Long-term Treatment with Corticosteroids/ACTH in Asthmatic Children

Hypothalamic-pituitary-adrenal (HPA) function was studied in 23 children with severe bronchial asthma during and after long-term treatment with prednisolone and/or ACTH_1-24 (depot tetracosactrin) by means of ACTH stimulation test and insulin tolerance test. In the 14 children primarily treated with depot tetracosactrin, the Cortisol levels in insulin tests were within normal limits both during and after treatment. An enhanced response to ACTH stimulation was found during the treatment period. During treatment with prednisolone a marked impairment of the adrenocortical function was found, with low basal plasma Cortisol levels and subnormal response to ACTH stimulation, more marked the lower the age at the start of treatment and the higher the dose per kg body weight. After substitution with depot tetracosactrin the HPA-function was restituted, with plasma Cortisol levels within normal limits. Growth hormone levels after insulin induced hypoglycemia were ±7 ng/ml during and after treatment with depot tetracosactrin. As long-term treatment with depot tetracosactrin has little side-effects in terms of suppression of the HPA-axis it is a useful alternative to oral prednisolone in severe asthma in children.     

Long-term treatment with glucocorticoids/ACTH in asthmatic children. III. Effects on growth and adult height

The effect on growth of long-term treatment with prednisolone and/or ACTH (tetracosactrin) depot preparation was studied in 40 children with severe bronchial asthma. Height velocity was subnormal before treatment. During treatment the group of 17 children primarily treated with ACTH showed a moderate increase in mean velocity. Their height was not significantly altered, and neither was the age at peak height velocity nor adult height. In the group of 23 children treated with prednisolone the mean velocity decreased, resulting in a relative decrease in height. Peak height velocity was delayed by about 2 years in the boys but occurred at the expected time in the girls, as did menarche. Mean adult height was lower than expected after adjustment for mid-parenteral height. In 10 children ACTH was substituted for prednisolone, and their height velocity increased but not enough to affect adult height, which was just as low as in the patients treated with prednisolone only.     

Long-term treatment with corticosteroids/ACTH in asthmatic children. IV. Skeletal maturation

Skeletal maturation in severe bronchial asthma was studied in 15 children during and after treatment with depot tetracosactrin and in 6 children during treatment with prednisolone. Attained skeletal maturity before treatment was below the reference mean in the majority of children. Skeletal maturation was enhanced during treatment with depot tetracosactrin, which led to more advanced attained skeletal maturity at withdrawal than at start of treatment. There was a tendency towards larger increases of skeletal maturity than of height. The influence of adrenal androgens, released by ACTH-stimulation and good control of the disease are probably relevant factors for the acceleration of skeletal maturation. After withdrawal of depot tetracosactrin the rate of skeletal maturation normalized. During prednisolone treatment there was a delay of skeletal maturation leading to a progressive relative decrease of attained skeletal maturity, and closely related to a delay in linear growth. Treatment with depot tetracosactrin may thus induce enhancement of skeletal maturation, but with the treatment regimen found to be efficacious in bronchial asthma, the effect is not very pronounced and does not perceptibly affect the ultimate outcome of growth.     

Long-term Treatment with Glucocorticoids/ACTH in Asthmatic Children III.

ABSTRACT. The effect on growth of long-term treatment with prednisolone and/or ACTH_1-24 (tetracosactrin) depot preparation was studied in 40 children with severe bronchial asthma. Height velocity was subnormal before treatment. During treatment the group of 17 children primarily treated with ACTH showed a moderate increase in mean velocity. Their height was not significantly altered, and neither was the age at peak height velocity nor adult height. In the group of 23 children treated with prednisolone the mean velocity decreased, resulting in a relative decrease in height. Peak height velocity was delayed by about 2 years in the boys but occurred at the expected time in the girls, as did menarche. Mean adult height was lower than expected after adjustment for mid-parenteral height. In 10 children ACTH was substituted for prednisolone, and their height velocity increased but not enough to affect adult height, which was just as low as in the patients treated with prednisolone only.     

