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Adrenal suppression from exogenous glucocorticoids: Recognizing risk factors and preventing morbidity

Posted: Jun 15, 2021


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Principal author(s)

Alexandra Ahmet, Anne Rowan-Legg, Larry Pancer; Canadian Paediatric Society, Canadian Pediatric Endocrine Group, Community Paediatrics Committee

Paediatr Child Health 2021 26(4): 242–247

Abstract

Adrenal suppression (AS), a potential side effect of glucocorticoid therapy (including inhaled corticosteroids), can be associated with significant morbidity and even death. In Canada, adrenal crisis secondary to AS continues to be reported in children. Being aware of symptoms associated with AS, understanding the risk factors for developing this condition, and familiarity with potential strategies to reduce risks associated with AS, are essential starting points for any clinician prescribing glucocorticoids. 

Keywords: Adrenal insufficiency; Adrenal suppression; Glucocorticoids; Inhaled corticosteroids (ICS)

Glucocorticoids (GCs), including inhaled corticosteroids (ICS), are fundamental for treating many paediatric disorders and have improved disease outcomes in children and youth considerably over decades of use [1][2]. However, hypothalamic–pituitary–adrenal (HPA) axis suppression, or adrenal suppression (AS), is one potential side effect of GC therapy that has been associated with significant morbidity and even death [3]-[8]

Symptoms of AS are often non-specific (Table 1) and can go undetected until a physiological stress, such as illness, surgery, or injury, precipitates an adrenal crisis [9]. There have been reports of adrenal crisis occurring in the absence of physiological stressors, which likely are secondary to unrecognized symptoms of AS [5][9]. Symptomatic AS, including adrenal crisis, can be prevented by recognizing children at risk and administering physiological GC replacement and/or higher doses of GCs during times of stress [6][7][9].

Table 1. Signs and symptoms associated with adrenal suppression (AS)

Signs and symptoms of possible AS

Poor linear growth*

Poor weight gain

Anorexia

Nausea or vomiting

Malaise

Weakness or fatigue

Headache

Abdominal pain

Myalgia/arthralgia

Psychiatric symptoms

Signs of adrenal crisis

Hypotension

Hypoglycemia (seizure or coma)

Signs associated with adrenal suppression

Cushingoid features
*Poor linear growth has been reported in close to 50% of patients with symptomatic AS (10). Children treated with GCs who experience poor linear growth should be evaluated for AS.
 Table adapted from reference [11]

AS in children treated with systemic GCs

Both clinical and biochemical evidence of AS following discontinuation of therapeutic doses of systemic GCs have been well described in children [8][11]-[14]. In practice, exposure for >2 weeks is used as a threshold for risk of clinically important AS [7][9]. Multiple short courses of GC therapy also need to be considered a risk factor for AS [15]. Duration of AS following prolonged GC exposure (i.e., years) has been reported to last up to 2 years, but is less after shorter term exposures. One month of GC exposure typically resolves within a few weeks or months [12][16]-[18]. Higher doses of GCs, longer term use, and the timing of administration (evening versus morning) are theoretical risks [19][20].

AS in children treated for asthma with ICS

There have been close to a hundred reported cases of adrenal crisis secondary to ICS, including a few associated deaths [4][21]-[23]. Most were reported in children receiving high-dose ICS therapy, most commonly 500 mcg of fluticasone propionate daily (or higher). Cases of symptomatic or biochemical AS associated with all forms of ICS have been reported, however [4][5][10][11][22]-[28]. Ciclesonide is a comparatively new ICS that appears to have reduced AS risk [5][23][28]. Children receiving 500 mcg of fluticasone propionate per day (or more), or high-dose ICS therapy, as defined by the Canadian Asthma Guidelines, should be considered at risk for clinically significant AS.

