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Pituitary-Adrenal Suppression and Recovery in Preterm Very Low Birth Weight Infants after Dexamethasone Treatment for Bronchopulmonary Dysplasia

Departments of Pediatrics and Chemical Pathology (C.W.K.L., D.C.F.C.), Prince of Wales Hospital, The Chinese University of Hong Kong; and the Department of Mathematics, The Hong Kong University of Science and Technology (M.Y.W.), Hong Kong

Address all correspondence and requests for reprints to: Dr. P. C. Ng, Department of Pediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

	Abstract

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High dose dexamethasone is frequently used for the treatment of neonatal respiratory conditions and to facilitate weaning from mechanical ventilation in preterm, very low birth weight infants. However, very little is known about the severity, site, and duration of steroid-induced hypothalamic-pituitary-adrenal axis suppression in this category of patients.

Twenty-three preterm, very low birth weight infants who received a full 3-week dose-tapering course of dexamethasone were prospectively studied, with a human CRH stimulation test performed at three different times: before the start of steroid treatment (week 0), immediately after the course (week 3), and 4 weeks after stopping dexamethasone (week 7). Plasma ACTH and serum cortisol concentrations were measured at 0 (baseline), 15, 30, and 60 min. Immediately after the steroid course (week 3), both basal and poststimulation plasma ACTH and serum cortisol concentrations were markedly suppressed. The hormone concentrations at 0, 15, 30, and 60 min in week 3 were significantly lower than their corresponding levels in week 0 (P < 0.0001 for both ACTH and cortisol) and week 7 (P < 0.0001 and P < 0.005 for ACTH and cortisol, respectively). In contrast, when the hormone levels in week 7 were compared to their corresponding concentrations in week 0, only the 60 min serum cortisol concentration in week 7 was significantly lower (P = 0.02).

The currently used dosage of dexamethasone caused severe pituitary-adrenal suppression immediately after treatment, but substantial recovery of the endocrine axis was observed 4 weeks after discontinuation of therapy. Although the recovery appeared to be earlier with the pituitary center, both pituitary and adrenal glands were capable of mounting a biochemically adequate response to exogenous human CRH stimulation at this stage. Steroid replacement therapy may be desirable at a time of stress in the immediate posttreatment period, but it would seem unnecessary 1 month after stopping dexamethasone treatment.

	Introduction

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HIGH DOSE dexamethasone is increasingly used for the treatment of bronchopulmonary dysplasia (BPD) in preterm, very low birth weight (VLBW) infants to facilitate weaning from mechanical ventilation (1). In recent years, its use has become more liberal, and there is now a tendency to prescribe the drug even earlier (1) and for lessening the severity of the respiratory distress syndrome (2). We previously investigated the adrenal response in preterm infants using the short tetracosactrin (Synacthen, Ciba, Basel, Switzerland) stimulation test before and after a 3-week course of dexamethasone and showed that the adrenal glands were suppressed at the end of steroid treatment (3). Although moderate recovery was noted 4 weeks after stopping therapy, a proportion of infants continued to have low basal cortisol concentrations, indicating possibly prolonged suppression of the hypothalamic-pituitary centers (3). In a recent study, we showed that the human CRH (hCRH) stimulation test is safe, reproducible, and capable of producing a consistent pituitary-adrenal response in preterm VLBW infants (4) similar to those seen in older children and adults (5, 6). As no systematic evaluation of pituitary-adrenal reserve has been performed with the hCRH stimulation test in this group of preterm infants before and after corticosteroid treatment for assessing the magnitude of dexamethasone-induced pituitary-adrenal suppression and recovery, this study was undertaken to prospectively evaluate a cohort of VLBW infants at risk of hypothalamic-pituitary-adrenal (HPA) axis suppression after receiving high dose dexamethasone for BPD.

