Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone.
ABSTRACT Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) > 400 microg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose.
Children recorded as prescribed FP > or = 500 microg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m2 intravenously) and was categorised as: biochemically normal (peak cortisol response > 500 nmol/l); impaired (peak cortisol < or = 500 nmol/l); or flat (peak cortisol < or = 500 nmol/l with increment of < 200 nmol/l and basal morning cortisol < 200 nmol/l).
A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6-19.3 years) were successfully tested. Of 194 receiving FP > or = 500 microg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of > or = 1000 microg/day.
Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving > or = 1000 microg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.
- SourceAvailable from: Bo Baslund[Show abstract] [Hide abstract]
ABSTRACT: Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.European Journal of Internal Medicine 06/2013; · 2.05 Impact Factor
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ABSTRACT: OBJECTIVE: Based on adult data, a peak cortisol ≥500 nmol/L to insulin induced hypoglycaemia constitutes a normal response. Age-specific reference ranges for basal morning cortisol have been developed for clinical use in the paediatric population. Such reference ranges are not clearly established for peak cortisol response to insulin-induced hypoglycaemia despite limited data suggesting an effect of age on peak cortisol. To assess factors affecting the cortisol response to insulin induced hypoglycaemia in children and determine whether peak cortisol was related to age. DESIGN: Retrospective cohort study METHODS: Retrospective analysis of Children and adolescents ≤18 years undergoing Insulin tolerance Test with adequate hypoglycaemia. Patients with hypopituitarism, severe hypothalamic-pituitary-adrenal axis impairment (peak cortisol <400 nmol/L) or using systemic glucocorticoids were excluded. RESULTS: Two hundred and twenty three (223) tests were analysed. Peak cortisol ≥500 nmol/L occurred in 183 (82%) tests. Age was negatively associated with peak cortisol (r = -0.15, p = 0.03). Peak cortisol <500nmol/L was significantly less common in patients <12 years (9/97 (9 %) vs. 31/126 (25 %); p=0.004). In children <12 years the median (5th - 95th centiles) peak cortisol values were 610 (480-806) nmol/L compared to 574 (442 - 789) nmol/L in children ≥12 years (p < 0.004). Similarly, median cortisol increment was significantly higher in younger patients (301 nmol/L compared to 226 nmol/L (p = 0.0004)). CONCLUSIONS: Use of a single peak cortisol threshold in children of all ages is not appropriate and will result in over-diagnosis of adrenal insufficiency in adolescents.European Journal of Endocrinology 05/2013; · 3.14 Impact Factor
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ABSTRACT: To examine serum cortisol responses to a simplified low dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels. EMSC and EMSCn samples were collected for three consecutive days. On day three Synacthen 500ng/1.73m(2) was administered intravenously. Samples were collected at 0, 15, 25, 35 minutes. 269 subjects (160 M: 109F), median (range) age 10.0 (5.1 - 15.2) years were studied. Peak cortisol in the LDSST was <500nmol/L in 101 subjects (37.5%) and <350nmol/L in 12 subjects (4.5%). Basal cortisol correlated with peak cortisol: r=0.55, (95% CI: 0.46, 0.63, p<0.0001). Time at which peak cortisol concentration was achieved was significantly related to the value of peak cortisol (p<0.0001), with higher cortisol peaks occurring later in the test and lower cortisol peaks occurring earlier. EMSC and EMSCn had no predictive value for the identification of patients with a peak cortisol <500nmol/L. EMSCn was superior to EMSC in identifying patients with a peak cortisol < 350nmol/L: a minimum EMSCn cut-off value of 12.5 nmol/L gave a negative predictive value of 99.2% and positive predictive value of 30.1%. Our data illustrate that basal measures of cortisol are likely to be of value in screening populations for patients at greatest risk of adrenal crisis. EMSCn shows promise as a screening tool for the identification of patients with severe adrenal insufficiency. This article is protected by copyright. All rights reserved.Clinical Endocrinology 07/2013; · 3.40 Impact Factor
Adrenal responses to low dose synthetic ACTH
(Synacthen) in children receiving high dose inhaled
J Paton, E Jardine, E McNeill, S Beaton, P Galloway, D Young, M Donaldson
............................................................... ............................................................... .