Other important risk factors for the development of AS in children with asthma include frequent or prolonged courses of systemic GCs and, possibly [4][5][11][28][29], concomitant intranasal corticosteroid use [5]. Duration of ICS exposure has not been identified as a risk factor for AS, but most studies have looked at longer exposures and found evidence for AS reported with use for 3 months or more [30][31]. Recent evidence has suggested a genetic susceptibility for development of AS in patients exposed to ICS, but further study is needed to delineate this risk [32].

ICS therapy has been clearly demonstrated to reduce or eliminate chronic symptoms of asthma, and is considered an essential treatment for asthma. When used according to current guidelines [2], ICS therapy is rarely associated with clinically significant AS. Canadian Thoracic Society guidelines from 2012 recommend that high-dose ICS (including doses >400 mcg of fluticasone in children) should only be used by asthma specialists [2].

AS in children treated with other forms of GCs

The use of intranasal corticosteroids in conjunction with ICS has been shown to be a risk factor for AS [33], while the risk of using intranasal corticosteroids alone has not been clearly established [34][35]

AS has been clearly demonstrated in children receiving oral viscous budesonide or swallowed fluticasone for eosinophilic esophagitis, and possibly when these medications are used in inflammatory bowel disease [10][36][37]. There have been rare reports of symptomatic AS with ocular GCs and with misuse of potent topical GCs, where cushingoid features served as a relevant clinical clue [38][39]. AS has been associated with intra-articular GCs in adults [40][41].

Medications potentiating systemic effects of GCs

CYP3A4 inhibitors, including several antiretrovirals (e.g., ritonavir), antifungal agents (e.g., ketoconazole), and select antibiotics (e.g., clarithromycin), prolong the biologic half-life of GCs. These medications have been implicated in several cases of symptomatic AS associated with relatively low doses of ICS, and are reported to prolong duration of AS in systemic GC exposure [8][11][42]-[44].

An evolving issue in AS: Glucocorticoid taper

It has been demonstrated that a gradual GC taper does not prevent AS [12], and there is no literature evaluating abrupt discontinuation of GCs following prolonged exposure. GCs should be tapered or discontinued at a rate determined by the underlying condition and need to maintain disease remission. When the rate of taper is not indicated to prevent disease relapse, the risk of contributing to ongoing AS from unnecessary GC exposure should be considered [7]. There is no evidence to support a specific approach to GC taper for the prevention of AS, however [6][45].

The approach suggested here is to consider total GC exposure in patients for whom a taper is not needed to treat underlying disease, with longer exposures requiring a more gradual taper. For example, consider no taper for an exposure of <1 month; a 1- to 2-week taper for an exposure of 1 to 3 months; a 2- to 3-week taper for an exposure of 3 to 6 months; and a 3- to 4-week taper for >6 months of exposure [6][45].

Children are at risk for symptomatic AS when GCs are tapered below a physiological GC dose of 8 mg/m2/day hydrocortisone equivalent [9]. Consider screening for AS with a first morning cortisol before discontinuing or tapering GCs below the physiological dose threshold (see Testing for AS, below). The first morning cortisol might suggest the need for stress dosing with or without daily physiological hydrocortisone replacement to allow HPA axis recovery before discontinuing GCs [7]. For cases of symptomatic AS, continue GCs at or above physiological dose level and consult endocrinology. Symptoms of GC withdrawal can also occur during a rapid taper, and may mimic symptoms of AS despite biochemical evidence of HPA system integrity, indicating the need for a more gradual taper [46]

