INTRODUCTION — Adrenal insufficiency is a potentially life-threatening condition defined by impaired synthesis and release of adrenocortical hormones. It can be caused by a variety of disorders that interfere with the production of adrenocortical hormones, including abrupt withdrawal of glucocorticoid medications or congenital adrenal hyperplasia (CAH).

Classic CAH, which is caused by 21-hydroxylase deficiency, is responsible for approximately 75 percent of cases of primary adrenal insufficiency. The diagnosis and treatment of this form of adrenal insufficiency are discussed in separate topic reviews:

●(See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

●(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

The treatment of adrenal insufficiency other than CAH will be discussed below. The causes, clinical manifestations (table 1), and diagnosis of adrenal insufficiency are discussed separately.

●(See "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

●(See "Causes of primary adrenal insufficiency in children".)

●(See "Causes of central adrenal insufficiency in children".)

OVERVIEW — Treatment of adrenal insufficiency depends upon the underlying mechanism:

●Primary adrenal insufficiency results from disease that is intrinsic to the adrenal cortex (table 2). The most common cause of primary adrenal insufficiency in children is classic congenital adrenal hyperplasia (CAH). (See "Causes of primary adrenal insufficiency in children".)

Treatment for patients with primary adrenal insufficiency includes physiologic replacement with glucocorticoid and mineralocorticoid. Glucocorticoid dosing must be increased during times of stress.  

●Central adrenal insufficiency is characterized by lack of adrenocorticotropic hormone (ACTH) stimulation of cortisol production. Central adrenal insufficiency can be caused by either pituitary disease that impairs production of ACTH (secondary adrenal insufficiency (table 3A)) or by interference with corticotropin-releasing hormone (CRH) release from the hypothalamus (tertiary adrenal insufficiency (table 3B)). The most common cause is chronic, high-dose glucocorticoid therapy, which suppresses the hypothalamic-pituitary-adrenal axis. (See "Causes of central adrenal insufficiency in children".)

Treatment for central adrenal insufficiency generally requires only glucocorticoid replacement because these patients do not have mineralocorticoid deficiency. However, they may have other pituitary hormone deficiencies that require treatment, depending on the underlying central nervous system disease.

ADRENAL HORMONE REPLACEMENT THERAPY

Glucocorticoids

Choice of glucocorticoid — We prefer to use hydrocortisone as the first-line approach to glucocorticoid replacement in pediatric cases of adrenal insufficiency. This is because hydrocortisone has short duration of action and lower potency than other glucocorticoids, allowing for fine titration to the optimal dose.

Instead of hydrocortisone, one can use prednisolone or prednisone, which have the advantage of less frequent dosing but the potential significant disadvantage of growth suppression. These synthetic glucocorticoids have a longer half-life than hydrocortisone, which makes it possible to administer doses daily or twice daily. They are also approximately four to five times more potent than hydrocortisone in terms of adrenocorticotropic hormone (ACTH) suppression [1] and may be 5 to 15 times more potent in terms of growth suppression [2].

Even more potent synthetic glucocorticoid preparations, such as dexamethasone, are not generally used for replacement therapy in children, although they are sometimes used for adults [3]. For dexamethasone, the ACTH-suppressive effect may be 35 to 50 times that of hydrocortisone, but the growth-suppressive effect may be 75 to 95 times higher. This great potency makes it difficult to titrate the appropriate dose for children. However, with the availability of a commercial oral suspension, dexamethasone has been used successfully in some children without causing growth suppression [4-6].

Prednisolone, prednisone, and dexamethasone lack significant mineralocorticoid activity (table 4). If these glucocorticoids are chosen for treatment of patients with primary adrenal insufficiency, the treatment regimen also must include the mineralocorticoid fludrocortisone (9-alpha-fluorocortisol), and the dose of fludrocortisone may need to be higher than was needed if glucocorticoid treatment was changed from hydrocortisone. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and 'Mineralocorticoids' below.)

Dosing — The glucocorticoid dosing requirement varies with the type of adrenal insufficiency:

●Classic congenital adrenal hyperplasia – For patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the doses of glucocorticoid required to suppress the ACTH-stimulated excessive adrenal androgens are substantially higher than those required to adequately treat other causes of adrenal insufficiency; doses required in neonates with congenital adrenal hyperplasia are about twofold higher than in older children, based on body surface area. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Medications and dosing'.)

