Primary adrenal insufficiency is a disorder characterized by insufficient adrenocortical synthesis and secretion of glucocorticoids, with or without deficiency in mineralocorticoids and adrenal androgens r1
Typical manifestations of primary adrenal insufficiency include hyperpigmentation, hypotension, hyponatremia, and hyperkalemia
Chronic adrenal insufficiency presents with nonspecific symptoms at onset, including abdominal pain, generalized weakness, fatigue, salt craving, and weight loss
Acute adrenal crisis presents with cardiovascular collapse and hemodynamic instability
Diagnostic process includes demonstration of low serum cortisol levels along with high plasma adrenocorticotropic hormone levels, followed by investigation to identify the underlying cause
Principal treatment is hormonal replacement of glucocorticoids and mineralocorticoids
Do not await laboratory confirmation of disease, if suspicion is high, before beginning treatment, because delays can result in poor outcomes
It is essential to intensively educate patients and families about the need to increase glucocorticoid doses during intercurrent illness and stress, to avoid adrenal crisis
Begin therapy with IV fluids and hydrocortisone, even before diagnostic test results are available r2
Adults
Rapidly infuse 1 L of isotonic saline IV within the first hour, followed by additional IV fluids as dictated by patient's volume status and blood pressure response (usual requirement is 4-6 L in 24 hours) r3
Immediate bolus injection of 100 mg hydrocortisone IV or intramuscularly, followed by continuous IV infusion of 200 mg hydrocortisone per 24 hours (alternatively, 50 mg hydrocortisone IV or intramuscularly, with injection every 6 hours) r3
Children
Rapidly infuse IV bolus of normal saline (0.9%) 20 mL/kg; can repeat up to a total of 60 mL/kg within 1 hour to treat shock r1
Treat with bolus IV injection of 50 mg/m² hydrocortisone, followed by continuous injection or injection every 6 hours of hydrocortisone (total 50-100 mg/m² over 24 hours) r1
If child is hypoglycemic, administer dextrose 0.5 to 1 g/kg or 2 to 4 mL/kg of D25W (maximum single dose: 25 g) infused slowly at a rate of 2 to 3 mL/minute r3
Pitfalls
Do not delay prompt treatment of suspected adrenal crisis while awaiting results of diagnostic measures. Delayed treatment may be fatal r2c1
For treatment of adrenal crisis, do not administer mineralocorticoids, because they are not needed when supraphysiologic doses of glucocorticoids are given r4
Terminology
Clinical Clarification
Primary adrenal insufficiency is a life-threatening condition in which the adrenal cortex is unable to produce sufficient glucocorticoids and mineralocorticoids r1
Adrenal androgen production varies
When primary adrenal insufficiency is caused by autoimmune disease, it is often called Addison disease
Acute adrenal crisis is a severe manifestation of adrenal insufficiency marked by cardiovascular collapse and hemodynamic instability r4r5
Medical emergency requiring immediate treatment; delayed treatment can be fatal
Infections are the major precipitating causes of adrenal crisis
Classification
Adrenal insufficiency has various causes and manifestations, depending on defect site
Reduced or complete absence of pituitary corticotropin (adrenocorticotropic hormone) secretion, ultimately resulting in adrenal cortex atrophy; defect is at pituitary level
Reduced or complete absence of corticotropin-releasing hormone secretion, leading to reduced pituitary corticotropin (adrenocorticotropic hormone) secretion, then adrenal cortex hypofunction; defect is at hypothalamus level
Most common cause is hypothalamic suppression after prolonged use of supraphysiologic doses of glucocorticoids;r6 other medications, including opioids,r7 can also be culprits
Rare X-linked recessive disorder that affects males and is caused by variants in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1)
Results in defective oxidation of very-long-chain fatty acids and their accumulation in the adrenal cortex and brain
Clinical features include neurologic impairment and primary adrenal insufficiency, which present in infancy or childhood (most commonly present from ages 2 to 8 years)
Adrenal insufficiency is often the initial clinical manifestation c106
Rare genetic causes
Congenital adrenal hyperplasia (rare in general but the most common cause in childrenr1) r20c107
Type 1: sequence variants in MC2R gene (adrenocorticotropic hormone receptor/melanocortin 2 receptor) c111
Type 2: sequence variants in MRAP gene (melanocortin 2 receptor accessory protein) c112