Testing for AS

Testing for adrenal insufficiency (AI), including AS, is a clinical challenge due to the lack of standardized cortisol assays or evidence-based thresholds for diagnosis [47][48]. While standard cortisol thresholds are typically used to diagnose AI, clinicians must be aware of the assay used in their local laboratory. First morning cortisol levels (at 7 to 9:00 a.m.) may have a role when evaluating the HPA axis. Importantly, a first morning cortisol is only specific for diagnosis of AI when levels are ≤100 nmol/L, in most individuals with a normal sleep-wake cycle, and in whom GCs have been withheld for 24 h to 48 h (48 h for longer acting GCs) [49][50]. Because cortisol production is under circadian regulation, a low morning cortisol cannot accurately predict AS in infants or in children who do not have a regular sleep-wake cycle. For these groups, adrenocorticotropic hormone (ACTH) stimulation testing is indicated if first morning cortisol is low [51]. A first morning cortisol value of 350 nmol/L to 500 nmol/L can predict normal HPA axis function [50]-[52]. From a practical perspective, a first morning cortisol value of 275 nmol/L has been used as a screening threshold in asymptomatic patients [5]. A first morning cortisol value between 100 nmol/L and 275 nmol/L suggests possible AS. In this scenario, consider empiric treatment (see GC replacement in AS, below) or provocative testing to assist diagnosis of AS. 

Provocative testing using synthetic ACTH (cosyntropin) is the best available test for evaluating central AI, including AS. Both standard-dose (250 mcg) and low-dose (1 mcg) ACTH stimulation tests are used in clinical practice, with significant debate about which is superior [51][53]. Without clear data to support the superiority of one test, use of either is reasonable when evaluating AS, though the accessibility of cosyntropin locally may limit testing options [7][48][51][53].

Clinicians should be aware that exogenous GCs, including ICS, can interfere with evaluation of the HPA axis and are therefore generally withheld for 24 h to 48 h before cortisol testing (24 h is appropriate for short-acting GCs and ICS; withhold longer for moderate- to long-acting GCs). 

GC replacement in AS

Cortisol production rises significantly during physiological stress in healthy individuals [54]. Children with proven or suspected AS should receive stress doses of GCs during a severe or critical illness, or before a major surgery, to prevent adrenal crisis [13][55]-[57]. Stress dosing for moderate illness or injury and for minor or moderate surgery is indicated in children with proven AS, and should be considered in all children at risk for AS (Table 2) [7].

Children with symptomatic and biochemically proven AS require daily physiological GC replacement [7]. Daily GC replacement is important to consider for children at high risk for AS who may not have clear symptoms but who have biochemical evidence of AS. However, this approach remains controversial among paediatric endocrinologists because there is no literature to support or refute it.

Table 2. Glucocorticoid replacement and stress dosing
Indication
Glucocorticoid dosea,b
Adrenal crisis, severe illness, or severe injury
Hydrocortisone 100 mg/m2 (maximum 100 mg) IV/IM STAT
then 100 mg/m2/24 h (maximum 200 mg) divided every 6 h or by continuous infusion
Approximate critical illness initial STAT dosing based on estimated BSA:
  • Infant 25 mg IV hydrocortisone
  • Small child (<15 kg) 50 mg IV hydrocortisone
  • Child or adolescent (≥15 kg) 100 mg IV hydrocortisone
Major surgery
Hydrocortisone 50 mg/m2 to 100 mg/m2 IV (maximum 100 mg) pre-op, then 100 mg/m2/24 h IV (maximum 200 mg) divided every 6 h or by continuous infusion
Minor or moderate surgery or procedure requiring general anesthesia
30 mg/m2/day hydrocortisone equivalentc divided x 3 until symptoms resolve
 
 
Duration >3 days should be reassessed by the health care teamd
Moderate illness, including fever ≥38.5oC, vomiting, diarrhea, severe head cold with fatigue, or injury
 
Unable to tolerate orally
Hydrocortisone must be given parenterally
30 mg/m2/day to 50 mg/m2/day hydrocortisone divided every 6 h (IV) or every 8 h (IM)
 
 
Consult endocrinology to reassess parenteral dose when the child is still unable to tolerate orally after 24 h of parenteral administration
Severe illness or moderate illness and unable to tolerate orally BEFORE arriving in emergency department (ED)
Consider teaching administration of IM hydrocortisone in all patients with AS
 