●Other causes of primary adrenal insufficiency – For children with primary adrenal insufficiency that is not due to congenital adrenal hyperplasia, the starting oral dose of hydrocortisone is in the range of 7 to 10 mg/m²/day [3]. Infants usually require somewhat higher doses for adequate replacement. The dose should then be titrated to the individual patient's needs depending on the clinical response and growth.

This is somewhat higher than the normal daily cortisol secretion rate (table 5) because of the short half-life of hydrocortisone given orally and its partial destruction by gastric acidity. The body surface area is calculated from the child's height and weight using a nomogram or calculator (calculator 1) [3]. The total daily oral hydrocortisone dose is usually divided into three doses and administered every eight hours. The dose for long-term replacement must be adjusted to the requirement of individual subjects, as indicated by biochemical and physiologic response to treatment including growth rate, as outlined below. (See 'Monitoring and dose adjustment' below.)

●Central adrenal insufficiency – Central (secondary or tertiary) adrenal insufficiency, which is characterized by ACTH deficiency, is treated with glucocorticoid at physiologic replacement doses in the lower end of the expected dose range, ie, hydrocortisone 7 to 10 mg/m²/day. The dose must be titrated carefully to prevent overtreatment, which seems to occur at lower doses in children with ACTH deficiency than in those with primary adrenal failure. Mineralocorticoid treatment is unnecessary as these patients have a normal renin-angiotensin-aldosterone axis and, hence, normal mineralocorticoid secretion. The growth rates in weight and height and general clinical well-being are the most useful parameters to follow for dose adjustments.

These starting doses for glucocorticoid therapy are based on the estimates of normal cortisol secretion rates, which vary based on the age of the subjects:

●For newborn infants, cortisol secretion rates are approximately 12 mg/m²/day. This was based upon studies from the 1960s that used older techniques that were eventually replaced by more sensitive assay methods. These earlier studies reported that cortisol secretion at birth was 1.5 times higher than in adults and by three weeks of age had decreased to 1.2 times that in adults [7].

●For older infants and children, the daily cortisol secretion rate is approximately 7 mg/m²/day. This is based on a series of stable isotope studies performed in the 1990s, which showed cortisol production rates of about 4 to 7 mg/m²/day in 8- to 17-year-old children [8,9] and approximately 6 mg/m²/day in young adults [10].

Mineralocorticoids

Indications — Patients with primary adrenal insufficiency require mineralocorticoid replacement with fludrocortisone. For children with central adrenal insufficiency, treatment with mineralocorticoids is not necessary. These children do not have mineralocorticoid deficiency, because ACTH is not the physiologic regulator of aldosterone release (which is mediated by the renin-angiotensin system). However, these patients may have deficiencies of other pituitary hormones that may require replacement. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Evaluate for cause'.)

Dosing — The usual daily dose of fludrocortisone is 0.1 mg when given in conjunction with hydrocortisone, which has some mineralocorticoid activity. When using prednisone or prednisolone (which contribute less mineralocorticoid activity) or dexamethasone (which has essentially no mineralocorticoid activity), higher fludrocortisone doses may be needed (table 4) [3]. Higher doses are also occasionally needed in infants. Otherwise, the mineralocorticoid dose is not adjusted by age or surface area, because the aldosterone secretion rate is nearly constant throughout the lifespan.

Infants younger than one year with mineralocorticoid deficiency should be supplemented with sodium chloride in addition to mineralocorticoid replacement. The dose is approximately 1 gram (17 mEq) daily. Infants require this sodium supplement because of their relatively low dietary sodium intake in formula and breast milk and a relative renal resistance to mineralocorticoids in this age group.

Monitoring and dose adjustment — In infants, the response to therapy should be evaluated monthly in the first three months after starting treatment, every three months in older infants, and every six months thereafter while the child is still growing. More frequent monitoring is sometimes clinically indicated. After completion of growth, annual monitoring may be adequate. Adjustments in the doses of hydrocortisone and fludrocortisone are based primarily upon rates of growth and on skeletal maturation (bone age). In addition, serial measurements of electrolytes and plasma renin activity (PRA) should be performed to monitor for mineralocorticoid sufficiency.

Close follow-up of somatic growth (height and weight velocities and rate of bone age change) provides the most important guidelines for dose adjustment.