	Subjects and Methods

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Study population

Twenty-three preterm infants admitted to the neonatal intensive care unit between August 1994 and December 1996 were prospectively enrolled in the study. Inclusion criteria were 1) a gestation of less than 32 weeks and a birth weight below 1500 g, 2) dependence on mechanical ventilation and/or supplemental oxygen of more than 40% on day 14 of age together with chest radiographic findings consistent with the changes of BPD, 3) commenced on a full 3-week course of systemic dexamethasone; and 4) did not receive postnatal inhaled corticosteroid treatment. Seventeen of the 23 infants received antenatal corticosteroid treatment. Infants were excluded if they had concurrent hypoglycemia, systemic infection, necrotizing enterocolitis, or major surgery in the preceding week.

Dexamethasone course

The decision to start systemic corticosteroid treatment rested entirely on the clinical judgment and discretion of the attending neonatologists. Our unit guidelines were 1) respirator dependence or oxygen requirement of more than 40% 2 weeks postnatally; 2) absence of any treatable cause that might prevent successful weaning, such as patent ductus arteriosus or infection; and 3) absence of any major contraindication for starting systemic corticosteroid therapy, such as uncontrollable hyperglycemia or hypertension, severe gastrointestinal hemorrhage, visceral perforation, or recent bowel surgery. Each infant was given a 3-week dose-tapering course of dexamethasone (dexamethasone sodium phosphate, Weimer Pharma, Rastatt, Germany) starting with 0.6 mg/kg·day during the first week; the dose was decreased to 0.3 mg/kg·day in the second week and was further reduced to 0.15 mg/kg·day in the third week (1, 3). The drug was given as a bolus iv injection in the morning (0800 h) and was changed to an oral preparation delivered via a nasogastric tube once full enteral feeding was established, and iv infusion was discontinued.

hCRH stimulation test

The hCRH stimulation tests were performed immediately before dexamethasone was started (week 0), at the end of the course (week 3), and 4 weeks after steroid treatment had ended (week 7). Almost all infants possessed an indwelling arterial line for blood sampling at the time of the first two tests, as most were still oxygen dependent. The third test was performed at the same time as the weekly measurement of hemoglobin and liver function via an intravascular venous line.

The hCRH stimulation test was performed between 0800–1000 h. Each vial (100 µg) of synthetic hCRH (Ferring, Arzneimittel, Wittland, Germany) was reconstituted and further diluted with sterile water to obtain a concentration of 2 µg/mL. Blood samples (0.5 mL) were taken from the indwelling intravascular line for measurement of baseline (0 min) plasma ACTH, and serum cortisol concentrations before hCRH (1 µg/kg) was administered by bolus iv injection. This dose of hCRH was based on our experience with preterm VLBW infants (4) and older children and on adult studies that demonstrated an effective stimulation of the pituitary and adrenal glands in the absence of any measurable adverse effects (5, 6). Three additional sets of blood samples were obtained 15, 30, and 60 min post-hCRH administration. Blood samples for plasma ACTH and serum cortisol assays were collected in chilled ethylenediamine tetraacetic acid bottles and plain containers, respectively. The blood samples were immediately immersed in ice and transported to the laboratory for processing. All samples were centrifuged at 3500 rpm for 15 min at 4 C, and the resulting plasma/serum was stored at -70 C until analysis. Vital signs of the patients, including temperature, heart rate, respiratory rate, blood pressure, and, for mechanically ventilated infants, serial arterial blood gases were monitored during and up to 2 h after the test.

ACTH and cortisol assays

The plasma ACTH concentration was measured by double antibody RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA), and serum cortisol was determined by solid phase RIA (Diagnostic Products Corp., Los Angeles, CA). The interassay coefficients of variation in the ACTH assay were 4.4% and 3.7% at 10.1 and 79.3 pmol/L, respectively. Those in the cortisol assay were 9.1%, 4.2%, and 4.0% at 159, 461, and 1260 nmol/L, respectively, with an accuracy better than the ±0.5 allowable limits recommended by the monthly Royal College of Pathologists of Australia quality assurance program. The plasma ACTH concentration in picomoles per L can be converted into picograms per mL by multiplying the figure by a factor of 4.5; likewise, the serum cortisol concentration can be converted from nanomoles per L to micrograms per dL by dividing the figure by 27.6.

