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Pituitary-Adrenal Suppression in Preterm, Very Low Birth Weight Infants after Inhaled Fluticasone Propionate Treatment

Department of Pediatrics and Chemical Pathology, Prince of Wales Hospital, Chinese University of Hong Kong (C.W.K.L.), and the Department of Mathematics, 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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Systemic corticosteroids prescribed for treatment of pulmonary diseases in preterm, very low birth weight infants caused severe suppression of the hypothalamic-pituitary-adrenal axis and produced serious physiological and metabolic disturbances. However, the effect of inhaled corticosteroids on their pituitary-adrenal functions is not known. We prospectively evaluate the pituitary-adrenal function using the human CRH stimulation test in a cohort of very low birth weight infants at risk for hypothalamic-pituitary-adrenal axis suppression in a double blind, randomized pilot study designed for assessing the efficacy and adverse effects of inhaled fluticasone propionate in newborn preterm infants who required mechanical ventilation for treatment of respiratory distress syndrome.

Twenty-five preterm (<32 gestational weeks), very low birth weight (<1500 g) infants were randomized to receive inhaled fluticasone propionate (n = 13) or a placebo inhaler (n = 12). The medication was given every 12 h (fluticasone propionate, 1,000 µg/day) for 14 days. All surviving infants had their pituitary-adrenal functions assessed by human CRH test on the following morning immediately after completion of the 2-week course. All basal (0 min) and poststimulation (15, 30, and 60 min) plasma ACTH and serum cortisol concentrations were significantly suppressed in the inhaled fluticasone group compared to their corresponding levels in the placebo group [basal plasma ACTH concentrations (F = 6.0; P = 0.02), poststimulation plasma ACTH concentrations (F > 8.6; P < 0.01), basal serum cortisol concentrations (F = 5.6; P = 0.03), and poststimulation serum cortisol concentrations (F > 15.6; P < 0.001)].

This is the first study in very low birth weight infants that demonstrates unequivocally that cumulative high dose inhaled corticosteroids can induce moderately severe suppression of both the pituitary and adrenal glands. The systemic bioactivity is probably associated with pulmonary vascular absorption, which effectively circumvents the hepatic first pass metabolism. Until the question of safety can be adequately addressed, inhaled fluticasone propionate should be used with caution in preterm infants.

	Introduction

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POTENT antenatal and postnatal systemic corticosteroids have been increasingly used for reducing the incidence and severity of respiratory distress syndrome (RDS) in preterm infants (1, 2) and to facilitate weaning from mechanical ventilation in those who developed bronchopulmonary dysplasia (3). Recently, it was further suggested that high dose postnatal dexamethasone should be given early, within the first day of life (4, 5), and before structural lung damage became irreversible (3). Unfortunately, systemic corticosteroid concentrations similar to those required for suppression of tissue inflammation would also inhibit the hypothalamic-pituitary-adrenal (HPA) function and produce serious unwanted metabolic effects (3, 6). In an attempt to minimize the systemic adverse effects of corticosteroids, we conducted a prospective, randomized, double blind pilot study to investigate the efficacy and side-effects of inhaled fluticasone propionate in preterm, very low birth weight (VLBW) infants who required mechanical ventilation for treatment of RDS.

Fluticasone propionate is a novel glucocorticosteroid derived from the 17ß-carbothioate series of androstane analogues, but without the conventional C-20 structure (6). It possesses potent topical antiinflammatory activity and unique pharmacological properties with virtually no demonstrable systemic effects after enteral or intranasal administration (6). The active drug is rapidly metabolized to an inactive 17-carboxylic acid metabolite, and it has a total blood clearance equivalent to that of the hepatic blood flow (6). In view of the theoretically favorable properties, fluticasone propionate was selected to further minimize the systemic effects of corticosteroids.

As far as we are aware, the effects of inhaled corticosteroids on the HPA axis in preterm, VLBW infants and, in particular, on pituitary function have not been previously reported. This study was designed to prospectively evaluate pituitary-adrenal function using the human CRH (hCRH) stimulation test in a cohort of VLBW infants at risk of HPA axis suppression after receiving inhaled fluticasone propionate.

