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Subscribe to eNeonatal ReviewFEBUARY 2009: VOLUME 6, NUMBER 6

Shock and Corticosteroids

In this Issue...

Shock in neonates can be the end result of several conditions, including hypovolemia, cardiac dysfunction, and peripheral vasodilation and capillary leak, as seen in sepsis. Often, despite treatment with fluid resuscitation and vasopressor agents, blood pressure can remain critically low, compromising adequate blood flow to vital organs. Low blood pressure has been associated with increased mortality, intraventricular hemorrhage, and adverse neurodevelopmental outcomes. Many symptoms observed in critically ill neonates, such as hypotension and electrolyte disturbances, are similar to the symptoms of adrenal insufficiency. The immaturity of the hypothalamic-pituitary-adrenal (HPA) axis in neonates can lead to an inadequate response to stress, a condition known as relative adrenal insufficiency, which may also contribute to the etiology of the hypotension.

In this issue, we will examine the use of corticosteroids, particularly hydrocortisone, for the treatment of hypotension in critically ill newborns. As hypertension is a common side effect in individuals of all age-groups treated with corticosteroids, these agents have thus been used to raise the blood pressure of those in shock. Physiologic stress doses of hydrocortisone have also been examined as a treatment for newborns with relative adrenal insufficiency.
THIS ISSUE
IN THIS ISSUE
COMMENTARY from our Guest Authors
HYDROCORTISONE FOR THE TREATMENT OF REFRACTORY HYPOTENSION IN NEWBORNS
CARDIOVASCULAR EFFECTS OF TRANSIENT ADRENAL INSUFFICIENCY AND RESPONSE TO TREATMENT WITH HYDROCORTISONE
UTILITY OF MEASURING CORTISOL CONCENTRATIONS IN PRE-TERM INFANTS
LONG-TERM NEURODEVELOPMENTAL OUTCOMES FOLLOWING HYDROCORTISONE THERAPY IN PREMATURE INFANTS
     
Course Directors

Edward E. Lawson, MD
Professor of Pediatrics
Johns Hopkins University
School of Medicine
Chief, Division of Neonatology
Vice Chair, Department of Pediatrics
Johns Hopkins Children's Center

Christoph U. Lehmann, MD
Associate Professor
Department of Pediatrics
Division of Neonatology
The Johns Hopkins University
School of Medicine

Lawrence M. Nogee, MD
Professor
Department of Pediatrics
Division of Neonatology
The Johns Hopkins University
School of Medicine

Mary Terhaar, DNSc, RN
Assistant Professor
Undergraduate Instruction
The Johns Hopkins University
School of Nursing
GUEST AUTHORS OF THE MONTH
Commentary
Susan W. Aucott, MD
Medical Director, NICU
The Johns Hopkins Hospital
Director, Neonatal Perinatal Fellowship Training Program
Johns Hopkins University School of Medicine
Baltimore, Maryland
     
Reviews
Monique D. Satpute, MD
Neonatology Fellow
Johns Hopkins University School of Medicine
Baltimore, Maryland
Guest Faculty Disclosure

Dr. Aucott does not have any financial relationships to disclosure

Dr. Satpute does not have any financial relationships to disclose.

Unlabeled/Unapproved Uses

The authors have indicated that they will reference the unlabeled/unapproved use of hydrocortisone for treating and preventing bronchopulmonary dysplasia in this publication.

Program Directors' Disclosures
LEARNING OBJECTIVES
At the conclusion of this activity, participants should be able to:

Review the signs and symptoms of relative adrenal insufficiency in newborns
Understand the physiologic impact of corticosteroids on the cardiovascular system of neonates
Discuss the indications for, and risks and benefits associated with, the use of corticosteroids for the treatment of hypotension in newborns
Program Information
CE Info
Accreditation
Credit Designations
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Learning Objectives
Internet CME/CNE Policy
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Length of Activity
1.0 hours Physicians
1 contact hour Nurses

Release Date
Febuary 25, 2009

Expiration Date
Febuary 24, 2011

Next Issue
March 12, 2009
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COMMENTARY
Refractory hypotension occurs when despite treatment with appropriate fluids and vasopressor therapy, low blood pressure and evidence of inadequate perfusion persist. Hypotension may be multifactorial, due to such underlying illnesses as poor cardiac output, sepsis, and hypovolemia. Relative adrenal insufficiency, a condition associated with an inadequate adrenal stress response to critical illness, may also contribute to the lack of response to routine therapy.1,2 In 2001, Seri and coworkers described the cardiovascular effects of administering physiologic doses of hydrocortisone, mimicking a stress response, to pre-term infants with refractory hypotension.3 Mean blood pressure increased significantly by 2 hours post-treatment, with continued improvement at 4 and 6 hours. Additionally, urine output improved, along with the decreased need for vasopressors. The use of hydrocortisone for the treatment of hypotension has since grown considerably.4

