24 hours prior to delivery, pituitary 
hypoplasia, congenital adrenal hyperplasia, or known chromosomal disorder), ~100-115 
mechanically ventilated infants in this gestational age range are admitted to NRN 
Centers each month and 25% of these received inotropes (21% if exclude 
encephalopathy, CDH, and omphalocele and those who receive cooling for HIE). We, 
therefore, anticipate ~22 to 25 eligible infants each month.    
Infants in the same age group within the NRN with hypoxic ischemic encephalopathy 
may be eligible for the ongoing cooling studies in the NRN. However, infants who are 
cooled or have HIE will be ineligible for this study. 
h. Estimated Recruitment Time 
With 60% consent, 48 months would be needed to enrollment goal. Anticipating delays 
in startup and missed infants, study enrollment should be completed in a little over four 
years.  
8. Risks and Benefits 
Short-term adverse events. The following will be reported within 72 hours of diagnosis and 24 
hours of discovery:  
 
Mortality. No study of hydrocortisone therapy in newborns or in other critically ill 
populations has shown an increase risk in mortality, and some have shown decreased 
risk of death.11,12 This study population is at high risk of death from the underlying 
diseases (1.2%–11%).18,39   
 
Late-onset (≥ 5 days) culture-confirmed infection. Recent large randomized controlled 
trials in adults and preterm newborn infants showed no increased risk of infection from 
7–14 days of glucocorticoid treatment.2,5 However, culture-proven late onset infection will 
be tracked and reported. Early and late onset culture-proven infection in this population 
is 1.4% and 4.2% respectively (Vermont Oxford Network 2009). Anticipated incidence 
<4.2%. 
 
Gastrointestinal perforation. In contrast to the extremely low birth weight infant where the 
incidence of spontaneous intestinal perforation is 4%, this patient population is 


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developmentally more mature and should not be at risk for this event, particularly since 
these patients will not be simultaneously exposed to indomethacin.14  
 
Hypertension. These infants are often on inotropes, which often cause high blood 
pressure by themselves. Glucocorticoids’ actions are to increase blood pressure. It is 
unknown if the combination of these two therapies results in a higher occurrence of 
hypertension. This will be tracked by counting the number of 12-hour periods in which 
the blood pressure was higher than 95thpercentile for weight and age and the receipt of 
any antihypertensive medication.48 Incidence is unknown. 
 
Hyperglycemia. Higher dose glucocorticoids can raise blood glucose levels acutely and 
for short periods of time (hours), without long-term consequences. No study to date has 
shown a need for insulin secondary to glucocorticoid administration for the treatment of 
hypotension. Data on the use of insulin will be collected if administered during the study 
drug time and when glucose is >180mg/dl on at least two determinations at least 6 hours 
apart.14 Anticipated incidence <1%. 
Other Potential issues 
 
Adrenal suppression. Even in the most premature infants, this brief period of therapy has 
not previously been associated with adrenal suppression.58 If any infant shows signs 
consistent with adrenal insufficiency after discontinuation of the study drug (hypotension, 
oliguria, hyponatremia, hyperkalemia), a blood sample can be sent for cortisol and 
therapy with hydrocortisone reinstituted if deemed necessary by the clinical care team.  
 
Neurodevelopmental deficits. The neurodevelopmental benefits or risks of using 
hydrocortisone for the treatment of cardiovascular insufficiency is unknown. This RCT 
will be an important addition to the literature regarding long-term risks/benefits of this 
therapy.59 No previous study has shown adverse neurodevelopmental effects of 
hydrocortisone treatment in the newborn period in extremely low birth weight 
infants.52,60,61 Because this study population is more mature, it is even less likely to 
adversely impact this proposed study population; however, our study design will enable 
us to evaluate that issue.  
 
