Evaluation of Hypothalamic-Pituitary-Adrenal Axis in Premature Infants Treated with Dexamethasone

Alkalay, Arie L.; Klein, Alan H.; Nagel, R.; Pomerance, Jeffrey J.

doi:10.1055/s-2007-994430

Cited by 37 publications

(33 citation statements)

References 17 publications

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“…Acute side effects of prolonged dexamethasone use in ELBW infants are well documented and include systemic hypertension, bowel perforation, infection, ventricular hypertrophy, metabolic derangements, and alteration of limbic-hypothalamic-pituitary-adrenal (LHPA) axis function (2,9,14,31,62,76,77). Although dexamethasone readily crosses the blood-brain barrier and binds glucocorticoid receptors (19,66,92), little animal data exist regarding possible glucocorticoid effects on long-term axis or central nervous system (CNS) in general.…”

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confidence: 99%

Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

Neal¹,

Weidemann²,

Kabbaj³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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Neal, Charles R., Jr., Gabrielle Weidemann, Mohamed Kabbaj, and Delia M. Vázquez. Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat. Am J Physiol Regul Integr Comp Physiol 287: R375-R385, 2004. First published April 29, 2004; 10.1152/ajpregu.00012.2004.-Until recently, the synthetic glucocorticoid dexamethasone was commonly used to lessen the morbidity of chronic lung disease in premature infants. This practice diminished as dexamethasone use was linked to an increased incidence of cerebral palsy and short-term neurodevelopmental delay. Of more concern is the fact that we know little regarding dexamethasone effects on long-term neurodevelopment. To study the effects of neonatal dexamethasone exposure on long-term neurodevelopment, we have developed a rat model where newborn pups are exposed to tapering doses of dexamethasone at time points corresponding to the neurodevelopmental age when human infants are traditionally exposed to this drug in the neonatal intensive care unit. Using a within-litter design, pups were assigned to one of three groups on postnatal day 2 (P2): handled controls, saline-injected controls, and animals receiving intramuscular dexamethasone between P3 and P6. Somatic growth was decreased in dexamethasone-treated animals. Dexamethasone-treated animals demonstrated slight delays in indexes of neurodevelopment and physical maturation at P7 and P14, but not P20. In adolescence (P45), there was no difference between groups in an open field test. However, as adult dexamethasone-treated animals were less active in the open field and spent more time in closed arms of the elevated plus maze. The serum corticosterone response to crowding stress in dexamethasone-treated animals was no different from controls, but they demonstrate a delay in return of corticosterone levels to baseline. These differences in behavior and hormonal stress responsiveness suggest that neonatal dexamethasone exposure may permanently alter function of the neuroendocrine stress axis. steroids; prematurity; brain; corticosterone; limbic-hypothalamicpituitary-adrenal axis SEVERE RESPIRATORY DISTRESS syndrome is commonly experienced in extremely low birth weight (ELBW) infants, resulting in various degrees of ventilator and/or oxygen dependency and subsequent onset of chronic lung disease (CLD). Until recently, administration of a prolonged course of postnatal dexamethasone to ELBW infants was frequently practiced in an attempt to lessen the progression of CLD. Although clinical trials using dexamethasone in this fashion failed to consistently demonstrate improvement in mortality or length of hospitalization, exposures of up to 42 days were commonly used in many neonatal units (4,8,17,55,56). A recent study examining the outcome of ELBW infants (birth weight between 500 and 750 g) found that 43% of those infants born from 1990 to 1992 received dexamethasone compared with 84% of ELBW infants born between 1993 and 1995 (40). Routine use of dexamethasone continued until Yeh and colleag...

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confidence: 99%

Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

Neal¹,

Weidemann²,

Kabbaj³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1 Treatment with intravenous dexamethasone has been shown to shorten the duration of mechanical ventilation in premature infants, 2 and to improve pulmonary function. 3 However, dexamethasone therapy has many potential side effects in premature infants, including hyperglycemia, 4 hypertension, 5 cardiomyopathy, 6 adrenal suppression, [7][8][9] and gastrointestinal bleeding. 10 Dexamethasone has been shown to cause neutrophilia and eosinopenia 11,12 in addition to inhibition of colony formation of the hematopoietic progenitor cells in in vitro experiments.…”

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Effect of Dexamethasone on Lymphocyte Subpopulations in Premature Infants with Bronchopulmonary Dysplasia

