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

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.

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 nonspecific (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 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

AS Adrenal suppression.

*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 07:00 to 09:00) 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 hours to 48 hours (48 hours 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 hours to 48 hours before cortisol testing (24 hours 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).

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	Hydrocortisone 50 mg/m2 IV (maximum 100 mg) pre-op, then as indicated by clinical status (typically moderate illness dosing for 1 to 2 days)
Moderate illness, including fever ≥38.5oC, vomiting, diarrhea, severe head cold with fatigue, or injury	30 mg/m2/day hydrocortisone equivalentc divided x 3 until symptoms resolve
Able to tolerate orally	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	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)
Unable to tolerate orally	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.

^aPoor evidence for paediatric dosing. These recommendations are based on expert opinion and best available evidence (9,58–60).

^bDosing may need to be adjusted in children receiving CYP3A4 inducers. Endocrinology should be consulted in such cases.

^cIn 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 achieved by dividing the therapeutic prednisone dose to be given two 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.

^dFrequent 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).

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.

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 (Supplementary 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.

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/documents for the most current version. Retired statements and practice points are removed from the website.

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.

Funding: There are no funders to report.

Potential Conflicts of Interest: AA reports consulting fees from Reveragen outside the submitted work. There are no other disclosures. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

ADRENAL SUPPRESSION WORKING GROUP

Members: Alexandra Ahmet MD, Ellen B. Goldbloom MD, Celine 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)

Liaison: Peter Wong MD (Community Paediatrics Section)

Principal authors: Alexandra Ahmet MD, Anne Rowan-Legg MD, Larry Pancer MD