Emergency Management of Adrenal Insufficiency in Children: Advocating for Treatment Options in Outpatient and Field Settings

Abstract

Adrenal insufficiency (AI) remains a significant cause of morbidity and mortality in children with 1 in 200 episodes of adrenal crisis resulting in death. The goal of this working group of the Pediatric Endocrine Society Drug and Therapeutics Committee was to raise awareness on the importance of early recognition of AI, to advocate for the availability of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or allow EMS personnel to administer patient’s HSS home supply to avoid delay in administration of life-saving stress dosing, and to provide guidance on the emergency management of children in adrenal crisis. Currently, hydrocortisone, or an equivalent synthetic glucocorticoid, is not available on most ambulances for emergency stress dose administration by EMS personnel to a child in adrenal crisis. At the same time, many States have regulations preventing the use of patient’s home HSS supply to be used to treat acute adrenal crisis. In children with known AI, parents and care providers must be made familiar with the administration of maintenance and stress dose glucocorticoid therapy to prevent adrenal crises. Patients with known AI and their families should be provided an Adrenal Insufficiency Action Plan, including stress hydrocortisone dose (both oral and intramuscular/intravenous) to be provided immediately to EMS providers and triage personnel in urgent care and emergency departments. Advocacy efforts to increase the availability of stress dose HSS during EMS transport care and add HSS to weight-based dosing tapes are highly encouraged.

Full text

MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999 1
Review
Emergency management of adrenal insufficiency
in children: advocating for treatment options in
outpatient and fieldsettings
Bradley S Miller, 1 Sandra P Spencer,2 Mitchell E Geffner,3 Evgenia Gourgari,4
Amit Lahoti,5 Manmohan K Kamboj,2 Takara L Stanley,6 Naveen K Uli,7
Brandy A Wicklow,8 Kyriakie Sarafoglou1
To cite: MillerBS,
SpencerSP, GeffnerME,
etal. J Investig Med Epub
ahead of print: [please
include Day Month Year].
doi:10.1136/jim-2019-
000999
For numbered affiliations see
end of article.
Correspondence to
DrBradley SMiller,
Department of Pediatrics,
University of Minnesota
Masonic Children’s Hospital,
2450 Riverside Ave,
Minneapolis, MN 55454,
USA; mille685@ umn. edu
The work has been
presented at Pediatric
Academic Society Meeting
2018, ’Year In Review:
Emergency Management
of Adrenal Insufficiency in
Children: A Clinical Practice
Guideline’, Toronto, Ontario,
Canada, May 2018.
Accepted 7 February 2019
© American Federation for
Medical Research 2019.
Re-use permitted under
CC BY-NC. No commercial
re-use. Published by BMJ.
ABSTRACT
Adrenal insufficiency (AI) remains a significant
cause of morbidity and mortality in children with 1
in 200 episodes of adrenal crisis resulting in death.
The goal of this working group of the Pediatric
Endocrine Society Drug and Therapeutics Committee
was to raise awareness on the importance of early
recognition of AI, to advocate for the availability
of hydrocortisone sodium succinate (HSS) on
emergency medical service (EMS) ambulances or
allow EMS personnel to administer patient’s HSS
home supply to avoid delay in administration of life-
saving stress dosing, and to provide guidance on the
emergency management of children in adrenal crisis.
Currently, hydrocortisone, or an equivalent synthetic
glucocorticoid, is not available on most ambulances
for emergency stress dose administration by EMS
personnel to a child in adrenal crisis. At the same
time, many States have regulations preventing the
use of patient’s home HSS supply to be used to
treat acute adrenal crisis. In children with known AI,
parents and care providers must be made familiar
with the administration of maintenance and stress
dose glucocorticoid therapy to prevent adrenal
crises. Patients with known AI and their families
should be provided an Adrenal Insufficiency Action
Plan, including stress hydrocortisone dose (both
oral and intramuscular/intravenous) to be provided
immediately to EMS providers and triage personnel
in urgent care and emergency departments.
Advocacy efforts to increase the availability of stress
dose HSS during EMS transport care and add HSS to
weight-based dosing tapes are highly encouraged.