●Insufficient glucocorticoid dose – Inadequate weight gain and gastrointestinal symptoms often suggest inadequate glucocorticoid dosing. However, they also may be symptoms of inadequate mineralocorticoid replacement, so they must be interpreted in the context of other symptoms (table 1) and laboratory monitoring of mineralocorticoid status. Increasing hyperpigmentation or morning headache are more specific for glucocorticoid deficiency. We do not routinely monitor plasma ACTH concentrations, because in patients on adequate replacement doses based on clinical parameters, levels are highly variable and typically remain above the normal range.

●Excessive glucocorticoid dose – Excessive weight gain with decreased height velocity, facial plethora, or other symptoms or signs of Cushing syndrome indicate excessive glucocorticoid replacement.

●Insufficient mineralocorticoid dose – Symptoms of inadequate mineralocorticoid replacement include salt craving and poor weight gain; signs include hypotension, dehydration, and hyponatremia with hyperkalemia on laboratory testing (table 1). In this situation, PRA will be elevated [3]. Elevated PRA may also indicate dehydration and may normalize with consumption of additional water. If PRA does not normalize following this maneuver, this suggests ongoing salt loss. The next step is to increase the fludrocortisone and/or the exogenous salt doses (in infants) to decrease the elevated PRA.

●Excessive mineralocorticoid dose - In this situation, elevated blood pressure is frequently present. A suppressed PRA reflects excessive mineralocorticoid dosing.

STRESS CONDITIONS — Patients with primary, secondary, or tertiary adrenal insufficiency require additional doses of glucocorticoids when subjected to physiologic stress [11]. In this setting, the primary goal of treatment is to avoid the serious consequence of adrenal crisis. The treatment regimens described below provide ample glucocorticoid coverage for acute stress, but ongoing monitoring and treatment are required if the physiologic stress is prolonged.

Illness — Minor infection and/or low-grade fever (sore throat, rhinorrhea, fever up to 38ºC) may not require a change in dose. During conditions of moderate stress (eg, severe upper respiratory infections), the dose should be double the usual glucocorticoid replacement dose. In major stress (eg, temperature above 38ºC and/or vomiting), the hydrocortisone dose should be increased to three times the normal replacement [3]. For patients receiving glucocorticoid therapy with dexamethasone or prednisone, it is important to note that increasing the dose of these medications during acute illness may not achieve the blood levels of cortisol that are needed for stress sufficiently quickly. Thus, it is preferable to use oral hydrocortisone for stress dosing to provide the advantages of rapid increases in serum cortisol levels as well as mineralocorticoid effect [12].

Under stress conditions, infants and children frequently are unable to tolerate oral therapy. In such cases, the parents are advised to administer an intramuscular injection of approximately 50 mg/m² of hydrocortisone sodium succinate (SoluCortef), using the body surface area calculated from the child's height and weight via a nomogram or calculator (calculator 1). Alternatively, a simpler age-based dose regimen can be used [3]:

●0 to 3 years old – Hydrocortisone 25 mg intramuscularly

●3 to 12 years old – Hydrocortisone 50 mg intramuscularly

●12 years and older – Hydrocortisone 100 mg intramuscularly

This treatment will provide up to six hours of coverage and allow the family time to get medical attention. For all patients with adrenal insufficiency, the treating endocrinologist should provide a letter outlining these steps and additional ones for management in the field and/or emergency department.

Every patient should wear medical identification (eg, bracelet or necklace such as those available from MedicAlert) and carry the emergency medical information card that is supplied with it, if available. Both should indicate the diagnosis "adrenal insufficiency" and the clinician to call in the event of an emergency. Patients can enroll in MedicAlert by calling (888) 525-5176 or through the internet at www.medicalert.org (United States) and www.medicalert.ca/ (Canada).

Surgical procedures — During general anesthesia, with or without surgery, the cortisol secretion rate in normal subjects increases greatly [13]. Similarly, in patients with adrenal insufficiency, the glucocorticoid requirement increases.

Minor to moderate surgical stress — In line with pediatric guidelines from the Endocrine Society [3], we recommend administration of intramuscular hydrocortisone as a single dose of 50 mg/m². Alternatively, the following simplified age-directed schema can be employed:

●0 to 3 years old – Hydrocortisone 25 mg intravenous bolus

●3 to 12 years old – Hydrocortisone 50 mg intravenous bolus

●12 years and older – Hydrocortisone 100 mg intravenous bolus

If the patient is hospitalized after the procedure, the initial bolus is followed by the same dose at a constant rate over a 24-hour period or in four divided doses over 24 hours. The stress doses of hydrocortisone are tapered rapidly according to the pace of clinical improvement, generally by reducing the dose back to physiologic replacement within one to two days.