	Subjects and Methods

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Study populations

Twenty-five preterm infants admitted to the neonatal intensive care unit between May 1995 and June 1996 were prospectively randomized by computer to receive inhaled fluticasone propionate or a placebo inhaler in the pilot phase of the study. Inclusion criteria were 1) a gestation of less than 32 weeks and a birth weight below 1500 g, 2) RDS requiring mechanical ventilation and oxygen supplementation, 3) the presence of an indwelling arterial cannula at the end of the 2-week course of inhaled corticosteroids, and 4) no postnatal systemic corticosteroid treatment before the hCRH test. Infants were excluded if they had concurrent hypoglycemia, systemic infection, necrotizing enterocolitis, or major surgery in the preceding week. All randomized infants received two doses of surfactant (5 mL/kg; Exosurf, The Wellcome Foundation, London, UK) given 12 h apart.

Drugs

Eligible infants were randomized in the first 24 h of life to receive either inhaled fluticasone propionate or a placebo aerosol. The aerosol canisters and plastic actuators were masked, packed in identical boxes, and dispensed by a different person to the investigators to ensure effective blinding. Immediately before drug administration, the tidal volume delivered to the infant was increased by stepping up the peak inspiratory pressure for 10% and prolonging the inspiratory time to 1 s. Aerosol was then delivered via a metered dose inhaler containing either fluticasone propionate (250 µg/actuation; Flixotide, Allen and Hanburys, Middlesex, UK) or placebo into a holding chamber (MV15 Aerochamber, Trudell, Canada) that was inserted between the endotracheal tube and the Y connector of the ventilator circuit just before the procedure. Two actuations (fluticasone propionate, 250 µg/actuation), spaced 1 min apart between each discharge, were delivered into the Aerochamber during each administration. The ventilator parameters would be returned to the initial settings after the infant had been given five ventilator breaths following the last actuation. This maneuver was comparable to hand ventilation, but was performed in a more controlled and standardized manner. The medication was given every 12 h (fluticasone propionate, 1,000 µg/day) for 14 days. As only 0.8–2% (8–20 µg) of the aerosol delivered would eventually be deposited in the infant’s lung (7), this represented a relatively small dose compared to the currently recommended 3- to 6-week course of iv dexamethasone (150–600 µg/kg·day) used for treatment of bronchopulmonary dysplasia (3).

hCRH stimulation test and hormone assays

Infants who received metered dose inhaler, either fluticasone propionate or placebo, had their pituitary-adrenal function assessed by hCRH stimulation test on the following morning immediately after completion of the 2-week course. The hCRH test was performed between 0800–1000 h, as previously described (8). The plasma ACTH and serum cortisol concentrations were measured by double antibody RIA and solid phase RIA, respectively (8).

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 for the demographic data were expressed as the mean and SEM. Wilcoxon’s rank sum test and Fisher’s exact test were used for comparison of continuous variables and proportions where appropriate. Multivariate repeated ANOVA was used to compare the hormone concentrations.

	Results

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Of 25 VLBW infants randomized, 13 received inhaled fluticasone propionate, and 12 received a placebo inhaler. One infant from the inhaled fluticasone group was excluded. He died on day 10 because of massive air embolism as a result of a complication associated with mechanical ventilation and did not receive the hCRH test.

The clinical characteristics of the study population are summarized in Table 1. None of the parameters listed in Table 1 differed significantly between the inhaled fluticasone and the placebo group. Table 2 and Figs. 1 and 2 show the plasma ACTH and serum cortisol concentrations in both treatment and placebo groups in relation to exogenous hCRH stimulation immediately after completion of the course on day 14. All basal (0 min) and poststimulation (15, 30, and 60 min) plasma ACTH and serum cortisol concentrations were significantly suppressed in the inhaled fluticasone group compared to their corresponding levels in the placebo group [basal plasma ACTH concentrations (F = 6.0; P = 0.02), poststimulation plasma ACTH concentrations (F > 8.6; P < 0.01), basal serum cortisol concentrations (F = 5.6; P = 0.03), and poststimulation serum cortisol concentrations (F > 15.6; P < 0.001)].