Familial glucocorticoid deficiency (sequence variants in various genes relevant to the pathway) c113
Risk factors and/or associations
Other risk factors/associations
Associated autoimmune diseases
Autoimmune polyendocrine syndrome type 1 (OMIM #240300) r15r21c114
Rare, autosomal recessive disorder caused by biallelic variants in AIRE gene (autoimmune regulator)
Common among people from Sardinia, Finland, and Iran
Characterized by chronic mucocutaneous candidosis, hypoparathyroidism, and adrenocortical insufficiency, which usually begin before ages 5, 10, and 15 years, respectively r1
Other autoimmune disorders, such as type 1 diabetes and pernicious anemia, can develop later in life
Autoantibodies against interferon-ω and interferon-α are present in more than 95% of patients r21
Autoimmune polyendocrine syndrome type 2 (OMIM %269200) r16r21c115
Polygenic inheritance
Characterized by autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 diabetes
Much more prevalent than autoimmune polyendocrine syndrome type 1, and onset is in adolescence or adulthood
Suspect a primary adrenal insufficiency diagnosis in acutely ill patients with otherwise unexplained symptoms or signs consistent with the condition, including volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or (especially in children) hypoglycemia r3r5
Diagnosis of adrenal insufficiency is suggested when there is a low morning cortisol level c116c117c118
Most patients require testing with corticotropin stimulation test to secure diagnosis c119
Patients do not require corticotropin stimulation test if they have a very low (lower than 3 mcg/dL) morning serum cortisol level and markedly elevated (higher than 300 pg/mL) adrenocorticotropic hormone level. These patients unequivocally have primary adrenal insufficiency
Diagnosis of adrenal insufficiency is confirmed by a low stimulated cortisol level
Perform standard-dose (250-mcg) IV corticotropin stimulation test
Collect blood sample to measure plasma adrenocorticotropic hormone level and baseline cortisol level at same time c120
Collect basal blood sample to measure plasma renin activity and aldosterone level at same time to determine if mineralocorticoid deficiency is present c121c122c123
Mineralocorticoid deficiency may be a laboratory sign that heralds early evolving phase of primary adrenal insufficiency r5r18
Alternative diagnostic testing
Morning (8:00 AM) cortisol level in combination with adrenocorticotropic hormone level is less preferred as a preliminary test; if this strategy is used, ideally it is followed by corticotropin stimulation test, when feasible r3c124
Low-dose (1-mcg) corticotropin stimulation test is recommended only when corticotropin is in short supply r3
Establishing primary versus secondary adrenal insufficiency r5r18
Determine if cortisol deficiency is independent of adrenocorticotropic hormone level (primary adrenal insufficiency) or due to inadequate secretion of adrenocorticotropic hormone (secondary adrenal insufficiency)
High adrenocorticotropic hormone level is consistent with primary adrenal insufficiency, whereas adrenocorticotropic hormone level that is low or within reference range is more consistent with secondary adrenal insufficiency
Additional investigations to determine underlying cause
Once a laboratory diagnosis of primary adrenal insufficiency is secured, determine underlying cause r12
First, assess for autoimmune adrenalitis by obtaining autoantibodies against 21-hydroxylase (CYP21A2) using a validated assay c125c126
For autoantibody-negative patients, seek other causes r3
For infants, select children, and rare adults: assess for possibility of congenital adrenal hyperplasia c127c128c129
Liquid chromatography–tandem mass spectrometry has reduced cross-reactivity with other steroid hormones; thus, it often measures lower cortisol levels than immunoassays
There is wide interassay variability among different immunoassays
Test confounders that require special consideration for interpretation
Total cortisol results can be affected by presence of nephrotic syndrome, cirrhosis, or critical illness; in these cases, the low cortisol binding globulin and/or albumin levels may lower total cortisol levels r24
Oral estrogen contraceptives increase cortisol-binding globulin; thus, total cortisol levels may overestimate so-called free cortisol r25
Cortisol results also can be affected by rare conditions and unusual situations such as cortisol-binding globulin deficiency, glucocorticoid resistance, or hypersensitivity to the injected corticotropin r26
Primary adrenal insufficiency: 8:00 AM plasma corticotropin level is high r6