The physiologic mechanisms involved in the impact of corticosteroids on blood pressure are twofold.3 Acutely, steroids inhibit catecholamine metabolism and prevent reuptake of catecholamines, resulting in a prompt increase in blood pressure within hours of drug administration. In addition, steroids increase cytosolic calcium availability in vascular and smooth muscle cells, and prevent inflammatory vasodilation by inhibiting prostacyclin and nitric oxide production. Secondarily, glucocorticoids upregulate cardiovascular adrenergic receptors through increased gene expression, resulting in a more sustained response to treatment. This is particularly advantageous, as the attenuated cardiovascular responsiveness to catecholamines in severe disease states may be related to downregulation of the adrenergic receptors and is reversible through the induction of gene expression by glucocorticoids.

Although relative adrenal insufficiency may play a role in the refractory hypotension observed in some neonates, defining a population that could most benefit from hydrocortisone therapy has been challenging.5 Cortisol levels are low in utero6 and can remain low postnatally without any undue effects in pre-term infants.7 In the studies by Masumoto et al. and Baker et al., reviewed in this newsletter, low cortisol values were not helpful markers for defining those infants most likely to benefit from hydrocortisone therapy. Regardless of the etiology of the hypotension or baseline cortisol concentrations, those infants who do not respond to volume administration and high-dose vasopressors can benefit from the use of hydrocortisone because of its regulatory effects on the cardiovascular system.

As hydrocortisone use began to increase, evidence also mounted for the adverse neurodevelopmental consequences associated with neonatal exposure to another steroid, dexamethasone. A 2002 American Academy of Pediatrics statement advocated limiting corticosteroid use in neonates, in light of an increased incidence of cerebral palsy reported following dexamethasone exposure.8 In neuronal cell culture, stimulation of glucocorticoid receptors promotes apoptosis, whereas mineralocorticoid receptors inhibit apoptosis. Dexamethasone is entirely glucocorticoid in its effects, with high doses suppressing innate adrenal mineralocorticoid production.9 Hydrocortisone administered in stress physiologic doses provides a balance of glucocorticoid and mineralocorticoid activity. Encouraging data are emerging that support this in vitro observation in clinical studies. Studies by Watterberg et al. and Rademaker et al., discussed in this newsletter, present long-term follow-up on hydrocortisone-exposed infants with reassuring results, although neither study used hydrocortisone specifically for the treatment of hypotension.

Hydrocortisone is thus helpful for treating neonates in shock, particularly when hypotension persists despite fluid and vasopressor therapies. Although dosing is aimed at providing levels necessary during physiologic stress, it varies from 0.5 to 6 mg/kg/day (approximately 10 to 60 mg/m2), and the length of treatment and need for ongoing maintenance therapy are still not well understood. .


Commentary References

1. Watterberg KL, Scott SM. Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia. Pediatrics. 1995;95(1):120-125.
2. Huysman MW, Hokken-Koelega AC, De Ridder MA, Sauer PJ. Adrenal function in sick very pre-term infants. Pediatr Res. 2000;48(5):629-633.
3. Seri I, Tan R, Evans J. Cardiovascular effects of hydrocortisone in pre-term infants with pressor-resistant hypotension. Pediatrics. 2001;107(5):1070-1074.
4. Finer NN, Powers RJ, Ou CH, Durand D, Wirtschafter D, Gould JB, et al. Prospective evaluation of postnatal steroid administration: a 1-year experience from the California Perinatal Quality Care Collaborative. Pediatrics. 2006;117(3):704-713.
5. Aucott SW, Watterberg KL, Shaffer ML, Donohue PK; PROPHET Study Group. Do cortisol concentrations predict short-term outcomes in extremely low birth weight infants? Pediatrics. . 2008;122(4):775-781.
6. Bolt RJ, van Weissenbruch MM, Popp-Snijders C, Sweep CG, Lafeber HN, Delemarre-van de Waal HA. Fetal growth and the function of the adrenal cortex in pre-term infants. J Clin Endocrinol Metab. 2002;87(3):1194-1199.
7. al Saedi S, Dean H, Dent W, Cronin C. Reference ranges for serum cortisol and 17-hydroxyprogesterone levels in pre-term infants. J Pediatr. 1995;126(6):985-987.
8. American Academy of Pediatrics Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in pre-term infants. Pediatrics. 2002;109(2):330-338.
9. Almeida OF, Condé GL, Crochemore C, Demeneix BA, Fischer D, Hassan AH, et al. Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. FASEB J. 2000;14(5):779-790
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HYDROCORTISONE FOR THE TREATMENT OF REFRACTORY HYPOTENSION IN NEWBORNS
Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E, et al. A double-blind, randomized, controlled study of a “stress dose” of hydrocortisone for rescue treatment of refractory hypotension in pre-term infants. Pediatrics. 2006;117(2):367-375.