et al. 1999

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OBJECTIVE:This study was designed to determine the effect of dexamethasone treatment on peripheral blood lymphocyte counts and subpopulations in premature infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN:Peripheral blood lymphocyte subpopulations in 12 premature infants with BPD were analyzed before treatment with a 6-week course of dexamethasone (day 0), on days 3 and 10 of treatment, and 2 weeks after discontinuing dexamethasone therapy (day 56). Lymphocyte immunophenotypes were determined using direct two-color immunofluorescent staining followed by flow cytometry. RESULTS:The percentage of lymphocytes was significantly lower on days 3 (17.55 Ϯ 2.55) and 10 (20 Ϯ 11.8) of dexamethasone therapy compared with before (30.36 Ϯ 6.41) or after treatment. The percentage of T cells was significantly lower on days 3 and 10 of dexamethasone therapy (mean Ϯ SEM; 58.09 Ϯ 1.93 and 60.09 Ϯ 2.47, respectively) compared with before (67.09 Ϯ 4.24) or after treatment. The absolute number of T cells was significantly lower on day 10 of therapy. The percentage of CD4 ϩ cells was significantly lower on days 3 (38.91 Ϯ 2.49) and 10 (40.45 Ϯ 2.24) of therapy, and this decrease persisted after dexamethasone was stopped (36.73 Ϯ 3.41). The absolute number of CD4 cells was significantly lower on day 10 (1328 Ϯ 216) of therapy and reached a nadir on day 56 (1143 Ϯ 106). Similarly, the CD4/CD8 ratio was also significantly lower on days 3 and 10 of treatment (1.56 Ϯ 0.18 and 1.64 Ϯ 0.14, respectively) and reached a nadir on day 56 (1.04 Ϯ 0.13). CONCLUSION:Dexamethasone significantly reduced the percentage and absolute number of lymphocytes, T cells, and CD4 cells, as well as the CD4/CD8 ratio. A reduction in CD4 cells and in the CD4/CD8 ratio persisted 2 weeks after dexamethasone therapy was stopped. In contrast, the absolute number of B cells increased transiently, and CD8 cells were unaffected by dexamethasone. This alteration in lymphocyte subpopulations may help account for the clinically beneficial anti-inflammatory effect of dexamethasone in the treatment of BPD complicated by respiratory failure. The dexamethasone-induced decrease in CD4 cells may also increase the susceptibility of these infants to infection.Bronchopulmonary dysplasia (BPD) is a chronic lung disease associated with mechanical ventilation in premature infants and a common cause of morbidity in the neonatal intensive care unit. The incidence of BPD is Յ40% among infants with respiratory distress syndrome who require mechanical ventilation. 1 Treatment with intravenous dexamethasone has been shown to shorten the duration of mechanical ventilation in premature infants, 2 and to improve pulmonary function. 3 However, dexamethasone therapy has many potential side effects in premature infants, including hyperglycemia, 4 hypertension, 5 cardiomyopathy, 6 adrenal suppression, 7-9 and gastrointestinal bleeding. 10 Dexamethasone has been shown to cause neutrophilia and eosinopenia 11,12 in addition to inhibition of colony formation of the hematopoietic progenito...

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“…The ACTH stimulation test of 1 g has been evaluated in healthy adult volunteers, adult and pediatric patients with suspected or verified endocrine disorders, and in adults, children, and preterm infants treated with steroids (6,22,(31)(32)(33)(34). Stimulation tests using these lower doses of ACTH have been reported to be more sensitive in detecting insufficient adrenal function in critically ill preterm infants compared with the standard test (22).…”

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confidence: 99%

Maturity of the Adrenal Cortex in Very Preterm Infants Is Related to Gestational Age

Bolt

2002

Pediatric Research

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To study the maturity of the adrenal cortex in preterms born before 33 wk of gestation, basal levels of cortisol and cortisone and the cortisol and 17-hydroxyprogesterone (17-OHP) response to 1 g/kg adrenocorticotropic hormone stimulation were measured in 24 appropriate-for-gestational age preterm infants (26-33 wk; 690-1985 g). Gestational age influenced the response of cortisol, 17-OHP, and the ratio between cortisol/17-OHP in the studied infants. In preterms born Ͻ30 wk of gestation, levels of cortisol, and the ratio between cortisol/17-OHP were lower compared with preterms born between 30 and 33 wk. Levels of cortisone were higher in preterms born Ͻ30 wk, suggesting a lower activity of 11␤-hydroxysteroid dehydrogenase that may be related to maturity as well. The adrenal gland plays an important role during gestation. Steroid hormones produced by the fetal adrenal cortex are involved in the maturation of organ systems necessary for intrauterine and extrauterine life. For example, secretion of cortisol in late gestation is essential for lung maturation in sheep, rats, monkeys, and possibly humans (1, 2). It has been suggested that the adrenal cortex function may be more closely related to gestational age rather than to birth (3, 4), which implicates that in very preterm infants the adrenal activity may still be immature. Immaturity of the hypothalamic-pituitaryadrenal (HPA)-axis in preterm infants has been suggested to be associated with the occurrence of respiratory distress syndrome, chronic lung disease of prematurity, or even cardiovascular instability (5-7). Therefore, the ability of the HPA-axis to regulate, synthesize, and secrete cortisol in response to stress may be critical for survival and pulmonary development in very preterm infants.To evaluate the adrenal function the plasma cortisol response to i.v. administered ACTH is a common screening test. In general, 250 g synthetic ACTH is given as a bolus dose to stimulate cortisol release from the adrenal cortex, in adults as well as children as described by Wood et al. in 1965 (8). This supra-physiologic dose is much higher than required to produce a maximal adrenal response and could elicit an appropriate response despite of adrenal insufficiency (9, 10). Therefore, a lower dose of ACTH has been proposed to study the adrenal function.We hypothesize that differences in the maturity of the HPAaxis related to gestational age can be observed in the levels of hormones produced by the adrenal cortex and the adrenal response to ACTH in preterm infants of different gestational ages. The objective was to study basal levels of glucocorticoids and to establish the effect of stimulation of the adrenal cortex with ACTH in very preterm infants at the end of the 1st week of life. PATIENTS AND METHODS Patients.The study group consisted of 24 preterm infants with gestational ages ranging from 26 to 33 wk and birth weights ranging from 690 to 1985 g. Patients admitted to our July 11, 2001; January 10, 2002

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Evaluation of Hypothalamic-Pituitary-Adrenal Axis in Premature Infants Treated with Dexamethasone

Cited by 37 publications

References 17 publications

Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

Effect of Dexamethasone on Lymphocyte Subpopulations in Premature Infants with Bronchopulmonary Dysplasia

Maturity of the Adrenal Cortex in Very Preterm Infants Is Related to Gestational Age

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