See end of article for
Dr J Y Paton, Division of
University of Glasgow,
Yorkhill Division, Greater
Glasgow Health Board,
Glasgow G3 8SJ,
Scotland, UK; J.Y.Paton@
Accepted 10 March 2006
Published Online First
23 March 2006
Arch Dis Child 2006;91:808–813. doi: 10.1136/adc.2005.087247
Background and Aims: Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone
proprionate (FP) .400 mg/day, the maximum dose licensed for use in children with asthma. Following
two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in
children receiving FP outwith the licensed dose.
Methods: Children recorded as prescribed FP >500 mg/day were invited to attend for assessment.
Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m2intravenously) and
was categorised as: biochemically normal (peak cortisol response .500 nmol/l); impaired (peak cortisol
(500 nmol/l); or flat (peak cortisol (500 nmol/l with increment of ,200 nmol/l and basal morning
cortisol ,200 nmol/l).
Results: A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were
not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6–19.3 years)
were successfully tested. Of 194 receiving FP >500 mg/day, six had flat responses, 82 impaired
responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five
with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had
encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat
responses and the symptomatic child were all receiving FP doses of > 1000 mg/day.
Conclusion: Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all
receiving >1000 mg/day, while impaired responses were seen in 39.6%. Children on above licence FP
doses should have adrenal function monitoring as well as a written plan for emergency steroid
confirmed their effectiveness compared with placebo in the
control of chronic persistent asthma.2
However, ICS, particularly at high doses, are associated
with systemic side effects3 4which can be divided into those
attributable to excess, such as Cushingoid features and
growth suppression,5and effects related to hypothalamic-
pituitary axis suppression6which can result in adrenocortical
atrophy and glucocorticoid insufficiency. Patients are at risk
of acute adrenal insufficiency if the adrenal cortex cannot
generate an adequate endogenous corticosteroid response to
stress, especially if corticosteroid treatment is interrupted
In 2001, a 5 year old girl presented to a hospital in the West
of Scotland with a day’s history of vomiting, impaired
consciousness, and visual disturbance. She developed pro-
gressive unconsciousness and seizures and died within nine
hours. Postmortem examination showed cerebral oedema
and small adrenal glands. Four weeks later, her 7 year old
brother was admitted with almost identical symptoms. He
had hyponatraemia and cerebral oedema but responded to
intensive care. After discharge, his initial plasma cortisol was
noted to be inappropriately low (225 nmol/l). Subsequent
adrenal testing showed a severely impaired cortisol response
(,30 nmol/l) to a low dose Synacthen test (LDST). Both
siblings had been receiving fluticasone proprionate (FP) for
asthma for a number of years in doses of up to 2000 mg/day.
We attributed these events to acute adrenal insufficiency
induced by high dose FP. This led us to screen adrenal
nhaled corticosteroids (ICS) are the most effective treat-
ment for controlling asthma in adults and children.1In
children, randomised controlled trials have repeatedly
function in all children with asthma attending the respiratory
clinics at the Royal Hospital for Sick Children, Glasgow who
were recorded as receiving FP outwith the manufacturer’s
licensed dose (.400 mg/day). Our primary objective was to
identify any child with evidence of adrenal insufficiency, and
ensure they had adequate adrenal replacement therapy and a
plan for emergency management of symptomatic acute
There are few published studies of adrenal function in
large numbers of children with asthma using high dose
ICS.9–11Here we report the results of adrenal function testing
in the children screened.
Electronic versions of clinic letters of children attending the
specialist respiratory clinics were searched for the words
‘‘fluticasone’’, ‘‘flixotide’’, or ‘‘seretide’’ and then scrutinised
to identify every child prescribed inhaled FP .400 mg/day
between January 2000 and April 2002. Parents and GPs of
these children were sent an explanatory letter with an
appointment for adrenal function testing.