Families who do not have rapid access to a hospital ED or who are planning remote travel (e.g., by airplane, or a camping trip) should be taught administration of IM hydrocortisone
Daily physiological hydrocortisone dosing
8 mg/m2/day hydrocortisone daily (divided 2 or 3 x when child is symptomatic, with higher dose in the mornings)
 
AS Adrenal suppression; BSA Body surface area; IM Intramuscular; IV Intravenous
a Poor evidence for paediatric dosing. These recommendations are based on expert opinion and best available evidence [9][58]-[60]
b Dosing may need to be adjusted in children receiving CYP3A4 inducers. Endocrinology should be consulted in such cases.
c In children on active GC therapy with  doses of  ≥30 mg/m2/day of hydrocortisone equivalent (≥7.5 mg/m2/day prednisone), stress dosing for moderate illness can be acheived by dividing the therapeutic prednisone dose to be given    2 times/day (i.e., therapeutic dose is sufficient for stress coverage). When therapeutic GCs are no longer needed, stress dosing should be provided using hydrocortisone.
d Frequent or prolonged stress dosing can contribute to AS. Stress dosing is not required for very mild symptoms, such as a persistent runny nose. 
Adapted from reference [7]

Recommendations

General considerations

  • Symptomatic AS, including adrenal crisis, though rare, is a serious potential adverse effect of both systemic and inhaled GC therapy.
  • Despite risk for AS, ICS therapy—when used according to current guidelines and for single short courses of systemic GC therapy—is rarely associated with clinically significant AS.
  • AS occurs at a relatively high frequency in paediatric patients being treated with ≥500 mcg of fluticasone propionate or high dose ICS therapy, as defined by national asthma guidelines, and in children or youth being treated with prolonged (i.e., >2 weeks) systemic therapy.

How should clinicians reduce risk for AS?

  • Be aware of risks for AS, and reduce risk through more thoughtful GC prescribing, using the lowest effective doses of GCs, and re-evaluating dose and need regularly.
  • Once-daily GC dosing should be administered in the morning, whenever possible, to minimize HPA axis suppression. This practice should be considered for all forms of GC therapy, including ICS approved for once-daily dosing. Other ICS should be administered in accordance with their approved dosing guidelines.

How should clinicians prevent morbidity related to AS?

  • Test for AS in all children with suggestive signs or symptoms or Cushing’s syndrome, and with current or recent history of GC/ICS use (Table 1).
  • All children with proven AS should receive stress dosing for moderate to severe illness or injury and surgery with consideration of daily GC replacement (Table 2).
  • Stress dosing should be provided for critical illness and major surgery in all children being actively treated with GCs, and should be considered in all children whose GC therapy has been recently discontinued (up to a year for several months’ exposure) unless their HPA axis has been proven to be normal. Cortisol should be drawn before initiating stress dosing during a critical illness, if possible, when the diagnosis of AS is not confirmed.
  • Families should be educated about the risk for AS, always with the understanding that the benefits of GC therapy far outweigh risks, and that medication adherence and clinical follow-up are the best preventative measures for symptomatic AS..
  • Families of children with AS should be educated about stress dosing (Table 2) and provided with a stress dosing card or handout outlining doses (see Appendix 1), indications for stress dosing, and indications to seek emergency help. 

Other considerations for preventing morbidity with AS

Given the lack of evidence and inconsistency in practice, the Adrenal Suppression Working Group recommends considering the following based on individual clinical practice:

  • Clinicians should be aware of the risk factors for developing AS and consider screening asymptomatic children at greater risk, including those receiving high-dose ICS therapy for ≥3 months, systemic therapy for >2 weeks, swallowed ICS therapy for > 1 month, or ICS of any dose for ≥3 months in conjunction with CYP3A4 inhibitors.
  • Consider empiric stress dosing for up to 6 to 12 months for asymptomatic children with a first morning cortisol of <275 nmol/L (versus ACTH stimulation testing to confirm the diagnosis).
  • Consider an endocrine consult for first morning cortisol < 100 nmol/L or symptomatic AS.