Long-term Treatment with Corticosteroids/ACTH in Asthmatic Children

ABSTRACT. Skeletal maturation in severe bronchial asthma was studied in 15 children during and after treatment with depot tetracosactrin and in 6 children during treatment with prednisolone. Attained skeletal maturity before treatment was below the reference mean in the majority of children. Skeletal maturation was enhanced during treatment with depot tetracosactrin, which led to more advanced attained skeletal maturity at withdrawal than at start of treatment. There was a tendency towards larger increases of skeletal maturity than of height. The influence of adrenal androgens, released by ACTH-stimulation and good control of the disease are probably relevant factors for the acceleration of skeletal maturation. After withdrawal of depot tetracosactrin the rate of skeletal maturation normalized. During prednisolone treatment there was a delay of skeletal maturation leading to a progressive relative decrease of attained skeletal maturity, and closely related to a delay in linear growth. Treatment with depot tetracosactrin may thus induce enhancement of skeletal maturation, but with the treatment regimen found to be efficacious in bronchial asthma, the effect is not very pronounced and does not perceptibly affect the ultimate outcome of growth.     

Adrenal Cortical Function in Children on Steroids

Adrenal cortical function was assessed in 20 children receiving 2·5 to 10 mg. prednisolone daily, by measuring plasma cortisol levels before and after the administration of the synthetic polypeptide β^1-24, tetracosactrin (Synacthen). 18 of the children were asthmatics, one had nephrosis, and one had dermatomyositis.Adrenal function was classified as (a) abnormal response to tetracosactrin, where basal plasma cortisol and post-tetracosactrin levels did not exceed 6 μg./100 ml.; (b) partial response, where there was a rise of 5-10 μg./100 ml. in plasma cortisol following tetracosactrin but the basal levels (< 10 μg./100 ml.) were below or only slightly above the lower normal limit; (c) normal response, where there was usually at least a doubling of the basal value and an incremental increase of at least 10 μg./100 ml. in the plasma cortisol concentrations following tetracosactrin.All 6 children receiving the higher dosage of 10 mg. prednisolone daily had abnormal adrenal function. 4 receiving the lower dosage of 2·5 mg./day had satisfactory adrenal reserve. Of the 10 children receiving the intermediate dosage of 5 mg. prednisolone daily, 2 had frankly abnormal adrenocortical function, 3 had poor adrenal reserve, and 5 produced good incremental values, though their baseline cortisol levels were low. At the 5 mg. prednisolone dose adrenocortical suppression was not correlated either with duration of therapy or with age.     

Adrenal response in very low birthweight babies after dexamethasone treatment for bronchopulmonary dysplasia.

The tetracosactrin stimulation test was used to assess the adrenal responsiveness of 22 very low birthweight babies who had received a three week course of dexamethasone for the treatment of bronchopulmonary dysplasia. Five babies were studied in detail with blood samples taken for cortisol concentrations at 30 minute intervals for four hours. The tests were performed before, during, and after treatment with dexamethasone. A distinctive pattern of cortisol response to tetracosactrin was found among these babies, which was quite unlike that found in older children and adults. Using our pretreatment results as control data we conclude that there is undoubtedly evidence of modest suppression of the adrenal axis during dexamethasone treatment, although there is considerable recovery one month after stopping steroids. Basal cortisol concentrations, however, remained low in some cases, which may indicate the need for temporary corticosteroid replacement during severe illness.     