At testing, the nurse inquired about the current inhaled FP
dose, any dosage changes in the last six months, the inhaler
device used, and the number of oral corticosteroid rescue
courses in the last year. We did not attempt to assess
compliance with inhaled FP.
Abbreviations: FP, fluticasone proprionate; ICS, inhaled
corticosteroids; LDST, low dose Synacthen test; SDS, standard deviation
All children who attended were tested, even if more
detailed inquiry at the time indicated that their FP dose was
now within license ((400 mg/day).
Children were asked to fast from midnight and to omit any
morning oral, but not inhaled, medications. The endocrine
nurse explained the testing and the reasons for it. A brief
enquiry was made for symptoms of chronic adrenal
insufficiency. Height was measured using a calibrated
stadiometer and weight measured using electronic scales.
Where both parents attended, their heights were measured
and a mid-parental height calculated.
Following application of local anaesthetic cream, the
children were cannulated between 08 00 and 10 00 hours.
Adrenal function was assessed by a synthetic ACTH
(Synacthen) test using a modification of the low dose
protocol of Crowley and colleagues.12Briefly, the Synacthen
dose was calculated on the basis of body surface area, giving
500 ng/1.73 m2, and prepared using serial dilution of 250 mg
Synacthen in 10 ml saline. Venous blood samples were taken
at time zero, and at 15, 20, 25, 30, and 35 minutes thereafter.
Serum cortisol was measured by immunoassay (Immulite
2000, Diagnostic Products Corporation, Los Angeles, CA,
We interpreted the cortisol results as follows:13 14
N Normal: peak .500 nmol/l
N Impaired: peak (500 nmol/l
N Flat: peak (500 nmol/l with increment ,200 nmol/l and
basal morning cortisol ,200 nmol/l.
Data were summarised using standard descriptive statistics.
Relationships between variables were investigated using
Pearson’s correlation. All analyses were done using Minitab
(Version 14) with a significance level of 5%.
Because of the serious adverse events encountered locally, it
was considered clinically essential to check whether other
children receiving high dose FP had evidence of adrenal
insufficiency. The investigation plan was agreed with the
Medical Director. In the circumstances, we did not consider it
appropriate to obtain permission for testing from the local
ethics committee. All parents were given a written and verbal
explanation of the reasons for testing their child.
Between January 2000 and March 2002, 422 children were
identified as prescribed FP, either alone or in combination
with salmeterol (seretide). A flow diagram shows the number
of children identified at each stage (fig 1). Two hundred and
two children were not tested for reasons listed in fig 1.
Table 1 presents demographic details of the 220 children in
whom testing was attempted. Children received FP from a
metered dose inhaler with spacer (137/ 220; 62%), or as a dry
Children identified as prescribed
flixotide or seretide
n = 422
n = 220
< 500 µg/day500 µg/day
500 µg/day or
< 500 µg/day
n = 26
n = 0
n = 4
n = 21
n = 1
n = 194
n = 6
n = 82
n = 104
n = 2
n = 202
Reason not tested
2. Off flixotide
1. Tested elsewhere
Flixotide < 500 µg/day
Transferred to adult care
n = 137
n = 24
n = 9
n = 7
n = 22
n = 3
Consort diagram of children
Adrenal responses to inhaled fluticasone809
powder. In 192 children, we had details of the duration of FP
prescription (median 4 years; range 0–9).
Height and weight standard deviation scores for the 220
children are in table 1, for all subjects and after sub-division
according to FP dose. There was no correlation between total
daily FP dose and either height (r=0.037, p=0.612) or
weight (r=0.099, p=0.161). In those children where mid-
parental height SD scores (SDS) were available, there was no
significant difference between the child’s height SDS and the
mid-parental height SDS (paired t test, p=0.563, 95% CI
20.219 to 0.398).