Summary

While biochemical AS is relatively common in children treated with GC therapy, symptomatic AS is less frequently seen. Risk for symptomatic AS can be reduced by responsible GC prescribing and follow-up, recognition of signs and symptoms (including poor growth), and consideration of screening and treatment for children at high risk. Educating clinicians and the families of at-risk patients about AS is fundamental to reducing morbidity associated with this iatrogenic condition. Uncertainty about management warrants consultation with an endocrinologist. Clinicians and families should not lose sight of the fact that GCs are essential for managing many paediatric conditions, and that risk for AS should not be a barrier to their use.

Appendix 1. Sample wallet card (hydrocortisone) is available as a supplementary file.

Acknowledgements

This statement was reviewed by the Acute Care, and Drug Therapy and Hazardous Substances Committees of the Canadian Paediatric Society. It was also reviewed by the CPS Paediatric Emergency Medicine, Hospital Paediatrics, and Respiratory Section Executives.


Members of the Adrenal Suppression Working Group:  Alexandra Ahmet MD, Ellen B Goldbloom MD, Céline Huot MD, Roman Jurencak MD, Harold Kim MD, Tom Kovesi MD, Preetha Krishnamoorthy MD, Anne Rowan-Legg MD, Arati Mokashi MD, Larry Pancer MD

 

CANADIAN PAEDIATRIC SOCIETY COMMUNITY PAEDIATRICS COMMITTEE
Members: 
Carl Cummings MD (past Chair), Michael Hill MD, Audrey Lafontaine MD, Alisa Lipson MD, Marianne McKenna MD (Board Representative), Larry Pancer MD (past member)
Liaisons: Peter Wong MD (Community Paediatrics Section)
Principal authors: Alexandra Ahmet MD, Anne Rowan-Legg MD, Larry Pancer MD