Major surgery — For surgeries requiring general anesthesia and/or associated with trauma, delivery, or disease that requires intensive care, we suggest using a protocol that includes ongoing doses of glucocorticoid, as follows [3]:

●Just prior to anesthesia induction, give hydrocortisone at a dose of 50 mg/m² by rapid intravenous injection (adult dose 100 mg). This is followed by hydrocortisone 50 to 100 mg/m²/day (adult dose 200 mg/day) as a continuous infusion or divided every six hours.

●The following day, give hydrocortisone at three to four times the patient's usual replacement therapy dose, either orally if clinically stable, or as a constant intravenous infusion or divided into four intravenous boluses given every six hours if clinically unstable. If the patient experiences significant hypotension or electrolyte abnormalities, additional hydrocortisone may be needed.

●Stress dosing is generally continued until the patient can tolerate oral intake, is afebrile, and is hemodynamically stable. The timing is dictated by the nature of the surgery and expected recovery time.

These high doses will provide the needed extra glucocorticoid as well as mineralocorticoid coverage, as parenteral preparations with purely mineralocorticoid effects are not available. Hydrocortisone 20 mg has approximately the same mineralocorticoid effect as 0.1 mg of fludrocortisone.

ADRENAL CRISIS — The rapid recognition and prompt therapy of a salt-losing crisis are critical to survival. Electrolyte and fluid therapy must be instituted as soon as possible [14]. A rapid overview guiding the recognition and treatment of adrenal crisis is shown in the table (table 6).

The predominant manifestations of adrenal crisis are hypotension and shock, usually with hyponatremia and hyperkalemia [15]. Patients often have nonspecific symptoms such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, fever, confusion, and/or coma (table 7). It is precipitated by mineralocorticoid deficiency. Thus, adrenal crisis can occur in patients who are receiving physiologic or even pharmacologic doses of synthetic glucocorticoid if their mineralocorticoid requirements are not met.

Adrenal crisis is most likely to occur in primary adrenal insufficiency because of the associated mineralocorticoid deficiency and salt loss. However, patients with central adrenal insufficiency also may present in crisis with hypotension and shock and require stress steroid coverage to prevent this. Such patients do not have the typical electrolyte disturbances and severe dehydration that is seen when patients with primary adrenal insufficiency have adrenal crisis.

In infants presenting with adrenal crisis, the cause may be classic congenital adrenal hyperplasia; the evaluation and management are discussed separately (see "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children"). However, with the availability of newborn screening, most of these infants are diagnosed before adrenal crisis occurs.

For infants and children with adrenal crisis not caused by congenital adrenal hyperplasia, we suggest the following measures be instituted as soon as an adrenal crisis is suspected (table 6):

●Baseline samples – Samples should be drawn for urgent testing of electrolytes and glucose. In patients without a diagnosis of adrenal insufficiency, additional blood samples must be obtained for the measurement of serum cortisol and plasma adrenocorticotropic hormone (ACTH) prior to the administration of glucocorticoid therapy.

●Fluids and electrolytes – Give a bolus of D5 normal saline (5% dextrose with 0.9% saline, without potassium), 20 mL/kg intravenously over one hour (table 6). This will improve the hyponatremic dehydration, as well as hypoglycemia if present. Patients with hypoglycemia may need additional dextrose infusions, as outlined in the table. The potassium concentration usually remains elevated, and the acidosis may persist. It may be necessary to use insulin and glucose or a sodium-potassium exchange resin such as Kayexalate if the hyperkalemia is associated with electrocardiogram changes. (See "Management of hyperkalemia in children".)