Low dose Synacthen test results
The adrenal responses classified on the peak cortisol result
and the FP doses at the time of testing are shown in table 1.
Testing failed in three subjects. Of the 192 receiving FP
>500 mg/day successfully tested, 6 (3%) had flat, 82 impaired
(43%), and 104 normal (54%) responses. Of the 25 receiving
FP ,500 mg/day at the time of testing successfully tested,
none was flat (fig 1) and four were impaired (16%).
There was a weak but significant inverse correlation
between peak cortisol and total daily dose (r=20.213,
p=0.002). Correcting the total daily FP dose for subject’s
weightdid notimprove the
p=0.006; fig 2). There was no relationship between peak
cortisol level and age (r=20.018, p=0.794; table 2) or
number of acute courses of prednisolone reported as given in
the previous 12 months (r=0.046, p=0.526; fig 3).
Basal morning cortisol levels
There was no correlation between prescribed FP dose and the
p=0.092). There was also no correlation between the
number of children with baseline cortisol ,100 nmol/l and
FP dose (r=20.152, p=0.573) (table 1).
Clinical correlates of impaired adrenal responses
Brief details of the children who had flat responses or
symptomatic impairment are given in table 3. Of the six with
flat responses, none had symptoms of chronic adrenal
Two children had episodes of acute adrenal insufficiency:
our index case (case 1, table 3); and one other (peak cortisol
289 nmol/l) who developed mild encephalopathy and hypo-
glycaemia with a tonsillitis who was the only one with
symptoms of chronic adrenal insufficiency (tiredness, poor
weight gain with dramatic improvement after adrenocortical
replacement therapy) (case 7, table 3).
No child with peak LDST cortisol levels of .300 nmol/l test
presented with either acute or chronic adrenal insufficiency.
Follow up and procedure adopted for steroid cover/
Families and GPs were sent the results and a recommended
plan including advice for managing any episodes of acute
adrenal insufficiency (available from corresponding author
on e-mail request).
For all children, a focused effort was made at review to
reduce the prescribed FP to a dose just sufficient to control
the child’s symptoms.
The identification and recall of all who had been prescribed
FP .400 mg/day proved a major logistic exercise. While the
majority were tested between May and December 2001, it
was only by the end of 2004 (three years after our index
cases) that we were confident that all at-risk patients had
been contacted and given appropriate advice.
Because of its potency and availability in high dose forms, FP
is commonly used when high dose ICS treatment is
prescribed for children with moderate/severe asthma.15
While its use is well established,16studies have shown that
Details of 220 children tested by low dose Synacthen testing
Children studiedAll tested Normal responseImpaired responseFlat response
Number220 (217 successful; 3
Average FP dose (mg/day);
Age (y); median (range)
Height SDS; median (range)
743/500 (50–2000) 1052/1000 (250–8000) 1083/1000 (1000–1500)
20.32 (24 to 1.8)
20.57 (23.5 to 1.4)
0.27 (23.8 to 3.9)
20.18 (22.9 to 1.8)
20.78 (23.5 to 1.4)
0.40 (22.8 to 3.9)
20.34 (24.1 to 1.8)
20.49 (22.7 to 0.9)
0.18 (23.8 to 2.2)
20.55 (22.3 to 0.90)
20.50 (21.0 to 1.1)
1.12 (22.2 to 1.8)
Mid-parental height SDS; median
Weight SDS; median (range)
No. prescribed FP
No. with basal cortisol ,100 nmol/l
26 (1 failed)
166 (1 failed)
28 (1 failed)
Total daily dose fluticasone per kg (µg/kg/day)
Peak cortisol (nmol/l)
stimulated cortisol (nmol/l) on LDST and total daily FP dose (mg/day)
corrected for weight.