INTRODUCTION
Prismatic clinical scenario
A 9-year-old boy presented to a local emer-
gency department (ED) with chronic abdom-
inal pain, acute onset of nausea and vomiting
for the previous 24 hours. Physical examina-
tion revealed an ill-appearing, thin male with
tachycardia (pulse 110 bpm), mild hypoten-
sion (85/60 mm Hg), signs of dehydration, and
hyperpigmentation. Laboratory testing showed
hyponatremia (sodium 129 mEq/L), hyperka-
lemia (potassium 5.8 mEq/L) and hypoglycemia
(glucose 55 mg/dL). Despite urgent fluid resus-
citation with 2 intravenous boluses of normal
saline and a bolus of 10% dextrose, hypoten-
sion persisted. Due to clinical and biochemical
features suggestive of primary adrenal insuffi-
ciency (AI), blood was drawn for measurement
of adrenocorticotropic hormone (ACTH) and
cortisol levels prior to administering 75 mg of
intravenous hydrocortisone sodium succinate
(Solu-Cortef). He was admitted and diagnosis
confirmed. Treatment was initiated with hydro-
cortisone and fludrocortisone. The patient and
family received education for the management
of primary AI and prevention of adrenal crises.
Two years later he developed acute gastro-
enteritis with fever, vomiting and diarrhea while
visiting his grandparents in a rural area. He
received triple his usual dose of oral hydrocor-
tisone, but vomited within 10 minutes. Grand-
parents had hydrocortisone sodium succinate
available for intramuscular injection, but
did not know how to administer it and called
911. The patient was unresponsive on arrival of
the ambulance 20 minutes later. Grandparents
informed the emergency medical technicians
(EMT) that he needs to receive hydrocortisone
sodium succinate intramuscularly for AI. Due
to emergency medical services (EMS) policy,
the EMTs were not allowed to administer the
child’s personal supply of hydrocortisone
sodium succinate and did not have an alterna-
tive medication on the ambulance. Glucometer
revealed a blood glucose of 30 mg/dL. While
EMTs attempted to place an intravenous cath-
eter, he experienced a seizure. He was intubated
and received intravenous dextrose with cessa-
tion of the seizure. He was transported to a
local ED that was 30 minutes away. In the ED,
he was given 75 mg intravenous hydrocortisone
sodium succinate and was admitted to the inten-
sive care unit where he later died of complica-
tions related to prolonged hypoglycemia and
aspiration pneumonitis.
BACKGROUND
Adrenal crisis is a life-threatening condi-
tion that can be prevented by recognition in
which patients with AI must receive additional
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2MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999
Review
glucocorticoids when under physiological stress. Adrenal
crisis can also occur as the initial clinical presentation of AI.
Appropriate management requires immediate recognition
of the clinical signs, symptoms and biochemical profile of AI
and the triggers for adrenal crisis. Therefore, primary care,
urgent care and ED providers must be trained to recognize
the diverse clinical circumstances in which AI can occur. In
children with known AI, parents and care providers must be
familiar with the administration of maintenance and stress
dose glucocorticoid therapy to prevent adrenal crises. This
can be facilitated by providing the family with a written
Adrenal Insufficiency Action Plan and Emergency Care
Letter. Currently, hydrocortisone, or an equivalent synthetic
glucocorticoid, is not available on most ambulances for
emergency administration by EMS personnel. In addition,
EMT training on the use of patient’s home medication is
not widely employed. Both of these situations can lead to
life-threatening delays in providing appropriate therapy to
prevent or treat adrenal crises.
AI is a significant cause of morbidity and mortality in chil-
dren1–3 with an annual estimated incidence of adrenal crisis
of 5–10 episodes per 100 patient-years, with increasing
rates in some countries.4 One in every 200 episodes of
adrenal crisis results in death.5 Therefore, the goal of this
working group was to raise awareness on the importance of
early recognition and provide guidance on the emergency
management of AI in children during illnesses, particularly
in the outpatient, EMS and ED settings.
ETIOLOGY
AI is characterized by impaired adrenal synthesis of gluco-
corticoids. When reduced production of mineralocorticoid
(aldosterone) is present it is associated with hyponatremia
due to salt-wasting and reciprocal hyperkalemia. AI can be
categorized as primary, where the defect is in the adrenal
gland, or secondary (central), where the defect is due to
hypothalamic and/or pituitary dysfunction. In the central
forms deficient secretion of ACTH leads to atrophy of the
zona fasciculata in the adrenal cortex (the source of gluco-
corticoids); mineralocorticoid production by the zona
glomerulosa is preserved because the renin-angiotensin
system is intact.