Adrenal function in children with severe asthma treated with high-dose inhaled glucocorticoids: recommended screening tests in outpatient conditions

BACKGROUND: A number of previous studies have suggested that adrenal suppression occurs in asthmatic children treated with high-doses of inhaled glucocorticoids (IGC). This study was designed to determine the frequency of adrenal suppression in children with severe asthma treated with recommended doses of IGC: namely 500-1,000 microg/day of fluticasone propionate or the equivalent of budesonide (1,000-2,000 microg/day) for a period of at least 12 months. METHODS: Early morning cortisol (F) and ACTH serum levels were measured in 27 severe asthmatics aged 6-16 years old. The children underwent a low dose ACTH test (1 microg/1.73 m2) with a parallel glucose measurement. Twenty-four hour urine collection was performed before examination for free F (UfF) and creatinine levels. There were no clinical manifestations of adrenal hypofunction in the analyzed children. RESULTS: Of the 27 patients, 22 had normal basal and post-stimulatory levels of F and normal UfF, and the other five (18.5%) had basal serum F levels of <400 nmol/l. Four of the five also had normal post-stimulatory levels of F and normal UfF. One child had a subnormal peak F value of 484 nmol/l during the ACTH test. None of the patients had a suppressed serum ACTH level, but an elevated ACTH level was found in four children. This study provided biochemical evidence of suboptimal adrenal function in one child in the examined group (3.7%) and a good response to stimulation in all the others, even in those with slightly reduced basal cortisol levels. CONCLUSION: This study showed that the use of fluticasone in doses of up to 1,000 microg/day (or the equivalent of budesonide) as long-term treatment of children with severe asthma did not substantially affect their adrenal function.     

The relation between adrenal function and the severity of bronchial hyperresponsiveness in children as measured by the methacholine provocation test

BACKGROUND: There is no satisfactory explanation why some individuals experience severe attacks of asthma, yet others, exposed to similar stimuli, have a milder form of the disease. OBJECTIVE: We tested the hypothesis that children with more severe disease may have relative adrenal insufficiency compared to the children with milder disease. PATIENTS AND METHODS: Sixteen children with chronic asthma aged 8-16 years old were studied. Adrenal function was evaluated by the 24-h excretion of urinary free cortisol (UFC) before and after ACTH stimulation, and by plasma cortisol levels before and 60 min after ACTH administration. The severity of bronchial hyperresponsiveness was evaluated by the methacholine provocation test. RESULTS: Nine children had 20% fall in forced expiratory volume in 1 sec (FEV1) after a provocative concentration (PC20FEV1) of methacholine > or =2.5 mg/ml and were considered as having mild-moderate bronchial hyperresponsiveness (Group A). Seven children had a PC20FEV1 of < or =1.25 mg/ml and were considered as having severe bronchial hyperresponsiveness (Group B). No significant difference was found between the peak plasma cortisol response to ACTH between the two groups (634+/-182 and 586+/-137 nmol/l, respectively). However, there was a significant statistical difference (p <0.01) in the 24-h UFC response to ACTH between the children from Group A (345+/-107 nmol/m2 ) and the children from Group B (161+/-125 nmol/m2). CONCLUSIONS: Based on the low levels of 24-h UFC secretion in severely asthmatic children in our study, we propose the encouragement of provision of a short course of inhaled steroids to be kept at home for the emergency therapy of those children identified as having high-risk asthma.     

Endocrinopathy in thalassaemia major.

Pituitary, adrenal, and pancreatic functions were investigated in 9 patients with thalassaemia major. 9 a.m. plasma ACTH values were 148-480 pg/ml (normal range 15-70 pg/ml). Cortisol and growth hormone response to insulin-induced hypoglycaemia was normal in all. 24-hour urinary excretions of 17-ketosteroids and 17-hydroxycorticosteroids were normal. There was normal cortisol response to intramuscular injection of ACTH. In a physiological adrenal stimulation test there was a significantly smaller response to each physiological dose of tetracosactrin. 4 patients had diabetic glucose tolerance tests--none are clinically diabetic. The mean plasma glucose utilization constant (Kgl=2-02) is significantly smaller than normal. Plasma insulin response both in the oral and the intravenous glucose tolerance test was significantly smaller than normal. The data were consistent with severe and widespread impairment of endocrine function and a plausible explanation would be iron deposition in endocrine organs. It is suggested that pituitary hyperfunction of ACTH secretion is due to target organ unresponsiveness which can be shown in its early stages only by a physiological test of the adrenal cortex. Skin pigmentation in thalassaemia seems to be due to the melanophore-stimulating effect of this raised plasma ACTH.     