References

  1. Gates A, Gates M, Vandermeer B, et al. Glucocorticoids for croup in children. Cochrane Database Syst Rev 2018;8(8):CD001955.
  2. Lougheed MD, Lemiere C, Ducharme FM, et al. Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults. Can Respir J 2012;19(2):127-64.
  3. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013;9(1):30.
  4. Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87(6):457-61.
  5. Kapadia CR, Nebesio TD, Myers SE, et al. Endocrine effects of inhaled corticosteroids in children. JAMA Pediatr 2016;170(2):163-70.
  6. Dinsen S, Baslund B, Klose M, et al. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur J Intern Med 2013;24(8):714-20.
  7. Ahmet A, Mokashi A, Goldbloom EB, et al. Adrenal suppression from glucocorticoids: Preventing an iatrogenic cause of morbidity and mortality in children. BMJ Paediatrics Open 2019;3(1):e000569.
  8. Rensen N, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers GJ. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev 2017;11(11):CD008727.
  9. Shulman DI, Palmert MR, Kemp SF; Lawson Wilkins Drug and Therapeutics Committee. Adrenal insufficiency: Still a cause of morbidity and death in childhood. Pediatrics 2007;119(2):e484-94.
  10. Goldbloom EB, Mokashi A, Cummings EA, et al. Symptomatic adrenal suppression among children in Canada. Arch Dis Child 2017;102(4):338-9.
  11. Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol 2011;7(1):13.
  12. Ahmet A, Brienza V, Tran A, et al. Frequency and duration of adrenal suppression following glucocorticoid therapy in children with rheumatic diseases. Arthritis Care Res (Hoboken) 2017;69(8):1224-30.
  13. Einaudi S, Bertorello N, Masera N, et al. Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2008;50(3):537-41.
  14. Goldbloom E, Ahmet A, Abish S, et al. Adrenal suppression in the pediatric population in Canada. Canadian Pediatric Surveillance Program. 2012 Results:18-20: https://cpsp.cps.ca/uploads/publications/Results-2012.pdf.
  15. Dolan LM, Kesarwala HH, Holroyde JC, Fischer TJ. Short-term, high-dose, systemic steroids in children with asthma: The effect on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol 1987;80(1):81-7.
  16. Wildi-Runge S, Deladoëy J, Bélanger C, et al. A search for variables predicting cortisol response to low-dose corticotropin stimulation following supraphysiological doses of glucocorticoids. J Pediatr 2013;163(2):484-8.
  17. Zora JA, Zimmerman D, Carey TL, O'Connell EJ, Yunginger JW. Hypothalamic-pituitary-adrenal axis suppression after short-term, high-dose glucocorticoid therapy in children with asthma. J Allergy Clin Immunol 1986;77(1 Pt 1):9-13.
  18. Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 2000;355(9203):542-5.
  19. Hawcutt DB, Jorgensen AL, Wallin N, et al. Adrenal responses to a low-dose short synacthen test in children with asthma. Clinical Endocrinol (Oxf.) 2015;82(5):648-56.
  20. Adam HM. Fever and host responses. Pediatr Rev 1996;17(9):330-1.
  21. Donaldson MD, Morrison C, Lees C, et al. Fatal and near-fatal encephalopathy with hyponatraemia in two siblings with fluticasone-induced adrenal suppression. Acta Paediatr 2007;96(5):769-72.
  22. Schwartz RH, Neacsu O, Ascher DP, Alpan O. Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: Case report and review of the literature. Clin Pediatr (Phila.) 2012;51(12):1184-90.
  23. Heller MK, Laks J, Kovesi TA, Ahmet A. Reversal of adrenal suppression with ciclesonide. J Asthma 2010;47(3):337-9.
  24. Zöllner EW. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2)--the risk as determined by gold standard adrenal function tests: A systematic review. Pediatr Allergy Immunol 2007;18(6):469-74.
  25. Patel L, Wales JK, Kibirige MS, Massarano AA, Couriel JM, Clayton PE. Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child 2001;85(4):330-4.
  26. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999;159(9):941-55.
  27. Bernstein DI, Allen DB. Evaluation of tests of hypothalamic-pituitary-adrenal axis function used to measure effects of inhaled corticosteroids. Ann Allergy Asthma Immunol 2007;98(2):118-27.
  28. Lipworth BJ, Kaliner MA, LaForce CF, et al. Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma. Ann Allergy Asthma Immunol 2005;94(4):465-72.
  29. Ducharme FM, Dell SD, Radhakrishnan D, et al. Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper. Paediatr Child Health 2015;20(7):353-71.
  30. Cavkaytar O, Vuralli D, Yilmaz EA, et al. Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use. Eur J Pediatr 2015;174(11):1421-31.
  31. Smith RW, Downey K, Gordon M, et al. Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid. Paediatr Child Health 2012;17(5():e34-9.