The most common cause of primary AI in children is
congenital adrenal hyperplasia (CAH), the leading cause of
atypical genitalia in female newborns. Less common causes
of primary AI include autoimmune adrenalitis (isolated
or part of autoimmune polyglandular syndromes), infec-
tions, bilateral adrenal hemorrhage, and various genetic
Table 1 Congenital causes of adrenal insufficiency
Condition
Affected
gene Clinical phenotype
Primary
CAH
21-α-hydroxylase deficiency CYP21A2 46,XX DSD/androgen excess;
salt-wasting
3-β-hydroxysteroid
dehydrogenase deficiency
HSD3B2 Ambiguous genitalia/salt-
wasting
11-β-hydroxylase deficiency CYP11B2 46,XX DSD/androgen excess;
hypertension (not infants)
P450 side-chain cleavage
syndrome
CYP11A 46,XY DSD; salt-wasting,
hypogonadism
Lipoid hyperplasia StAR 46,XY DSD; salt-wasting;
hypogonadism
P450 oxidoreductase
deficiency (PORD)
POR 46,XY DSD, salt-wasting,
hypogonadism, Antley-Bixler
malformation; altered drug
metabolism
Congenital adrenal hypoplasia SF-1
(NR5A1)
46,XY DSD, gonadal
insufficiency
DAX-1
(NROB1)
Hypogonadotropic
hypogonadism
CDKN1C IMAGe syndrome (intrauterine
growth retardation,
metaphyseal dysplasia, genital
anomalies)
Triple A or Allgrove AAAS Achalasia, alacrima
Isolated familial glucocorticoid
deficiency (FGD)
MC2R,
MRAP
Tall stature, normal
mineralocorticoid production
FGD–DNA repair defect MCM4 NK-cell defect, short stature,
recurrent viral infections,
microcephaly, chromosomal
breakage
Glucocorticoid resistance GCCR Mineralocorticoid/androgen
excess
Metabolic diseases
Adrenoleukodystrophy ABCD1 Neurologic deterioration
Zellweger PEX Cerebrohepatorenal syndrome
Smith-Lemli-Opitz DHCR7 46,XY sex reversal, polydactyly,
mental retardation
Wolman LIPA Hepatomegaly
Mitochondrial disease
Kearns-Sayre Ophthalmoplegia, myopathy
Secondary: hypothalamus
Holoprosencephaly GLI2,
FGF8
CRH deficiency
Maternal hypercortisolemia
Secondary: pituitary/hypothalamus
Isolated ACTH deficiency TPIT
Multiple anterior pituitary
hormone deficiencies due to
pituitary aplasia/hypoplasia
HESX1 Septo-optic dysplasia (optic
nerve hypoplasia), nystagmus
PROP1
LHX4
OTX2 Anophthalmia, developmental
delay
SOX3 Xlinked, mental retardation,
ectopic posterior pituitary
Isolated ACTH deficiency TPIT
(TBX19)
Continued
Condition
Affected
gene Clinical phenotype
Proopiomelanocortin deficiency POMC Severe early-onset hyperphagic
obesity, red hair
Proprotein convertase 1
mutation
PCSK1 Hypoglycemia, malabsorption,
gonadotropin deficiency
ACTH, adrenocorticotropic hormone;CAH, congenital adrenal
hyperplasia;CRH, corticotropin-releasing hormone;DSD, disorder of sex
development;NK, natural killer.
Table 1 Continued
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syndromes including X linked adrenoleukodystrophy6–8
(see table 1 and box 1).
The most common cause of secondary (central) AI is low
ACTH due to iatrogenic suppression of the pituitary corti-
cotrophs by prolonged use of supraphysiological doses of
oral glucocorticoids typically prescribed for the treatment
of medical conditions including but not limited to asthma,
hematologic/oncologic conditions, inflammatory bowel
disorders, rheumatologic conditions, nephrotic syndrome,
neurologic disorders, postneurosurgical procedures, and
hematopoietic and solid organ transplants. Glucocorti-
coids administered by intra-articular, topical, intradermal,
and inhaled routes may also suppress the hypothalamic-pi-
tuitary-adrenal (HPA) axis.9 10 Other medications, such as
megestrol acetate, ketoconazole, and mifepristone, also
impair adrenal function via direct and indirect mecha-
nisms. Less common secondary causes of ACTH deficiency
involving the pituitary and hypothalamus include tumors,
radiation exposure, congenital anomalies, and specific
gene defects (table 1 and box 1). Inherited forms of ACTH
deficiency are usually associated with additional pituitary
hormone deficiencies.