View larger version (12K): [in this window] [in a new window]   Figure 1. The effect of hCRH stimulation on plasma ACTH concentrations (mean ± SEM) in preterm, VLBW infants who received inhaled fluticasone propionate (n = 12) or placebo treatment (n = 12). Plasma ACTH concentrations were significantly suppressed in the inhaled fluticasone group compared to their corresponding levels in the placebo group (* and **, P < 0.05 and P < 0.01, respectively).

View larger version (13K): [in this window] [in a new window]   Figure 2. The effect of hCRH stimulation on serum cortisol concentrations (mean ± SEM) in preterm, VLBW infants who received inhaled fluticasone propionate (n = 12) or placebo treatment (n = 12). Serum cortisol concentrations were significantly suppressed in the inhaled fluticasone group compared to their corresponding levels in the placebo group (* and **, P < 0.05 and P < 0.001, respectively).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The results of this study showed that a 2-week course of inhaled fluticasone propionate (1,000 µg/day) produced moderately severe suppression of ACTH and cortisol secretion in VLBW infants. This suppressive effect could be explained by its systemic bioactivity and pharmacological properties. It is known that the potency of fluticasone propionate is at least 2-fold greater than those of other commonly used corticosteroids such as budesonide or beclomethasone (20, 21) and has a much greater glucocorticoid receptor affinity (20), lipophilicity (22), tissue binding ability (22), and glucocorticoid/receptor complex half-life (23) and thus a more prolonged plasma elimination half-life compared to those of other corticosteroids (24). Moreover, as opposed to the oral route of administration, fluticasone propionate delivered via the respiratory tract could most likely be absorbed by the pulmonary vasculature and effectively circumvent the first pass hepatic metabolism. It would, therefore, seem entirely logical that inhaled fluticasone propionate could exert its potent systemic effect, resulting in suppression of the HPA axis.

We also compared the results of this study to those of our previous work that involved 23 VLBW infants who received a 3-week course of postnatal systemic dexamethasone and had their pituitary-adrenal function assessed by hCRH test immediately after completion of treatment (25). Infants who received inhaled fluticasone propionate had similar magnitudes of pituitary suppression (mean plasma ACTH concentrations between the inhaled fluticasone group and their corresponding levels in the systemic dexamethasone group at 0, 15, 30, and 60 min were 4.2 vs. 3.7, 5.5 vs. 5.8, 5.5 vs. 5.8, and 5.0 vs. 4.8 pmol/L, respectively; F < 0.51; P > 0.48), but significantly less severe suppression of the adrenal glands (mean serum cortisol concentrations between the inhaled fluticasone group and their corresponding levels in the systemic dexamethasone group at 0, 15, 30, and 60 min were 187 vs. 68, 229 vs. 117, 298 vs. 131, and 246 vs. 92 nmol/L, respectively; F > 7.7; P < 0.01). However, one should interpret such results with caution, as different corticosteroid preparations, dosages, durations of treatment, and routes of administration were used in the two groups of patients.

In conclusion, this is the first study that demonstrates that inhaled fluticasone propionate (2-week course, 1,000 µg/day) causes pituitary-adrenal suppression in VLBW infants. The systemic bioactivity is probably associated with pulmonary vascular absorption, which effectively circumvents the hepatic first pass metabolism. Contrary to earlier reports that inhaled fluticasone produced insignificant adrenal suppression (6, 9, 10, 11, 12, 13, 14, 15, 16), this study showed that cumulative high dose inhaled corticosteroids induced moderately severe suppression in both the pituitary and adrenal glands. However, none of the treated infants developed clinical signs or electrolyte disturbances suggestive of adrenal insufficiency at the end of the 2-week course. Further studies should be directed at selecting the most appropriate corticosteroid preparation, dosage, regimen, and route of drug administration for treatment of pulmonary conditions in VLBW infants to maximize the benefit/risk ratio. Until the question of safety can be adequately addressed, inhaled corticosteroid treatment should be used with caution in preterm infants.

Received November 19, 1997.

Revised February 24, 1998.

Accepted April 2, 1998.

	References

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