Dose-response curve showing relationship between peak
810 Paton, Jardine, McNeill, et al
the dose-response curve for FP appears to plateau at 100–
200 mg/day. Doses .400 mg/day may occasionally confer
extra benefit in some children with severe asthma, but at
this level there may be evidence of adrenal suppression.17
Previous reports have highlighted the dangers of sympto-
matic adrenal insufficiency in children receiving high dose
ICS, particularly FP.7 18–20
Our experience of two serious adverse events and
published reports led us to test adrenal function in children
prescribed FP .400 mg/day. Overall, we found evidence of
adrenal suppression in 42.4% of the children tested (2.8%
flat; 39.6% impaired). There has been no previous large
survey using LDST in children prescribed above licence doses
of inhaled FP for prolonged periods. Previous reports have
generally either been case series21or studies of adrenal
function during short term trials of high dose FP.9 10One
exception is a cross-sectional study of adrenal function in 50
children and adolescents receiving FP >1000 mg/day for
>6 months who were thought to be adherent with therapy.11
Using a standard Synacthen test, biochemical adrenal
insufficiency was found in only 12% of those tested. The
greater numbers of children with impaired responses in this
present report likely reflect the greater sensitivity of the
Other estimates of the prevalence of biochemical adrenal
suppression in children on high dose ICS vary. Our finding of
42% should be compared to the estimates of: 25% in the study
of Kannisto and colleagues22and 35% in the report of Broide
et al in children and young adults,14both using the LDST; 50%
prevalence using insulin tolerance testing in the small study
of Mahachoklertwattana and colleagues;10and to the report
of Fitzgerald et al where FP 750 mg/day was compared with
beclomethasone dipropionate at 1500 mg/day in a 12 week
randomised controlled crossover study—67% and 70% of
children respectively had impaired adrenal function on
LDST.9These different prevalence estimates presumably
reflect differences in the populations studied and methods
used to characterise adrenal function. Nevertheless, they
suggest that between one quarter and two thirds of children
of children on high dose ICS will show biochemical adrenal
suppression on sensitive testing.
In agreement with others, we confirmed that serum
morning basal cortisol alone is not a reliable indicator of
adrenocortical function in children with asthma on high dose
ICS.11 13 14
We did not find other features of corticosteroid excess.
Only one child, who was also receiving daily oral corticoster-
oids, had Cushingoid features. We found no evidence of a
significant dose dependent effect of FP on height.23In
children with mid-parental height measurements, there
was no significant difference between the child’s height
SDS and the mid-parental height SDS in keeping with a lack
of significant growth suppression despite high FP doses.
Dunlop et al also recently reported potentially severe adrenal
suppression in some children who were growing at a normal
rate despite taking high dose inhaled corticosteroids.23
(,500 mg/day, 500–1000 mg/day, .1000 mg/day)
Responses to low dose Synacthen in relation to age and dose; total number
Age (y) n Failed testingNormal response Impaired responseFlat response
13 (2, 9, 1)
86 (15, 63, 8)
121 (8, 94, 19)
1 (1, 0, 0)
1 (0, 1, 0)
1 (0, 0, 1)
11 (2, 8, 1)
48 (12, 32, 4)
66 (7, 53, 6)
1 (0, 1, 0)
32 (3, 26, 3)
53 (1, 40, 12)
0 (0, 0, 0)
5 (0, 4, 1)
1 (0, 1, 0)
No. of acute courses of oral corticosteroids
in the previous year
Peak cortisol (nmol/l)
number of courses of oral corticosteroid (nmol/l) reported as taken in the
Relation between peak stimulated cortisol on LDST and
Clinical details of children who had flat adrenal response (cases 1–6) or symptomatic adrenal insufficiency (case 7)
Dose of FP
On oral prednisolone
at time of testing?