The magnitude of suppression of the HPA axis in rela-
tion to dose, duration, and type of glucocorticoid therapy
can vary among individuals due to variability in glucocor-
ticoid pharmacokinetics and interindividual glucocorticoid
receptor sensitivity.11 Generally, the HPA axis recovers
rapidly when the duration of glucocorticoid treatment is
short, that is, less than 7–10 days, even when high doses
are used. In these circumstances, it is appropriate to discon-
tinue glucocorticoids abruptly. However, if the duration of
therapy is 3 weeks or longer, it is recommended that the
glucocorticoid dose be tapered gradually to avoid precip-
itating symptoms of steroid dependence and/or AI.12
Protracted use of supraphysiological glucocorticoid doses
may result in severe adrenal gland atrophy and prolonged
AI lasting up to 34 weeks requiring glucocorticoid tapering
to be extended over many months.13 14
A Cochrane review of 8 studies of 9218 children with
acute lymphoblastic leukemia treated with prolonged
courses of supraphysiological doses of long-acting gluco-
corticoids, including dexamethasone, prednisolone and
prednisone, revealed that AI occurred in nearly all children
in the first days after discontinuation of glucocorticoids.13
However, the precise duration of glucocorticoid therapy
and tapering protocol were not reported in the majority of
the studies. While most of the children recovered within
several weeks, a few children had prolonged AI lasting up
to 34 weeks. Fluconazole was noted in one of these studies
to possibly prolong the duration of AI while another study
identified stress and infection to be risk factors.15
A meta-analysis examining the role of inhaled corticoste-
roids (ICS) in suppression of the HPA axis noted no AI with
ICH doses of ≤400mcg of beclomethasone dipropionate
daily.9 16 However, subsequent reports have noted HPA
axis suppression at lower ICS doses.3 17 Since the bioavail-
ability and bioequivalence of ICS preparations vary along
with individual glucocorticoid sensitivity, it is difficult to
identify a threshold dose for all ICS that will cause HPA
axis suppression.18 Therefore, it is important to recog-
nize chronic ICS therapy as a risk factor for AI. A study of
infants with hemangiomas treated with high-dose glucocor-
ticoid therapy for 12–26 weeks demonstrated the return of
normal circadian response in salivary cortisol levels within
6 weeks and normal response to administration of low-dose
ACTH stimulation by 12 weeks after stopping treatment.14
During the process of recovery from HPA suppression,
physiological circadian secretion of cortisol may recover
before return of the ability of the hypothalamus to respond
to stress.19 Therefore, a patient may have a normal 8:00
AM cortisol, but still be unable to show an appropriate
serum cortisol response to stress.20 21 The wide variability in
Box 1 Acquired causes of adrenal insufficiency
PrimaryPrimary
►Autoimmune adrenalitis (Addison disease)
– Isolated.
– Autoimmune polyendocrinopathy type 1.
– Autoimmune polyendocrinopathy type 2.
►Bilateral hemorrhage/infarction
– Trauma.
– Waterhouse-Friderichsen syndrome.
– Anticoagulation.
►Drug effect: mifepristone, aminoglutethimide, mitotane,
ketoconazole, etomidate, metyrapone, rifampin,
phenytoin, barbiturates, tyrosine kinase inhibitors (eg,
sunitinib)
►Infection
– Viral: HIV, cytomegalovirus.
– Fungal: coccidioidomycosis, histoplasmosis,
blastomycosis, cryptococcosis.
– Mycobacterial: tuberculosis.
– Amebic.
►Infiltrative
– Hemochromatosis, histiocytosis, sarcoidosis,
amyloidosis, neoplasm.
►Surgery: bilateral adrenalectomy
Secondary: hypothalamusSecondary: hypothalamus
►Corticosteroid withdrawal after prolonged
administration (inhaled, intranasal, oral, rectal,
intravenous and topical).
►Corticosteroid withdrawal after parenteral
administration of high doses of potent and longeracting
preparations (intramuscular, intradermal and intra-
articular routes).
►Drug effect: megestrol, mitotane, medroxyprogesterone,
rifampin, phenytoin, barbiturates, tyrosine kinase
inhibitors (eg, sunitinib).
►Inflammatory disorders.
►Trauma.
►Radiation therapy.
►Surgery.
►Tumors: craniopharyngioma, germinoma.