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Baker CFW, Barks JDE, Engmann C, Vazquez DM, Neal CR Jr, Schumacher RE, et al. Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns. J Perinatol. 2008;28(6):412-419.

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Ng and associates conducted a prospective, double-blind, randomized, controlled study to assess the effectiveness of “stress dose” hydrocortisone for rescue treatment of refractory hypotension in pre-term, very low birth weight (VLBW) infants during the first week of life. Stress dose hydrocortisone referred to the dosage considered equivalent to endogenous physiologic secretion of cortisol under the stress of acute illness. A total of 48 infants with refractory hypotension were recruited in a tertiary care neonatal intensive care unit (NICU). Subjects had a gestational age <32 weeks, a birth weight <1500 grams, systemic hypotension despite treatment with volume expanders (isotonic saline ≥30 mL/kg), and dopamine infusion ≥10 μg/kg/min within the first week of life. Half of the enrolled infants received stress dose hydrocortisone (1 mg/kg every 8 hours for 5 days), and the remainder received an equivalent volume of isotonic saline. Strict guidelines were provided for attending neonatologists regarding the use of volume expanders and vasopressors for the treatment of systemic hypotension.

There were no significant differences between the groups in terms of demographic or clinical characteristics, including gestational age, birth weight, Apgar score, age at commencement of vasopressors, lowest mean blood pressure, and age at commencement of hydrocortisone or placebo. A total of 79% of hydrocortisone-treated infants were weaned off vasopressor support within 72 hours of initiating the trial drug, compared with 33% in the placebo group. Subjects treated with hydrocortisone also had lower cumulative doses of vasopressors, less use of volume expanders, and shorter durations of vasopressor treatment compared with controls. Major respiratory and clinical outcomes did not differ significantly between the groups. Additionally, rates of chronic lung disease, necrotizing enterocolitis, and mortality, as well as length of hospitalization, were the same in both groups. The study was powered only to demonstrate an improvement in the number of patients who could be weaned off vasopressor support within 72 hours of starting treatment, not to change major clinical outcomes.

A 2008 retrospective, observational study by Baker and colleagues investigated 117 infants who received hydrocortisone for the treatment of refractory hypotension. The objective of the study was to evaluate the safety and efficacy of hydrocortisone therapy, and to determine the utility of serum cortisol values in predicting response to treatment. The authors hypothesized that hydrocortisone would be effective in the treatment of refractory hypotension and that the degree of response would depend on pretreatment baseline cortisol concentrations. Baseline serum cortisol concentrations were measured prior to the administration of stress dose hydrocortisone (45 mg/m2/day) to determine the extent of adrenal dysfunction and to help guide the maintenance dose regimen following stress dose treatment. After completion of 48 hours at stress doses, continuing treatment was based on cortisol values. The administration of hydrocortisone was associated with an increase in arterial pressure, a decrease in inotropic dose, and a reduction in oliguria. No correlations were observed between pretreatment baseline cortisol concentrations and gestational age, birth weight, or response to hydrocortisone treatment.