Ethical approval

Ethical approval of the study was obtained from the research ethics committee of the Chinese University of Hong Kong. Informed parental consent was obtained for each case before commencement of the test.

Statistical analysis

The descriptive statistics on the demographic data were expressed as the mean and SEM, and for comparisons of hormone levels, multivariate repeated ANOVA was used.

	Results

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All 23 VLBW infants received the week 0 (pretreatment) and week 3 (immediately posttreatment) hCRH tests, but 5 missed the week 7 (4 weeks posttreatment) test. Of these 5 patients, 3 received repeated courses of dexamethasone because of severe BPD and died as a result of respiratory failure; the other 2 were discharged from the neonatal unit before the third test.

The clinical characteristics of the study population are summarized in Table 1. Table 2 and Figs. 1 and 2 show the plasma ACTH and serum cortisol concentrations in relation to exogenous hCRH stimulation during the three test periods. Immediately after the steroid course (week 3), both basal and poststimulation plasma ACTH and serum cortisol concentrations were markedly suppressed. The hormone concentrations at 0, 15, 30, and 60 min in week 3 were significantly lower than their corresponding levels in week 0 (F > 19.2; P < 0.0001 for both ACTH and cortisol) and week 7 (F > 19.8; P < 0.0001 and F > 10.9; P < 0.005 for ACTH and cortisol, respectively). In contrast, when the hormonal levels in week 7 were compared to their corresponding concentrations in week 0, only the 60 min serum cortisol concentration in week 7 was significantly lower (F = 6.2; P = 0.02).

View larger version (16K): [in this window] [in a new window]   Figure 1. The effect of hCRH stimulation on plasma ACTH concentrations (mean ± SEM) in preterm VLBW infants (n = 23) before (week 0), immediately after (week 3), and 4 weeks after completion (week 7) of a 3-week dexamethasone treatment course.

View larger version (17K): [in this window] [in a new window]   Figure 2. The effect of hCRH stimulation on serum cortisol concentrations (mean ± SEM) in preterm VLBW infants (n = 23) before (week 0), immediately after (week 3), and 4 weeks after completion (week 7) of a 3-week dexamethasone treatment course.

	Discussion

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Suppression of the HPA axis is one of the most serious adverse effects of corticosteroid therapy. As high dose dexamethasone is now widely prescribed for the treatment of various neonatal respiratory conditions (1, 2, 7, 8), an understanding of its influence on the HPA response in VLBW infants is important. Very little is known about the severity, site, and duration of dexamethasone-induced HPA axis suppression in this category of infants. As there is evidence to suggest that a single measurement of serum cortisol does not permit reliable assessment of pituitary-adrenal function because of episodic secretion (9), stimulation tests are essential for identifying infants with diminished endocrine reserve and impaired endogenous hormone production (10, 11). Tests with a central stimulating effect, such as the insulin stress test and metyrapone and CRH tests, are the commonly available methods for evaluating pituitary suppression. The insulin stress test, which induces hypoglycemia and stimulates the release of other hormones, including vasopressin, catecholamines, and oxytocin, is considered undesirable and possibly dangerous because of its potential adverse effects on the developing brain. The metyrapone test may cause acute adrenal insufficiency and cannot be recommended for sick preterm neonates. Synthetic ovine CRH has a relatively long plasma half-life compared to that of hCRH and may cause nonphysiological and prolonged stimulation on its target organs (12, 13). In contrast, hCRH causes shorter episodes of ACTH and cortisol secretion, which simulates more closely the physiological episodic secretion of endogenous CRH (13). Despite the potential problem that exogenous hCRH may become rapidly bound to the circulating CRH-binding protein in vivo, we have demonstrated that the configuration of the response curve, the magnitude of response, and the timing of peak concentrations for both plasma ACTH and serum cortisol in VLBW infants resulting from exogenous hCRH stimulation are comparable to those in normal human adult subjects (4). However, as there is no established reference standard against which to assess the adequacy of the pituitary-adrenal response in VLBW infants, we chose to perform the hCRH tests at the three time periods in relation to steroid administration so that the first test performed immediately before starting dexamethasone treatment could provide a reference point against which later responses might be judged.