►Infiltrative disease: sarcoidosis, histiocytosis.
Secondary: pituitarySecondary: pituitary
►Corticosteroid withdrawal after prolonged
administration.
►Trauma.
►Tumor: craniopharyngioma.
►Radiation therapy.
►Lymphocytic hypophysitis.
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4MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999
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timing of recovery of the HPA axis after discontinuation of
glucocorticoid exposure emphasizes the need for clinicians
to be aware of clinical scenarios with an increased risk of AI.
DIAGNOSIS OF ACUTEAI
Triggers
Diagnosis of AI can be challenging as the clinical signs are
not specific and may progress insidiously over time. Adrenal
crisis can be precipitated by acute illness, physical stress or
injury requiring increased cortisol production above basal
needs in the setting of normal adrenal function. In addition,
induction of anesthesia and surgery can precipitate acute
AI.
Clinical signs
Acute AI can present with fatigue, weakness, tachycardia,
hypotension, dizziness, nausea, vomiting, abdominal pain,
diaphoresis and seizures. If unrecognized and not treated
quickly, AI can progress to coma and death.3 6 9 22–25
Prolonged cholestatic jaundice, failure to gain weight and
hypoglycemia may be the presenting clinical features in
neonates and infants. Micropenis, bilateral cryptorchidism
and, rarely, central diabetes insipidus may also be present in
neonates who have AI due to panhypopituitarism. Individ-
uals with primary AI may have hyperpigmentation of the
skin (particularly creases, folds and scars), gums and buccal
mucosa.
General biochemistry
In acute AI, hyponatremia is the most consistent biochem-
ical finding.12 Hyperkalemia is present in primary, but not
secondary AI, and can be associated with hypercalcemia
and metabolic acidosis. Hypoglycemia is more frequent
in neonates and infants regardless of the type of AI. Other
findings include normocytic anemia, lymphocytosis and
eosinophilia.
Hormonal measurements and provocative testing
The diagnosis of primary AI is suggested by blood tests pref-
erably performed at 8:00 AM that show an ACTH level
greater than 100 pg/mL and a cortisol level less than 10
mcg/dL1 or by an ACTH level that is twofold greater than
the upper limit of the normal range and a cortisol level less
than 5 mcg/dL.8 26 Low serum aldosterone with elevated
plasma renin activity is the hallmark of mineralocorticoid
deficiency. Secondary AI is associated with low levels of
both cortisol and ACTH. An 8:00 AM serum cortisol level
of≤3mcg/dLishighlysuggestiveofthediagnosiswhereas
acortisolvalueof≥18mcg/dL essentially excludesAI.1 If
AI is suspected during an acute illness, a random cortisol
and ACTH should be obtained prior to initiating gluco-
corticoid therapy. A serum cortisol concentration less than
18 mcg/dL during acute illness can be indicative of AI.12
Cortisol and ACTH levels may be difficult to interpret in
neonates and infants as circadian pattern of secretion does
not appear until 4 months27 and cortisol-binding globulin is
low causing low total, but not free, serum cortisol.
If levels of plasma ACTH and/or serum cortisol are equiv-
ocal, dynamic testing of adrenal function with cosyntropin
should be done. Typically a high-dose cosyntropin stimula-
tion test is preferred when primary AI is suspected (usual
dose is 15 mcg/kg in neonates, 125 mcg in infants <2 years,
and 250 mcg in older children). In secondary AI, dynamic
testing with either high or low-dose cosyntropin (1 mcg)
has been used for evaluation of the HPA axis. Regardless of
the cosyntropin dose used, a serum cortisol level >18 mcg/
dL rules out AI. The low-dose protocol is not universally
accepted primarily due to technical factors influencing the
test results. A dose of 1 mcg cosyntropin requires prepara-
tion by the person carrying out the test. Also, the prepared
dilution should be given intravenously without using a
catheter made of ‘fluorinated ethylene propylene’ plastic to
which the cosyntropin binds.12 26 28–30
TREATMENT
There is limited empirical evidence to guide the optimal
glucocorticoid stress-dosing of children and adolescents
who have AI. While the debate about what constitutes phys-
iological stress is unresolved, several situations are gener-
ally accepted as significant stress including: fever >38°C
(100.4°F), intercurrent illness with emesis, prolonged or
voluminous diarrhea, infectious disease requiring antibi-
otics, acute trauma requiring medical intervention (eg,
fracture) and anesthesia and associated surgical procedures.