Adrenal responsiveness in children with steroid responsive idiopathic nephrotic syndrome

Impaired adrenal cortical responsiveness to ACTH has been reported in children with steroid responsive nephrotic syndrome. Plasma cortisol levels at 8 AM and 2 hours post ACTH stimulation were measured on 42 occasions in 33 children with steroid-responsive nephrotic syndrome. Twenty-two of 42 fasting 8 AM plasma cortisol and 39 of 42 post-ACTH plasma cortisol values were subnormal. Plasma cortisol values were similar in children evaluated prior to, immediately following or 2-24 moths after prednisone therapy. No relationship was observed between 8 AM or post-ACTH plasma cortisol values and serum albumin concentration or the presence of edema. Impaired adrenal responsiveness to ACTH was not helpful in predicting the length of clinical remission. Hydrocortisone replacement therapy given to five children with impaired ACTH-responsiveness did not alter the rate of relapses observed prior to this treatment.     

Primary adrenal insufficiency in a child after busulfan and cyclophosphamide-based conditioning for hematopoietic stem cell transplantation

High rates of skeletal complications, growth disturbances, thyroid and gonadal dysfunction have been described in children undergoing stem cell transplantation. Although secondary adrenal insufficiency has been diagnosed, no primary adrenal insufficiency has been reported after busulfan and cyclophosphamide (Bu/Cy)-based conditioning regimens for stem cell transplantation in children. A 9-year-old girl with myelodysplastic syndrome was treated with stem cell transplantation of allogeneic origin. She received myeloablative conditioning chemotherapy, Bu and Cy. Her serum cortisol level was normal before stem cell transplantation. Then, 17 months after stem cell transplantation, chronic graft-versus-host disease developed and was treated with methyl prednisolone for 3 months. The control endocrinological investigation revealed low serum cortisol and high serum adrenocorticotropin (ACTH) levels 6 months after completion of methyl prednisolone treatment. The ACTH stimulation test demonstrated primary adrenal insufficiency, and the other etiologies of primary adrenal insufficiency were excluded. The patient received oral prednisolone replacement therapy. She was followed-up for 44 months and required increases in steroid doses during stress periods. Primary adrenal insufficiency which was observed in our patient after Bu/Cy-based conditioning regimen for stem cell transplantation has not been reported in children and adrenal function should be closely monitored in these patients both before stem cell transplantation and after stem cell transplantation.     

Bestimmung des Plasmacortisols bei ACTH-behandelten Kindern mit Morbus Still und Rheumatoider Arthritis

Zusammenfassung Die basalen Plasmacortisolwerte bei 15 allein mit ACTH behandelten Kindern mit Rheumatoider Arthritis und Morbus Still entsprachen der Norm; unter ACTH erfolgte ein kräftiger Anstieg, woraus auf eine normal funktionierende Nebennierenrinde geschlossen wird.Bei 32 Kindern, die zusätzlich Corticosteroide erhielten, lagen fast ausnahmslos verminderte Plasmacortisolwerte, d. h. eine Nebennierenrindeninsuffizienz vor, jedoch erfolgte auch hier unter ACTH ein Anstieg von anfänglich erniedrigten auf normale Werte.Bei nicht corticosteroidbehandelten Kindern sinken die Cortisolspiegel nach Beendigung der ACTH-Anwendung abrupt auf subnormale Werte ab, um sich anschließend allmählich der Norm anzugleichen. Patienten, die unter einer Corticosteroiddauertherapie standen, zeigten auch noch am Tag nach Beendigung der ACTH-Anwendung gegenüber den Ausgangsspiegeln erhöhte Werte.Die Anwendung von ACTH in den Fällen, bei welchen nichthormonelle Antirheumatica alleine keine ausreichende therapeutische Wirkung erzielen, ist zu empfehlen, um einer bei Corticosteroidgabe zu erwartenden Entwicklung einer Nebennierenrindeninsuffizienz vorzubeugen.