●Glucocorticoids and mineralocorticoids – Treatment with a glucocorticoid should be initiated as soon as possible and is given as an intravenous bolus over several minutes. We use hydrocortisone sodium succinate (SoluCortef), with a dose of 50 mg/m² for children or 100 mg for adults [3]. Alternatively, age-based dosing may be used, as follows:

•0 to 3 years old – Hydrocortisone 25 mg intravenously

•3 to 12 years old – Hydrocortisone 50 mg intravenously

•12 years and older – Hydrocortisone 100 mg intravenously

The initial bolus is followed by the same dose at a constant rate over a 24-hour period or in four divided doses over 24 hours. Throughout the treatment, electrolytes and water balance must be monitored very carefully to prevent water retention and its complications. After the initial crisis is treated, a maintenance dose of glucocorticoid can be calculated and initiated. Mineralocorticoid replacement (fludrocortisone) is not necessary while the patient is on high doses of hydrocortisone, because this glucocorticoid supplies adequate mineralocorticoid activity. Fludrocortisone should be resumed as the maintenance dose of glucocorticoid is resumed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Society guideline links: Adrenal insufficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Congenital adrenal hyperplasia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Primary adrenal insufficiency, also known as Addison's disease, results from pathology intrinsic to the adrenal cortex (table 2). These patients have glucocorticoid deficiency, with or without deficiencies of mineralocorticoids and adrenal androgens. Central adrenal insufficiency is caused by impaired production of adrenocorticotropic hormone (ACTH) in the brain (table 3A-B). Patients with central adrenal insufficiency typically have only glucocorticoid deficiency. (See 'Introduction' above.)

●All patients with adrenal insufficiency require glucocorticoid replacement. The total daily oral hydrocortisone dose is divided into three doses and administered every eight hours. The optimal dose depends on the type of adrenal insufficiency. (See 'Adrenal hormone replacement therapy' above.)

•For patients with primary adrenal insufficiency other than congenital adrenal hyperplasia, initial replacement doses of hydrocortisone are approximately 7 to 10 mg/m²/day when given orally. Doses for infants are on the higher end of this range, and doses for patients with central adrenal insufficiency are on the lower end of this range.

•Infants with congenital adrenal hyperplasia typically require substantially higher initial replacement doses of hydrocortisone. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Medications and dosing'.)

•The dose should then be titrated to the individual patient's needs depending on the clinical response and growth.

●For infants and children with primary adrenal insufficiency, we suggest treatment with hydrocortisone rather than prednisone or prednisolone (Grade 2C). The relatively low potency and short duration of action of hydrocortisone allows for fine titration of the dose. Longer-acting synthetic glucocorticoids such as prednisone and dexamethasone may be used in older adolescents and adults but lack mineralocorticoid effects. (See 'Glucocorticoids' above.)

●Patients with primary adrenal insufficiency also require mineralocorticoid replacement. The dose of mineralocorticoid depends on the type of glucocorticoid given concurrently and is further adjusted based on the clinical response. Doses of mineralocorticoid may need to be adjusted to optimize growth, prevent salt craving, and maintain normal electrolytes and plasma renin activity (PRA), especially in infants. Beyond the newborn period, the fludrocortisone dose is close to 0.1 mg/day and does not need frequent adjustment. (See 'Mineralocorticoids' above.)

●Glucocorticoid doses must be increased during physiologic stress using two to three times the replacement dose, depending on the stressor. Children who are unable to tolerate oral therapy should be given an intramuscular injection of hydrocortisone sodium succinate (SoluCortef) to meet their urgent need and should then seek medical attention. (See 'Stress conditions' above.)

For patients receiving glucocorticoid therapy with dexamethasone or prednisone, it is important to note that increasing the dose of these medications during acute illness may not achieve the blood levels of cortisol that are needed for stress sufficiently quickly. Thus, it may be preferable to use oral hydrocortisone for stress dosing to provide the advantages of rapid increases in serum cortisol levels as well as mineralocorticoid effect.

●General anesthesia sharply increases glucocorticoid requirements, in addition to the stress of surgery itself. Typical regimens for corticosteroid replacement during surgery include an intravenous bolus at the beginning of surgery, followed by variable regimens postoperatively, depending on the length of the surgery and the degree of surgical stress. (See 'Surgical procedures' above.)

●Adrenal crisis is generally precipitated by mineralocorticoid deficiency in patients with primary adrenal insufficiency. The predominant clinical finding is hypotension or shock, often with hyponatremia and hyperkalemia (table 7). Patients with central adrenal insufficiency may present in crisis with hypotension and shock but do not have significant electrolyte imbalance or dehydration. All patients with suspected adrenal crisis should be urgently treated with fluid boluses and a glucocorticoid, as described in the rapid overview (table 6). (See 'Adrenal crisis' above.)