Guidelines on cortisol requirement in times of physiological
stress have been based on the general acceptance that condi-
tions of maximal stress increase the serum cortisol levels by
2–3 times.1 5 26 31 Treatment recommendations below are
based on recent literature on glucocorticoid replacement
therapy.
OUTPATIENT PREVENTION OF ACUTE AI
General pediatricians and endocrinologists
Following the diagnosis of AI, comprehensive educa-
tional outreach should include the family and caregivers,
the primary care physician, and the local emergency care
providers regarding the signs, symptoms and treatment
of cortisol deficiency to prevent adrenal crises. Electronic
medical records (EMR) may be used to flag patients with
known or at high risk for AI to increase provider atten-
tion.32 33
The first step in preventing acute AI is maintenance
glucocorticoid replacement therapy. Maintenance dosing
of glucocorticoid is based on the secretory rate of cortisol
which has been reported to be 5–8 mg/m2/d in healthy
controls.34 35 For primary AI other than CAH, hydrocorti-
sone at 8–12 mg/m2/d in 3 divided doses is recommended.1 26
In CAH, the consensus dosing is 10–15 mg/m2/d.36 Patients
with secondary AI may be maintained on a lower dose.1 37
A challenge with hydrocortisone therapy is its short
median elimination half-life, especially in children with
CAH (58 minutes (range: 41–105 minutes)) allowing most
of the hydrocortisone dose to be eliminated from the body
within 4–7 hours.11 38 To prevent alternating periods of
hypocortisolemia and hypercortisolemia throughout each
day in children with AI, hydrocortisone should be adminis-
tered in at least 3 divided doses. A 6-hour pharmacokinetic/
pharmacodynamic study in children with CAH showed that
maximum suppression of adrenal steroids (17-hydroxy-
progesterone and androstenedione) occurs 3–4 hours
after hydrocortisone dose and that adrenal steroids
rebounded toward elevated baseline concentrations by the
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end of 6 hours.11 This suggests that the elimination half-life
of cortisol is more relevant to adrenal steroid suppression
than the biological or pharmacological half-life of cortisol
(8 hours).39 Because of hydrocortisone pharmacokinetic
properties and in order to mimic physiological circadian
cortisol profiles, the highest hydrocortisone dose should be
given in the morning.11 31 40
Long-acting glucocorticoids such as dexamethasone,
prednisone and prednisolone are not recommended for
maintenance glucocorticoid therapy in growing chil-
dren.26 36 41 42 The use of long-acting glucocorticoids, such
as dexamethasone, in treatment of initial adrenal crisis will
prevent the provider from performing an ACTH stimula-
tion test during the initial hospitalization to establish the
definitive diagnosis. Prednisolone and dexamethasone are
15-fold and 80–100-fold more potent, respectively, than
hydrocortisone in terms of growth suppression.42 43 A modi-
fied-release formulation of hydrocortisone (Chronocort)
given twice daily has been studied in adults with CAH44 but
failed to meet the phase 3 trial primary objective confirming
its superiority over conventional treatment.45
During infancy to early childhood, smaller doses and
incremental adjustments are required to avoid the adverse
effects of glucocorticoid excess including obesity, hyperten-
sion, impaired growth, osteoporosis and insulin resistance.
However, lack of availability of tablets in strengths lower
than 5 mg makes dosing of infants difficult and less precise.