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Determination of plasma cortisol levels in children treated with ACTH during Still's disease and rheumatoid arthritis

Plasma cortisol was determined in children being treated with ACTH for rheumatoid arthritis and Still's disease. The initial values in 15 children treated with ACTH only were in the normal range. A marked rise following administration of ACTH suggests a normal function of the adrenal cortex.We noted reduced plasma cortisol levels, i.e. insufficiency of the renal cortex, almost without exception in 32 children treated with corticosteroids in addition to ACTH, although initially depressed levels rose to normal values during ACTH medication in this group also.In children not treated with corticosteroids the levels of cortisol fell suddenly to subnormal values when ACTH was discontinued, subsequently rising towards normal values. The decrease was less abrupt in patients undergoing long-term treatment with corticosteroids; in this group the values were still higher than the initial values even on the day after discontinuation of ACTH.ACTH is recommended in cases where treatment with nonhormonal antirheumatic agents is ineffective, to prevent the development of insufficiency of the renal cortex.

     

Filter paper cortisol profiles in secondary adrenocortical insufficiency.

The use of filter paper four point 24 hour cortisol profiles in the diagnosis and management of secondary adrenocortical deficiency was examined. Eighteen children with familial short stature and isolated growth hormone deficiency had normal 24 hour and morning plasma cortisol concentrations measured. Eight of 11 children with multiple pituitary hormone deficiencies had evidence of hypocorticalism despite previously normal baseline cortisols or responses to insulin hypoglycaemia or tetracosactrin. Nine of 11 children with hypopituitarism on replacement treatment (4.9-12.5 mg/m2/day) had satisfactory concentrations of cortisol, though morning cortisols were often low. Filter paper profiles are a simple, inexpensive, and relatively non-invasive way of managing children with suspected hypocorticalism and of monitoring their treatment.     

Functional Tests of Adrenal Axis in Children with Measurement of Plasma Cortisol by Competitive Protein Binding

The competitive protein binding assay is the method of choice for estimation of plasma cortisol in children. Resting plasma cortisol levels in children without evidence of endocrine disease and with conditions affecting the hypothalamicpituitary-adrenal axis are reported. These showed wide variation, and stimulation tests are therefore essential for diagnosis.A normal response in the 30-minute tetracosactrin (Synacthen) test is defined as an increment of at least 10 μg/ml, with a final level of at least 25 μg/100 ml. 8 children with Addison''s disease showed a minimal or negative response and 7 of 9 with hypopituitarism showed a subnormal response.Similar criteria, an increment of at least 10 μg/100 ml, with a final level of at least 25 μg/100 ml one hour after insulin, define a normal response to the intravenous insulin tolerance test. This test provides good discrimination between normal children and those with hypopituitarism, but negative results must be interpreted with caution.     

Correlation between plasma and salivary cortisol levels in preterm infants

We sought to determine correlations between plasma and salivary cortisol levels in preterm infants in the basal state and after adrenocorticotropic hormone (ACTH) stimulation during the first week of life. Infants (n = 48) were given ACTH or saline solution; each injection was separated by 24 hours. Salivary and plasma cortisol levels correlated at baseline (r = 0.67, P <.0001) and 1 hour after ACTH stimulation (r = 0.40, P =.0047). ACTH increased cortisol levels in plasma from 12.3 +/- 6.4 to 30.3 +/- 13.2 microg/dL (P <.0001) and in saliva from 1.0 +/- 0.8 to 2.6 +/- 1.0 microg/dL (P <.0001). The adrenal response to ACTH can be detected in the saliva of premature newborns during the first week of life.     