The results from both studies support the use of hydrocortisone in newborns with refractory hypotension, in order to wean them from vasopressor support. This finding is beneficial, because high doses of vasopressors can compromise cardiac output and systemic perfusion. Baker and colleagues showed that obtaining cortisol levels was not helpful in guiding therapy with hydrocortisone. The use of hydrocortisone in combination with indomethacin has been associated with an increased risk for spontaneous gastrointestinal perforation. Ng and coworkers suggested that the small number of perforations reported in their study could have been due to the shorter course of hydrocortisone or to the use of prophylactic omeprazole. In the study by Baker and associates, rates of grade III and IV intraventricular hemorrhage, nosocomial bacterial and fungal infections, and hyperglycemia among hydrocortisone-treated infants were similar to those among institutional historic controls, further supporting the safety of hydrocortisone therapy in this patient population.
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CARDIOVASCULAR EFFECTS OF TRANSIENT ADRENAL INSUFFICIENCY AND RESPONSE TO TREATMENT WITH HYDROCORTISONE
Yoder B, Martin H, McCurnin DC, Coalson JJ. Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons. Pediatr Res. 2002;51(4):426-432.

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Noori S, Friedlich P, Wong P, Ebrahimi M, Siassi B, Seri I. Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated pre-term and term neonates. Pediatrics. 2006;118(4):1456-1466.

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Yoder and coworkers used an animal model to determine the postnatal urinary cortisol excretion rate (UCER) as a measure of postnatal adrenal function, and evaluated the relationship of UCER with cardiac performance and early hydrocortisone replacement therapy. Pregnant baboons underwent scheduled hysterectomy at 125 days' gestation (term=185 days); the premature animals were intubated, given surfactant, and started on parenteral nutrition. Significant hypotension was defined as mean arterial blood pressure <25 mm Hg. Hypotension was initially treated with additional volume supplementation and the use of inotropic support. Dopamine was initiated and increased to a maximum of 20 μg/kg/min, as needed. If hypotension continued, dobutamine was added. If mean blood pressure failed to improve within 2 to 4 hours, hydrocortisone was administered at doses of 0.5 to 1 mg/kg in 6-hour intervals, until either mean blood pressure increased to >28 mm Hg or a maximum of 4 doses were administered. Echocardiographic studies were performed at 1, 6, and 24 hours of age, then at 24-hour intervals, until elective necropsy at 14 days of age. Urine was collected continuously at 6-hour intervals for cortisol assays.

Of the 21 baboons studied, 8 received hydrocortisone therapy for refractory hypotension. Reduced UCER patterns were observed in the first 24 hours in those who required hydrocortisone. Cortisol-treated animals had lower mean blood pressure, worse metabolic acidosis, increased fluid needs, and impaired left ventricular function between 12 and 48 hours of age. Adrenal cortisol secretion improved significantly (p<0.02) over the first 3 days in immature baboons; failure to achieve increased UCER after the first day of life correlated with poor cardiovascular function that improved with hydrocortisone therapy. No differences in gas exchange or ventilatory support were observed between the 2 groups.

In this study, the findings of an impaired early cortisol stress response in immature baboons and its impact on cardiovascular stability are consistent with those described in very premature infants. Limitations of this model included elective C-section, lack of premature labor/rupture of the membranes, absence of chorioamnionitis, and no antenatal steroid therapy. However, this model may be useful for future studies of pharmacologic therapies for adrenal insufficiency in premature humans.

The cardiovascular effects of hydrocortisone were also investigated by Noori and associates. The authors conducted a prospective, observational study investigating whether hydrocortisone administration was associated with systemic hemodynamic changes in neonates, specifically examining the effects of hydrocortisone on cardiac function and organ blood flow. A total of 15 pre-term and 5 term neonates who required high-dose dopamine (≥15 μg/kg/min) received intravenous hydrocortisone 2 mg/kg/dose. Up to 4 additional doses of hydrocortisone, 1 mg/ kg every 12 hours, were administered if the patient remained hypotensive. Echocardiograms and vascular Doppler studies were performed before the first dose of hydrocortisone, and at 1, 2, 6 to 12, 24, and 48 hours thereafter. Measured cardiovascular parameters included cardiac output, stroke volume, systemic vascular resistance, myocardial performance index, and shortening fraction. Blood flow velocity measurements of the middle cerebral artery and the renal artery were also performed. The results of the study showed that hydrocortisone improved blood pressure up to 31% without compromising cardiac function, systemic perfusion, or end organ blood flow.

The sample size was small in this study, which was also not randomized, as each subject served as his/her own control. However, this is the first study to examine the systemic effects of hydrocortisone on cardiac function and organ blood flow in VLBW infants. This is significant, because high-dose vasopressors are often used to elevate blood pressure by increasing systemic vascular resistance, which can compromise cardiac output and systemic perfusion. Treatment with hydrocortisone may help to increase blood pressure and avoid these negative effects.
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UTILITY OF MEASURING CORTISOL CONCENTRATIONS IN PRE-TERM INFANTS
Ng PC, Lee CH, Lam CWK, Ma KC, Fok TF, Chan IH, et al. Transient adrenocortical insufficiency of prematurity and systemic hypotension in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):F119-F126.