Currently there is no commercially available liquid formu-
lation that provides dosing in 0.1 mg increments since with-
drawal of hydrocortisone cypionate suspension in 2001.46
Quartering 5 mg (6.5 mm) or 10 mg (8 mm) hydrocortisone
tablets can lead to inconsistent cortisol levels and result in
either undertreatment or overtreatment due to unaccept-
able dose variability.47 48 Crushed, weighed hydrocortisone
capsules from a compounding pharmacy may also lead to
inconsistent cortisol levels and overtreatment.49 50 Alco-
hol-free hydrocortisone oral suspension (2 mg/mL) prepared
from 10 mg tablets provides good dose repeatability when
shaken before use and was stable for 90 days when stored in
either a bottle or syringe at either 4°C or 25°C.51 A pharma-
cokinetic study in children with CAH showed no difference
in the extent or rate of hydrocortisone absorption between
alcohol-free hydrocortisone suspension prepared from
10 mg tablets by a compounding pharmacy and hydrocor-
tisone tablets.52 Future studies may encourage the develop-
ment of a Food and Drug Administration (FDA)-approved
commercially available alcohol-free hydrocortisone suspen-
sion. Uncoated minitablets of 2.5 mg (3 mm) could also be
an alternative.48 53 54 Multiparticulate hydrocortisone gran-
ules (Alkindi) with doses of 0.5, 1, 2 and 5 mg have been
recently licensed in Europe.55
In this guideline, we outline an Adrenal Insufficiency
Action Plan (figure 2) and an Adrenal Insufficiency Instruc-
tions for Emergency Room Staff (figure 3), a stepwise
approach to hydrocortisone dosing during illness similar
to the extremely successful Asthma Action Plan.56 Our
goal is to provide clear guidance for caregivers, primary
care physicians, urgent care and emergency providers for
appropriate stress dosing of hydrocortisone or its equiva-
lent in children with known AI during illness and surgical
procedures to prevent and treat adrenal crisis. The Adrenal
Insufficiency Action Plan provides instructions for oral
stress dosing with hydrocortisone (double or triple the daily
dose given every 6–8 hours) and injectable hydrocortisone
dosing when unable to take oral stress dose. All children
with AI should be provided with an individualized care plan
(Adrenal Insufficiency Action Plan and/or medical letter, see
figures 1, 2 and 3), which could be made available in EMRs.
The use of such tools has been shown to improve patient
education regarding management of physiological stress in
outpatient settings.32 33 In addition, children with AI need a
medical alert identification for EMS personnel.
All caregivers should be educated on the use of injectable
intramuscular hydrocortisone sodium succinate in the event
of emesis or an altered state of consciousness. As adminis-
tration of intramuscular hydrocortisone sodium succinate
requires multiple preinjection steps, a prefilled, single-use
autoinjector (ZENEO Hydrocortisone) is in development
in France. The use of rectal hydrocortisone suppositories in
the management of adrenal crisis may not achieve desired
cortisol concentrations.57
EMSand hospital transport treatment of acute AI
Children with known AI requiring EMS transport should
receive an intramuscular injection of potentially life-saving
hydrocortisone sodium succinate as soon as possible by
the family/caretaker or by EMS providers either using the
family’s supply or having hydrocortisone sodium succinate
available in the EMS vehicles, including mobile care units.
Prolonged transportation times for patients living in rural
areas may delay administration for several hours further
underscoring the importance of EMS access to hydrocorti-
sone sodium succinate. Clearly, local and state regulations
and provider practice scope need to be considered by the
agency’s medical director prior to implementation. In addi-
tion, we need to advocate that local and state regulations be
updated to support the emergent administration of hydro-
cortisone sodium succinate by EMS personnel outside the
hospital to individuals with known AI. A small number of
states and provinces have legislation allowing administra-
tion of patient-carried medication and have EMS gluco-
corticoid protocols in place.58 59 In this emergency setting,
hydrocortisone sodium succinate should be administered
at 50–100 mg/m2 intramuscularly (5–10 times the physio-
logic cortisol secretory rate).1 5 26 60 The Endocrine Society
Clinical Practice Guideline suggests stress doses of hydro-
cortisone sodium succinate based on patient’s age: chil-
dren ≤3 years: 25mg; school-age children (>3and <12
years): 50mg; and older children and adolescents (≥12
years): 100 mg as an initial stress dose.26 61 62 We recom-
mend using the 100 mg/2 mL vial as its dilution is simple
if smaller doses are needed. Finally, we also recommend
adding age-related hydrocortisone sodium succinate dosing
to weight-based dosing tapes used in emergency care of
children, as their use is ubiquitous.63
Regarding other glucocorticoids, dexamethasone sodium
phosphate (1.5–2 mg/m2/dose)1 has been available in some
EMS settings and used in secondary AI. However, it is
not suitable for treatment of salt-wasting adrenal crisis
in primary AI because it has no mineralocorticoid effect.
Methylprednisolone sodium succinate (10–25 mg/m2/dose
intramuscular) may be used to treat adrenal crisis although
it has less mineralocorticoid activity than hydrocortisone.64
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6MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999
Review
ED TREATMENT OF ADRENAL CRISIS
Vague and non-specific symptoms of AI make the diagnosis
of adrenal crisis easily overlooked in the ED triage process.