Y (4 mg daily)
Well and off all treatment
Remains on prednisolone 5 mg daily and FP
Now on 400 mg/day mometasone; weaning
off hydrocortisone replacement
FP now reduced to 250 mg/day; oral
prednisolone stopped at 7.5 years
On 5 mg daily of prednisolone and 500 mg/
Unsuccessful attempts to reduce FP; now on
maintenance dose of prednisolone
Well and on treatment with Symbicort
3 9.3F 1000 N (but 7 short courses in
previous 12 mth)
5 11.7F 1000N 98/227N
6 6.2F 1000N (but .8 short courses in
7 6.1M 1000118/269Y
Adrenal responses to inhaled fluticasone811
Monitoring growth is, therefore, not an adequate screening
test to identify children with adrenal suppression.
We were able to wean our index case from ICS treatment
completely, while the child with symptoms of chronic adrenal
insufficiency is now on a modest dose of an alternative ICS,
suggesting that both did not have severe asthma. Systemic FP
effects may have been more pronounced due to greater
pulmonary absorption from relatively normal lungs.24 25The
attempts to reduce FP in the other children with flat
responses resulted in unacceptable worsening of asthma
symptoms, reflecting the value of high dose FP in children
with more severe asthma.4 17
We made no attempt to evaluate compliance with inhaled
FP treatment. Non-compliance is well recognised in children
receiving inhaled medications,26has been shown to increase
with duration of treatment,27and is a potentially important
confounder of any dose dependent systemic effects of inhaled
corticosteroids. We found a very small although significant
negative correlation between the daily FP dose and the peak
cortisol level on LDST, similar to other studies. Sim et al
(r=20.42) between FP dose and peak cortisol on a short
Synacthen test.11The relevant graph in their paper (figure 111)
shows a wide distribution of cortisol values at each FP dose
level very similar to our own results (fig 2). Broide and
colleagues14found no relation between peak cortisol on LDST
and daily dose of ICS. We also noted no relation between the
number of reported rescue oral steroid courses in the last year
and peak cortisol, although in some cases the reported
number of courses used was improbably high. We speculate
that the lack of a more definite relation between FP dose and
biochemical adrenal impairment may reflect the effect of
While we found only a weak negative correlation between
FP dose and peak cortisol level, it is reassuring that
a flat response was only found in children prescribed FP
The question arises as to the daily ICS level that justifies
adrenal testing.4 28
Some of our children were taking
FP,500 mg/day when tested, but showed evidence of
biochemical adrenal impairment. It is likely that some others
of the 137 children on FP doses within license would also
have had impaired responses. The decision not to investigate
these children was a practical one based on the logistic
difficulties of testing large numbers of children as well as the
fact that the literature suggests, and our data confirms, that
the risk of clinically significant adrenal side effects is related
to FP doses well above license.4 17
We conclude that families and clinicians should be aware
of the possibility of clinical adrenal suppression in children
with asthma on inhaled FP doses above license (.400 mg/
day). Since adrenal insufficiency is easily treated if recog-
nised, families with children on high doses of FP (and other
high dose inhaled corticosteroids) should be aware of the
possibility of acute adrenal insufficiency and the potential
need for emergency treatment. We would recommend they
carry a steroid card, and have specific written advice about
steroid replacement in the event of severe intercurrent illness.
Finally, these results support advice in current asthma
guidelines to ensure that the dose of inhaled corticosteroids is
only sufficient to control the disease and that doses be
stepped down when control is achieved.29In children with a
poor response to treatment, ICS dose should not be increased
without careful review.
We gratefully acknowledge the calm forbearance of families and
children prescribed off license doses of FP to adrenal function testing,
the help of our consultant colleagues (Drs Cochrane, Gibson, and
Devenny) in planning the testing protocol, and the assistance of all
the nurses who performed the testing. We are especially grateful to
Anne Wilson and Christine Kerr for their painstaking tabulation of
all the data.
J Paton, E Jardine, E McNeill, S Beaton, P Galloway, M Donaldson,
Division of Developmental Medicine, University of Glasgow, Royal
Hospital for Sick Children, Glasgow, UK
D Young, Department of Statistics and Modelling Science, University of
Strathclyde, Glasgow, UK
Competing interests: JYP has received financial support for clinical
trials, attending conferences and postgraduate meetings, and from
companies who make inhaled steroids, including GlaxoSmithKline,
AstraZeneca, 3M Healthcare, and Novartis. His spouse has shares in
GlaxoSmithKline, which makes fluticasone.