A comparison of pituitary-adrenal responses to corticotropin-releasing hormone,hypoglycaemia and metyrapone in children with brain tumours and growth hormone deficiency

To assess hypothalamic-pituitary function, a corticotropin-releasing hormone (CRH) stimulation test was performed in nine children following treatment for brain tumours and in 27 growth hormone deficient (GHD) children whose pituitary adrenocorticotropin (ACTH) secretion was normal. In both groups, CRH tests were compared with ACTH and cortisol responses to insulin-induced hypoglycaemia and with ACTH response to metyrapone stimulation. In the patients with brain tumours (five craniopharyngiomas, two suprasellar germinomas, one cerebellar medulloblastoma and one cerebellar ependymoma), ACTH responses to CRH varied greatly with absent or blunted, normal, and exaggerated reactions. Cortisol and ACTH responses were not always correlated. In GHD children but not in children with brain tumours the responses to CRH, insulin tolerance test and metapyrone test were correlated. The marked variability of the CRH test was possibly caused by compounding factors such as preceding corticosteroid therapy, concomitant desmopressin therapy and spontaneous regeneration of damaged brain structures.     

Hormonal background of the hypertension and fluid derangements associated with adrenocorticotrophic hormone treatment of infants

We studied the hormonal background of the fluid derangements and arterial hypertension associated with adrenocorticotrophic hormone (ACTH) treatment for infantile spasms in ten infants aged 5–22 months. They received a 6 week course of (carboxymethyl-cellulose-)ACTH: 80IU at 0800 hours daily in weeks 1–3, then tapering, and termination at the end of week 6. The infants showed large, variable increases in 24 h urine cortisol during treatment. The mean plasma cortisol concentration (24 h after ACTH injection) was not significantly increased, but was correlated with the relative dose of ACTH. The mean plasma aldosterone concentration decreased. No significant change occurred in plasma renin activity (PRA), or in the concentrations of renin substrate (RS) or arginine vasopressin (AVP). Seven infants developed arterial hypertension, which was severe in three. This severe hypertension was associated with the highest relative ACTH doses and the highest plasma RS and cortisol concentrations. In the group as a whole, systolic blood pressure correlated with plasma RS and cortisol concentrations, but not with the other parameters. At the end of treatment urine and plasma cortisol dropped below the pretreatment levels and stayed low for >2 weeks. There was a sharp peak in PRA and plasma aldosterone concentration, and a decrease in plasma RS. Plasma AVP levels dropped markedly. The mean body weight increased sharply and urine flow decreased. Mean plasma electrolyte levels remained unaltered. The danger at termination of ACTH treatment appears to be associated with a sudden transition from hypercortisolism to hypocortisolism, activation of the renin-angiotensin-aldosterone axis, and suppression of AVP secretion.Abbreviations ACTH adrenocorticotrophic hormone - AVP arginine vasopressin - PRA plasma renin activity - RS renin substrate - 17-KGS 17-ketogenic steroids Dedicated to Professor Walter Teller on the occasion of his 60th birthday     

Adrenal function after long term treatment with beclomethasone dipropionate in childhood asthma (author's transl)

Evaluating plasma levels of cortisol and corticosterone after ACTH-stimulation, and the urinary metabolites tetrahydrocortisone and tetrahydrocortisol in asthmatic children it could be demonstrated, that in most cases there was no suppression of adrenal function following treatment over 6 to 18 months with a daily dose of 200 to 300 microgram beclomethasone dipropionate. Since in a few patients suppression was found, an ACTH stimulation after a six months treatment is recommended.     

Adrenal Cortical Function in Asthmatic Children on Alternate Day Steroids

Adrenal cortical function was determined in 16 children receiving prednisolone or prednisolone stearoylglycolate on alternate days. The dosages of the corticosteroids varied from 2·5 to 10 mg prednisolone, or 6·65 to 13·30 mg of its stearoylglycolate ester; the duration of therapy ranged from 2 to 26 months. Adrenocortical function was assessed from the plasma cortisol response to a single injection of β^1-24 tetracosactrin (Synacthen); repeat tests were performed after altering steroid dosages or for reassessment of individual patients.The effects of prednisolone stearoylglycolate are compared with those of prednisolone, and the effects of alternate-day prednisolone therapy are compared with those found when this corticosteroid was given daily to similar (in three cases, the same) children.