  32. Hawcutt DB, Francis B, Carr DF, et al. Susceptibility to corticosteroid-induced adrenal suppression: A genome-wide association study. Lancet Respir Med 2018;6(6):442-50.
  33. Zöllner EW, Lombard C, Galal U, Hough S, Irusen E, Weinberg E. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids--More common than expected? J Pediatr Endocrinol Metab 2011;24(7-8):529-34.
  34. Patel D, Ratner P, Clements D, Wu W, Faris M, Philpot E. Lack of effect on adult and adolescent hypothalamic-pituitary-adrenal axis function with use of fluticasone furoate nasal spray. Ann Allergy Asthma Immunol 2008;100(5):490-6.
  35. Skoner DP, Berger WE, Gawchik SM, Akbary A, Qiu C. Intranasal triamcinolone and growth velocity. Pediatrics 2015;135(2):e348-56.
  36. Ahmet A, Benchimol EI, Goldbloom EB, Barkey JL. Adrenal suppression in children treated with swallowed fluticasone and oral viscous budesonide for eosinophilic esophagitis. Allergy Asthma Clin Immunol 2016;12:49.
  37. Cohen SA, Aloi M, Arumugam R, et al. Enteric-coated budesonide for the induction and maintenance of remission of Crohn's disease in children. Curr Med Res Opin 2017;33(7):1261-8.
  38. Buluş AD, Andıran N, Koçak M. Cushing's syndrome: Hidden risk in usage of topical corticosteroids. J Pediatr Endocrinol Metab 2014;27(9-10):977-81.
  39. Chiang MY, Sarkar M, Koppens JM, Milles J, Shah P. Exogenous Cushing's syndrome and topical ocular steroids. Eye (Lond) 2006;20(6):725-7.
  40. Duclos M, Guinot M, Colsy M, et al. High risk of adrenal insufficiency after a single articular steroid injection in athletes. Med Sci Sports Exerc 2007;39(7):1036-43.
  41. Johnston PC, Lansang MC, Chatterjee S, Kennedy L. Intra-articular glucocorticoid injections and their effect on hypothalamic-pituitary-adrenal (HPA)-axis function. Endocrine 2015;48(2):410-6.
  42. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: A review of the literature. HIV Med 2008;9(6):389-96.
  43. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 2009;360(22):2328-39.
  44. Gilchrist FJ, Cox KJ, Rowe R, et al. Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis. J Cyst Fibros 2013;12(4):399-402.
  45. Richter B, Neises G, Clar C. Glucocorticoid withdrawal schemes in chronic medical disorders. A systematic review. Endocrinol Metab Clin North Am 2002;31(3):751-78.
  46. Dixon RB, Christy NP. On the various forms of corticosteroid withdrawal syndrome. Am J Med 1980;68(2):224-30.
  47. Hawley JM, Owen LJ, Lockhart SJ, et al. Serum cortisol: An up-to-date assessment of routine assay performance. Clin Chem 2016;62(9):1220-9.
  48. Ng SM, Agwu JC, Dwan K. A systematic review and meta-analysis of synacthen tests for assessing hypothalamic-pituitary-adrenal insufficiency in children. Arch Dis Child 2016;101(9):847-53.
  49. Maguire AM, Biesheuvel CJ, Ambler GR, Moore B, McLean M, Cowell CT. Evaluation of adrenal function using the human corticotrophin-releasing hormone test, low dose synacthen test and 9am cortisol level in children and adolescents with central adrenal insufficiency. Clin Endocrinol (Oxf.) 2008;68(5):683-91.
  50. Le Roux CW, Meeran K, Alaghband-Zadeh J. Is a 0900-h serum cortisol useful prior to a short synacthen test in outpatient assessment? Ann Clin Biochem 2002;39(Pt 2):148-50.
  51. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: A metaanalysis. J Clin Endocrinol Metab 2008;93(11):4245-53.
  52. Woods CP, Argese N, Chapman M, et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. Eur J Endocrinol 2015;173(5):633-42.
  53. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: Systematic review and meta-analysis. J Clin Endocrinol Metab 2016;101(2):427-34.
  54. Salem M, Tainsh RE, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg 1994;219(4):416-25.
  55. Leblicq C, Rottembourg D, Deladoëy J, Van Vliet G, Deal C. Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed? J Pediatr 2011;158(3):492-8 e1.
  56. Rix M, Birkebaek NH, Rosthøj S, Clausen N. Clinical impact of corticosteroid-induced adrenal suppression during treatment for acute lymphoblastic leukemia in children: A prospective observational study using the low-dose adrenocorticotropin test. J Pediatr 2005;147(5):645-50.
  57. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: A prospective study. J Clin Endocrinol Metab 2015;100(2):407-16.
  58. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet 2014;383(9935:2152-67.
  59. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015;3(3):216-26.
  60. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101(2):364-89.

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.

Last updated: Feb 8, 2024