Our results suggested that the pituitary-adrenal response to exogenous hCRH before postnatal systemic steroid treatment (week 0) were comparable to those observed in our previous study (4) and those in healthy adult subjects (6), which further supports the idea that the pituitary-adrenal axis is functionally mature at these early times of gestation (4). We also demonstrated that antenatal maternal dexamethasone therapy did not influence the HPA axis response to hCRH stimulation at 2–3 weeks of postnatal age. Severe pituitary-adrenal suppression was, however, observed immediately after the 3-week course of dexamethasone. This was followed by substantial improvement in endocrine function 1 month after stopping steroid treatment. There are several possible explanations for the progressive changes and distinct pattern of pituitary-adrenal response at the three different time periods. One possibility is that the sequential changes in response were unrelated to dexamethasone, and we were simply observing the normal maturation process of the pituitary and adrenal glands during late fetal and early neonatal life. This is unlikely, as there is no conceivable reason to explain the sudden regression and subsequent rapid recovery of pituitary-adrenal function in the absence of external influences. Another plausible explanation that could be partially contributory, is that the changes in response might have been stress related, as most of these infants were less ill at the end of the steroid course. This hypothesis, however, could not fully explain the return of a highly responsive pattern at week 7 when most infants were clinically stable. The most important factor is likely to be the suppressive effect of dexamethasone on the pituitary-adrenal axis, with almost full recovery 4 weeks after stopping steroid treatment. The pituitary higher center was able to recover earlier than the adrenal glands. The 60 min cortisol level in week 7 was still significantly lower than the corresponding concentration in week 0, indicating that there was a minor degree of residual adrenal suppression. This phenomenon has also been observed in adult patients treated with high dose corticosteroids (14, 15), suggesting that the pattern and sequence of HPA axis recovery are already ‘programed’ at this early stage.

Other studies have reported various degrees of adrenal suppression in preterm neonates after receiving dexamethasone treatment (3, 16, 17, 18). Only one study examined the effect of systemic dexamethasone on pituitary reserve using ovine CRH (19). Although this study showed suppression of the HPA axis immediately after steroid treatment, it was limited by having only one poststimulation hormone measurement at 30 min and did not attempt to assess the duration of pituitary-adrenal suppression. Furthermore, our results demonstrated unequivocally for the first time in VLBW infants that the pituitary center was almost fully recovered 4 weeks after discontinuation of dexamethasone. These findings refute our previous postulation that corticosteroid treatment causes prolonged suppression of the higher centers (3) and further illustrates the importance of performing a properly conducted stimulation test as opposed to taking a random cortisol measurement for the assessment of pituitary-adrenal reserve.

We conclude that the currently used dosage of dexamethasone, as described in this study, induces severe pituitary-adrenal suppression in VLBW infants immediately after treatment, which is followed by substantial recovery 4 weeks after stopping therapy. Both the pituitary and adrenal glands are capable of mounting a biochemically adequate response to exogenous hCRH stimulation at this stage, but the sequence of improvement appears to be earlier for the pituitary higher center. Throughout the recovery phase, none of our infants developed any signs of clinical or electrolyte disturbances suggestive of adrenal insufficiency. Steroid replacement therapy may be desirable at a time of stress in the immediate posttreatment period, but it would seem unnecessary 1 month after stopping steroid treatment. The rapid recovery of the HPA axis is of particular relevance to the anesthetist and pediatric surgeon for assessing emergency cases who have recently received systemic dexamethasone treatment and also for planning elective surgery, such as closure of colostomy after necrotizing enterocolitis or repair of inguinal hernia in BPD infants before discharge from the hospital. Likewise, our findings will be helpful to neonatal clinicians for the management of steroid-treated infants with medical emergency or sepsis. We, however, urge vigilant surveillance in monitoring electrolytes, blood pressure, and signs of HPA axis insufficiency in severely ill infants, as the pituitary and adrenal glands, although considered biochemically active, may have less reserve compared to their pretreatment state.

Received February 21, 1997.

Revised April 7, 1997.

Accepted April 21, 1997.

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