1 Anon. British guideline on the management of asthma. Thorax
2 Calpin C, Macarthur C, Stephens D, et al. Effectiveness of prophylactic inhaled
steroids in childhood asthma: a systematic review of the literature. J Allergy
Clin Immunol 1997;100:452–7.
3 Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a
systematic review and meta-analysis. Arch Intern Med 1999;159:941–55.
4 Russell G. The use of inhaled corticosteroids during childhood: plus ca change.
Arch Dis Child 2004;89:893–5.
5 Price J, Hindmarsh P, Hughes S, et al. Evaluating the effects of asthma therapy
on childhood growth: what can be learnt from the published literature? Eur
Respir J 2002;19:1179–93.
6 Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six
inhaled corticosteroid preparations. Am J Respir Crit Care Med
7 Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associated
with inhaled corticosteroids in the United Kingdom. Arch Dis Child
8 Patel L, Clayton PE. Adrenal insufficiency after treatment with fluticasone.
Lowest possible dose of inhaled glucocorticoids should be given. BMJ
9 Fitzgerald D, Van AP, Mellis C, et al. Fluticasone propionate
750 micrograms/day versus beclomethasone dipropionate
1500 micrograms/day: comparison of efficacy and adrenal function in
paediatric asthma. Thorax 1998;53:656–61.
10 Mahachoklertwattana P, Sudkronrayudh K, Direkwattanachai C, et al.
Decreased cortisol response to insulin induced hypoglycaemia in asthmatics
treated with inhaled fluticasone propionate. Arch Dis Child 2004;89:1055–8.
11 Sim D, Griffiths A, Armstrong D, et al. Adrenal suppression from high-dose
inhaled fluticasone propionate in children with asthma. Eur Respir J
12 Crowley S, Hindmarsh PC, Holownia P, et al. The use of low doses of ACTH in
the investigation of adrenal function in man. J Endocrinol 1991;130:475–9.
13 Agwu JC, Spoudeas H, Hindmarsh PC, et al. Tests of adrenal insufficiency.
Arch Dis Child 1999;80:330–3.
14 Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals
impaired adrenal function in patients taking inhaled corticosteroids. J Clin
Endocrinol Metab 1995;80:1243–6.
What is already known on this topic
N While inhaled corticosteroids are the most effective
treatment for childhood asthma, high doses are
associated with systemic side effects
N Clinical adrenal insufficiency has been particularly
associated with above license doses (.400 mg/day) of
inhaled fluticasone propionate (FP)
What this study adds
N Of children on above licensed doses of FP, 42% had
biochemical adrenal insufficiency on sensitive testing
N A flat adrenal response was only found in children
receiving >1000 mg/day FP
812Paton, Jardine, McNeill, et al
15 Devoy M. Use of inhaled corticosteroids in children. Arch Dis Child
16 Adams NP, Bestall JC, Lasserson TJ, et al. Inhaled fluticasone versus placebo
for chronic asthma in adults and children. Cochrane Database Syst Rev
17 Masoli M, Weatherall M, Holt S, et al. Systematic review of the dose-response
relation of inhaled fluticasone propionate. Arch Dis Child 2004;89:902–7.
18 Patel L, Wales JK, Kibirige MS, et al. Symptomatic adrenal insufficiency
during inhaled corticosteroid treatment. Arch Dis Child 2001;85:330–4.
19 Todd G, Dunlop K, McNaboe J, et al. Growth and adrenal suppression in
asthmatic children treated with high-dose fluticasone propionate. Lancet
20 Drake AJ, Howells RJ, Shield JP, et al. Symptomatic adrenal insufficiency
presenting with hypoglycaemia in children with asthma receiving high dose
inhaled fluticasone propionate. BMJ 2002;324:1081–2.