Persistent hypotension. Infants will be treated in the routine manner by the attending 
clinicians in their respective centers to allow real-world design. Open-label 
hydrocortisone is discouraged but if given, the recommended plan is listed in the 
methods section above. Data on infants who receive open-label hydrocortisone will be 
collected and/or on infants who receive 3 different types of inotropes or more.  
Data Safety and Monitoring Committee (DSMC) Safety Monitoring.    
 
a. Adverse events to be monitored 
Adverse events to be monitored will be those previously associated with 
glucocorticoid therapy, including hyperglycemia, hypertension and gastrointestinal 
perforation. Any infant who develops new, sustained hyperglycemia (>180mg/dl on at 
least two determinations at least 6 hours apart or receiving insulin) or new, sustained 
hypertension (mean arterial pressure >95th percentile for age on four serial 
determinations over at least 12 hours or receiving antihypertensive) may have study 
drug held or discontinued if, in the opinion of the attending neonatologist, there is no 
plausible alternative explanation for these findings (such as new thrombus). Not enrolling 
very preterm infants and excluding infants receiving indomethacin/ibuprofen should 
minimize the possibility for spontaneous GI perforation. These short term adverse events 
as defined here, should be reported within 24 hours of discovery to PI. 


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Also similar to the NRN hydrocortisone extubation trial, we will also specifically 
monitor for signs of adrenal insufficiency for 3 days after study drug is discontinued, 
including hypotension and oliguria, as well as hyponatremia and hyperkalemia on 
clinically obtained electrolyte specimens. Signs of adrenal insufficiency within 3 days 
after study will be reported within 24 hours of discovery. Previous studies of 
hydrocortisone at various doses have not reported these signs after discontinuation of a 
tapering course of the drug.  
Patients who develop hypotension and oliguria (shock) significant enough in the 
judgment of the attending neonatologist to require support with volume and/or 
vasopressors may have a clinically indicated blood sample drawn for cortisol and may 
be restarted on hydrocortisone or other therapy for shock at the discretion of the clinical 
attending. Open-label hydrocortisone should be given at a test dose of 1mg/kg, with 
continuation of the therapy based on clinical response to the first dose. Persistent 
hypotension despite inotrope therapy and study drug will be treated per the routine of 
each center as directed by the treating clinician. Open-label hydrocortisone use will be 
considered a protocol deviation and it will be reported to DSMC if this deviation occurs in 
more than 20% of those enrolled.  
Serious adverse events to be reported to NICHD within 24 hours include death, late 
onset sepsis, hyperglycemia receiving insulin, hypertension receiving antihypertensive  
medication or intestinal perforation with an assessment as best as possible as to the 
cause of the perforation (NEC, spontaneous, other). 
b. Interim safety monitoring  
The DSMC will compare the incidence of death and a composite of serious adverse 
events including death, late onset sepsis, intestinal perforation, and hyperglycemia 
requiring insulin between the two treatment arms after every 100th infant reaches status 
(death, discharge, transfer or 60 days of age). Since 646 infants are to be enrolled in this 
trial, this will involve interim looks approximately once every 9 months, or after the 
enrollment of every additional 160 infants, giving a Pocock boundary of 2.413, with a 
corresponding significance level of p<0.0158 (Pocock, 1977). Such reports will be 
forwarded to the Chair of the DSMC when there is any suggestion of a trend towards a 
difference between the two treatment arms emerging. They will also be made available 
to the full DSMC at their scheduled meetings after 50% and 75% of the trial infants reach 
status as defined by the GDB. Interim efficacy analysis using O’Brien-Fleming stopping 
bounds will also be made available to DSMC when 50% of primary outcome data is 
available.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(ef) 


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Nomenclature 
 
ACTH 
adrenocorticotropic hormone 
ARDS 
acute respiratory distress syndrome 
BP 
blood pressure 
BSID 
Bayley Scales of Infant Development 
CLD 
chronic lung disease 
CRH 
corticotrophin-releasing hormone 
CT 
computed axial tomography 
DSMC 
Data Safety and Monitoring Committee 
ECMO 
extracorporeal membrane oxygenation 
GA 
gestational age 
GMF 
gross motor function 
HPA 
hypothalamic-pituitary-adrenal 
HUS 
head ultrasound 
IVH 
intraventricular hemorrhage 
NEC 
necrotizing entercolitis 
NICU 
newborn intensive care unit 
NRN 
Neonatal Research Network  
PMA 
postmenstrual age 
PVL 
periventricular leukomalacia 
RCT 
randomized controlled trial 
SD 
standard deviation 
SIP 
spontaneous intestinal perforation 
 
 
 
 
 
 
 
 


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