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Masumoto K, Kusuda S, Aoyagi H, Tamura Y, Obonai T, Yamasaki C, et al. Comparison of serum cortisol concentrations in pre-term infants with or without late-onset circulatory collapse due to adrenal insufficiency of prematurity. Pediatr Res. 2008;63(6):686-690.

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In a prospective study, Ng and coworkers investigated the relationship between the pituitary-adrenal response and systemic blood pressure using the human corticotrophin-releasing hormone (hCRH) stimulation test, seeking to identify the site of hormonal dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis in VLBW infants. The stimulation test was performed on 125 infants at 1 week of life and 101 infants at 2 weeks of life in a tertiary care NICU. Blood samples were obtained for measurement of plasma adrenocorticotrophin (ACTH) and serum cortisol concentrations before hCRH (1 μg/kg) administration, and then at 15, 30, and 60 minutes after injection.

A significant association between serum cortisol concentration and the lowest blood pressure in the first 2 weeks of life, which was independent of gestational age and birth weight, was revealed. There was a negative correlation between cortisol concentrations and maximal and cumulative doses of dopamine, dobutamine, and adrenaline, as well as total volume of crystalloid and duration of inotrope treatment. Infants who required inotropic support had significantly higher ACTH responses on days 7 and 14 compared with those who did not require inotropes, suggesting that the pituitary reacts vigorously to exogenous stress. In contrast, infants who required vasopressors had poor cortisol responses in the presence of raised plasma ACTH concentrations on day 7, which signified adrenal hyporesponsiveness. Circulating cortisol concentrations increased substantially by the end of the second week of life, representing a significant recovery of adrenal function after 14 days.

The objective of the prospective, case-controlled study conducted by Masumoto and colleagues was to determine the difference in cortisol concentrations in pre-term infants with circulatory collapse beyond the first week of life compared with age-matched controls without cardiovascular compromise, using gas chromatography-mass spectrometry. A total of 22 infants were studied, with 11 in each group. There were no significant differences in clinical characteristics between the groups. Steroid hormones and their precursors were measured prior to hydrocortisone administration in the patient group, and were compared with the concentrations measured at the same times in the control group.

Cortisol concentrations did not differ significantly between the groups. However, the infants with late-onset circulatory collapse had a significantly higher accumulation of cortisol precursors compared with the control group (72.2 ± 50.3 vs 25.0 ± 28.5 μg/dL, respectively; P<.05). Specifically, the sum of the concentrations of DHEA (dehydroepiandrosterone), 17-OH-pregnenolone, pregnenolone, and their sulfates was elevated in the hypotensive group. The authors believe that this indicated limited 3β-hydroxysteroid dehydrogenase activity in these infants.

Masumoto and associates suggest that late-onset adrenal insufficiency in pre-term infants is thus not the result of an absolute deficiency in cortisol production, but rather a decreased ability to synthesize sufficient cortisol for the degree of clinical stress due to limited 3β-hydroxysteroid dehydrogenase activity. This phenomenon is transient, however, and appropriate cortisol production occurs with full 3β-hydroxysteroid dehydrogenase activity by the second week of life. The findings by Ng and coworkers support the hypothesis that the primary site of endocrine dysfunction in pre-term infants is located at the adrenal cortex. Although the results of both studies help to further elucidate the pathophysiology of adrenal insufficiency in these infants, these findings are unlikely to influence clinical practice. Obtaining cortisol levels prior to administration of hydrocortisone is not helpful when treating cardiovascular compromise in pre-term infants.
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LONG-TERM NEURODEVELOPMENTAL OUTCOMES FOLLOWING HYDROCORTISONE THERAPY IN PREMATURE INFANTS
Rademaker KJ, Uiterwaal C, Groenendaal F, Venema MM, van Bel F, Beek FJ, et al. Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in pre-term-born children. J Pediatr. 2007:150(4):351-357.

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Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ, et al. Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics. 2007;120(1):40-48.