21 Todd GR, Acerini CL, Buck JJ, et al. Acute adrenal crisis in asthmatics treated
with high-dose fluticasone propionate. Eur Respir J 2002;19:1207–9.
22 Kannisto S, Korppi M, Remes K, et al. Adrenal suppression, evaluated by a
low dose adrenocorticotropin test, and growth in asthmatic children treated
with inhaled steroids. J Clin Endocrinol Metab 2000;85:652–7.
23 Dunlop KA, Carson DJ, Steen HJ, et al. Monitoring growth in asthmatic
children treated with high dose inhaled glucocorticoids does not predict
adrenal suppression. Arch Dis Child 2004;89:713–6.
24 Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of
pharmacokinetics and systemic effects of inhaled fluticasone propionate in
patients with asthma and healthy volunteers: a randomised crossover study.
25 Harrison TW, Wisniewski A, Honour J, et al. Comparison of the
systemic effects of fluticasone propionate and budesonide given by
dry powder inhaler in healthy and asthmatic subjects. Thorax
26 Gibson NA, Ferguson AE, Aitchison TC, et al. Compliance with inhaled
asthma medication in preschool children. Thorax 1995;50:1274–9.
27 Jonasson G, Carlsen KH, Mowinckel P. Asthma drug adherence in a long term
clinical trial. Arch Dis Child 2000;83:330–3.
28 Russell G. Inhaled corticosteroids and adrenal insufficiency. Arch Dis Child
29 Hawkins G, McMahon AD, Twaddle S, et al. Stepping down inhaled
corticosteroids in asthma: randomised controlled trial. BMJ
Outcomes of cardiac arrest in hospital
The cardiac arrest is usually a result of progressive respiratory failure or shock. The outcomes
of cardiac arrest in hospital have been reported for 855 children in a multicentre US study
(Ricardo A Samson and colleagues. New England Journal of Medicine 2006;354:2328–39).
Data were gathered from 159 hospitals contributing to the National Register of
Cardiopulmonary Resuscitation between January 2000 and June 2004. There were 1005
patients under the age of 18 years with in-hospital cardiac arrest. One hundred and fifty
patients were excluded from the analysis because the initial cardiac rhythm was unknown
(131) or because they had ventricular fibrillation or tachycardia but it was not known
whether this was present initially or developed during resuscitation (19). The median age of
children with ventricular fibrillation or tachycardia was 4.0 years and of those without these
rhythms, 1.4 years. The most common conditions leading to cardiac arrest were respiratory
insufficiency, hypotension, congestive heart failure, and pneumonia or septicaemia.
Metabolic or electrolyte disturbances were present in 178 patients (21%). Most arrests
were witnessed and occurred during ECG monitoring. Ventricular arrhythmias were
described as initial or subsequent (occurring during resuscitation). Ventricular fibrillation or
tachycardia was documented in 272 (27%) of the original 1005 patients and 253 of the 855
patients in the analysis. They were the initial rhythms in 104 of the 253 patients and developed
duringresuscitationin 149. Six hundred andtwo patients did not haveventricular fibrillationor
tachycardia. Survival to hospital discharge occurred in 35% of patients with initial ventricular
fibrillation or tachycardia, 11% of patients with subsequent ventricular fibrillation or
tachycardia, and 27% of patients without ventricular fibrillation or tachycardia.
Among children with cardiac arrest in hospital the rate of survival to hospital discharge is
highest when the first cardiac arrest rhythm is ventricular fibrillation or tachycardia,
intermediate when there is no ventricular fibrillation or tachycardia, and lowest when
ventricular fibrillation or tachycardia appear during resuscitation.
mong children with cardiac arrest cardiac rhythms that respond to electric shocks
(ventricular fibrillation or tachycardia) are much less common than in adults:
children are much more likely to have electrical asystole or pulseless electrical activity.
Adrenal responses to inhaled fluticasone813