Hypotension and hypoglycemia can develop suddenly in
the ED,65 even after normal triage assessments. Providers
must exercise a high index of suspicion for adrenal crisis in
any child who is at risk of AI (table 1 and box 1). In cases of
known AI the ED letter (figure 1, modified from ref 66) or
Adrenal Insufficiency Action Plan should be given to triage
personnel on arrival to the ED to speed the process.
The initial stress dose of hydrocortisone sodium succi-
nate given by family, EMS, or in ED should be followed by
50–100 mg/m2/d divided into 4 doses given every 6 hours or
given by continuous infusion.1 5 26 60 In the ED, intravenous
Figure 1 Adrenal Insufficiency Emergency Care Letter.
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MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999
Review
Figure 2 Adrenal Insufficiency Action Plan.
Figure 3 Adrenal Insufficiency Instructions for EmergencyRoom Staff.CBC, complete blood count;IV, intravenous.
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8MillerBS, etal. J Investig Med 2019;0:1–10. doi:10.1136/jim-2019-000999
Review
dosing is preferred for the initial stress dose, however, if
an intravenous catheter cannot be placed quickly, the initial
dose should be given intramuscularly. Ongoing stress doses
are typically given parenterally for the first 24–48 hours
and then transitioned to oral dosing if feasible. Because
hydrocortisone sodium succinate in high doses has miner-
alocorticoid effect, no fludrocortisone is needed while
the patient receives intravenous fluids and stress doses of
hydrocortisone.
Appropriate evaluation (as described above) should
include biochemical documentation of the AI (serum
cortisol and plasma ACTH levels), assessment of hydration
and acid-base status, and investigation of an underlying
precipitant. Ideally, a blood sample should be collected
prior to administration of hydrocortisone sodium succinate,
especially for patients with a suspected new diagnosis of AI;
however, treatment should NOT be delayed if obtaining a
blood sample proves difficult.
In an acute adrenal crisis, hypovolemia should be rapidly
reversed with a 20 mL/kg bolus of isotonic solution, prefer-
ably normal saline. Hypoglycemia should be treated with a
2.5 mL/kg bolus of 10% dextrose solution and repeated if
the response is not adequate.
CONCLUSIONS
Patients with AI (primary or secondary) may present to
EMS personnel or the ED in an acute life-threatening crisis
needing prompt and effective management to avoid severe
consequences. This document offers evidence and consen-
sus-based expert guidelines for most effective management
of AI in the emergent scenario. A high index of suspicion
needs to be maintained in all patients at risk for acute
adrenal crisis.
Author affiliations
1Department of Pediatrics, University of Minnesota Masonic Children’s
Hospital, Minneapolis, Minnesota, USA
2Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio,
USA
3Department of Pediatrics, Children’s Hospital of Los Angeles, Los Angeles,
California, USA
4Department of Pediatrics, MedStar Georgetown University Hospital,
Washington, DC, USA
5Department of Pediatrics, Le Bonheur Children’s Hospital, Memphis,
Tennessee, USA
6Department of Pediatrics, Massachusetts General Hospital, Boston,
Massachusetts, USA
7Department of Pediatrics, UH Rainbow Babies and Children’s Hospital,
Cleveland, Ohio, USA
8Department of Pediatrics and Child Health, University of Manitoba, Winnipeg,
Manitoba, Canada
Contributors All the authors have participated in the concept and design,
analysis and interpretation of data, drafting or revising of the manuscript, have
approved the manuscript as submitted, and have agreed to be accountable for
all aspects of the work.
Funding This research received no specific grant from any funding agency in
the public, commercial or not-for-profit sectors.
Competing interests BSM is a consultant for AbbVie, Ascendis, Ferring,
Novo Nordisk, Pfizer, Sandoz, Soleno and Tolmar and has received research
support from Alexion, Ascendis, BioMarin, Endo Pharmaceuticals, Genentech,
Genzyme, Novo Nordisk, Opko, Sandoz, Sangamo, Shire, Tolmar and Versartis.
MK received grant support from T1D Exchange Quality Improvement
Collaborative. MG is a consultant for Spruce Biosciences, Millendo, Pfizer,
and BridgeBio. KS receives research support from the DHHS Federal Food and
Drug Administration, NIH National Cancer Institute, March of Dimes, National
Science Foundation, Spruce Biosciences, Alexion and Neurocrine.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited, an indication of whether changes were
made, and the use is non-commercial. See: http:// creativecommons. org/
licenses/ by- nc/ 4. 0/.
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Summary of recommendations
►Patients with known AI and their families should
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