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Rademaker and associates conducted a retrospective study to investigate neurodevelopment at school age in pre-term infants who received hydrocortisone therapy for bronchopulmonary dysplasia (BPD) in the neonatal period. A total of 226 infants were evaluated, of whom 62 received hydrocortisone for BPD and 164 did not. Hydrocortisone was initiated in ventilator-dependent children at 1 week of life. The treatment regimen was 5 mg/kg/day for 1 week, followed by a tapering schedule over 15 days. In the absence of respiratory improvement or when respiratory deterioration occurred after reduction of the dose, corticosteroid treatment was either prolonged or repeated at the discretion of the attending neonatologist. Patients returned for follow-up testing at school age. The Wechsler Intelligence Scale for Children-Revised (WISC-R) was used to estimate Intelligence Quotient (IQ), and magnetic resonance imaging (MRI) of the brain was performed. The patients were also given a 15-Word Memory Test (requires children to recall 15 unrelated words after 20 minutes) and a Visual-Motor Integration (VMI) test. Those offering the tests were blinded to the child's neonatal history. All children were seen by a pediatric physiotherapist who was blinded to the MRI findings, and the Movement Assessment Battery for Children (ABC) was administered to those without cerebral palsy.

The mean gestational age and birth weight of the steroid-treated children were lower than those of the non-steroid-treated children. The severity of illness was greater in treated children, who had increased needs for mechanical ventilation, surfactant, and inotropes, and an increased incidence of patent ductus arteriosus. No differences in occurrence of brain lesions on MRI were reported between the 2 groups. The unadjusted mean IQ at school age in the hydrocortisone-treated group was 98, compared with 101 in the unexposed group (P=.08), but was clearly not different when adjusted for gestational age, birth weight, gender, need for mechanical ventilation, and small for gestational age. Memory tests and VMI were the same in both groups. The incidence of cerebral palsy did not differ significantly between the hydrocortisone-treated and untreated groups.

Watterberg and colleagues conducted a multicenter, randomized, controlled trial to evaluate the efficacy of using hydrocortisone prophylaxis for the prevention of BPD. The initial study included infants with birth weights between 500 and 999 grams who were intubated in the first 12 to 48 hours of life. Randomization was stratified by study center and birth weight. Infants were given normal saline placebo or hydrocortisone, 1 mg/kg/day for 12 days, followed by 0.5 mg/kg/day for 3 days. No overall improvement in survival without BPD was observed in hydrocortisone-treated infants. A follow-up study examined patient outcomes at 18 to 22 months' corrected age. At the follow-up visit, growth parameters, standardized neurologic examinations, and developmental assessment using the Bayley Scales of Infant Development-II were performed. Neurodevelopmental impairment was defined as Mental Developmental Index or Psychomotor Developmental Index of <70, cerebral palsy, blindness, or deafness.

A total of 252 of the 291 survivors were evaluated at 18 to 22 months. Outcomes in the hydrocortisone-treated and placebo-treated infants were similar, with the exception of gastrointestinal perforation. Enrollment in the original study was halted early because of an increased incidence of spontaneous gastrointestinal perforation in hydrocortisone-treated infants, likely because of the interaction with early indomethacin therapy. The primary outcome of the study was the incidence of cerebral palsy, which did not differ significantly between the hydrocortisone- and placebo-treated groups. Growth was also similar between the groups.

Although hydrocortisone was not administered for hypotension, this is the first randomized, controlled trial aimed at evaluating the long-term effects of hydrocortisone therapy, with no increase in the incidence of cerebral palsy or in neurodevelopmental impairment reported. This is significant, because worse developmental outcomes and increased rates of cerebral palsy were observed in earlier studies of high-dose dexamethasone. Additional studies are needed to evaluate which patients would benefit from this therapy, bearing in mind the short-term side effects of gastrointestinal perforation when hydrocortisone is used along with indomethacin therapy. Although the study by Rademaker and coworkers was not a randomized, controlled trial, the findings also suggest that treatment with hydrocortisone does not adversely affect long-term neurodevelopmental outcome.

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At the conclusion of this activity, participants should be able to:

Review the signs and symptoms of relative adrenal insufficiency in newborns
Understand the physiologic impact of corticosteroids on the cardiovascular system of neonates
Discuss the indications for, and risks and benefits associated with, the use of corticosteroids for the treatment of hypotension in newborns
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Edward E. Lawson, MD has indicated a financial relationship of grant/research support from the National Institute of Health (NIH). He also receives financial/material support from Nature Publishing Group as the Editor of the Journal of Perinatology.
Christoph U. Lehmann, MD has received grant support from the Agency for Healthcare Research and Quality and the Thomas Wilson Sanitarium of Children of Baltimore City.
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