Secondary adrenal insufficiency: 8:00 AM plasma corticotropin level is low or within reference range
Combination of a morning plasma corticotropin level twice the upper limit of reference range with a low morning cortisol level is highly predictive of primary adrenal insufficiency r3
Adrenocorticotropic hormone reference range is approximately 20 to 52 nanograms/L (reference range is assay dependent) r12
Elevated plasma renin level plus reference-range or low serum aldosterone level is suggestive of primary adrenal insufficiency and is a pattern often seen in early phases of disease r14
Are detected in approximately 85% of patients with primary adrenal insufficiency but only rarely in patients with other non–immune-related causes of adrenal insufficiency r12
To investigate underlying cause of biochemically confirmed, autoantibody-negative adrenal insufficiency
Imaging appearance of hemorrhage depends on duration of bleeding r27
Acute mild hemorrhage shows peripheral gland enhancement and central low attenuation together with periadrenal infiltration
With ongoing bleeding the adrenal gland enlarges, giving appearance of a mass
CT demonstrates an oval or rounded adrenal mass with attenuation value higher than simple fluid (ranging from 50 to 90 Hounsfield units) r28
Granulomatous diseases (eg, tuberculosis, histoplasmosis) appear with bilateral enlargement in early stages of disease and, after administering contrast material, show peripheral rim enhancement with a necrotic center r29
Metastases tend to be heterogeneous with irregular margins, particularly when metastases are large and have attenuation values of higher than 10 Hounsfield units on unenhanced CT r27
To investigate underlying cause of biochemically confirmed adrenal insufficiency
Hemorrhage appearance depends on bleeding duration r27
In acute stage (up to 7 days), a hematoma has low signal intensity on T2-weighted images
In subacute stage (1-7 weeks), a hematoma is hyperintense on T1-weighted images
In chronic stage (more than 7 weeks), a hemorrhage has low signal intensity on both T1- and T2-weighted images
Metastases usually exhibit low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with heterogeneous enhancement after administration of contrast material r27
In most cases, used to confirm primary adrenal insufficiency diagnosis,r3 unless basal cortisol level result is unequivocally low (ie, lower than 3 mcg/dLr12) and adrenocorticotropic hormone is high (higher than 300 pg/mL)
Many protocol variations exist; one that is commonly used is as follows: r3
At time just before 0, draw blood for baseline levels of serum cortisol and adrenocorticotropic hormone
At time 0, administer IV bolus of corticotropin. Usual dosages:
Adults and children age 2 years and older: 250 mcg
Children younger than 2 years: 125 mcg
Neonates: 15 mcg/kg
At time 30 minutes, draw blood for cortisol level
At time 60 minutes, draw blood for cortisol level
Test result interpretation
Peak cortisol level should equal or exceed 18 mcg/dL; a level below this threshold indicates adrenal insufficiency
Test caveats
Can use low-dose 1-mcg corticotropin stimulation test as an alternative, but use is recommended only if there is a corticotropin shortage
Low-dose 1-mcg corticotropin stimulation test is no more accurate than the 250-mcg corticotropin stimulation test r30
Sensitivity of standard-dose (250-mcg) adrenocorticotropic hormone stimulation test for diagnosis of primary adrenal insufficiency is about 92%; thus, testing captures most cases r3
Test is not affected by diurnal variations and can be performed at any time of day r23
Test confounders that require special consideration for interpretation
Total cortisol levels can be affected by presence of nephrotic syndrome, cirrhosis, or critical illness. In these cases, low cortisol-binding globulin and/or albumin levels may lower total cortisol levels r24r31
Oral estrogen contraceptives increase cortisol-binding globulin levels; thus, total cortisol levels may overestimate free cortisol r25
Cortisol results also can be affected by rare conditions and unusual situations such as cortisol-binding globulin deficiency, glucocorticoid resistance, or hypersensitivity to the injected corticotropin r26
For children
Newer studies propose adding 15-minute and 30-minute serum or salivary cortisol levels to the low-dose corticotropin stimulation test to correctly identify adrenal insufficiency r20
Chronic persisting or relapsing fatigue of a generalized nature, causing significant disruption of usual daily activities, and present for more than 6 months
Presents with pronounced disabling fatigue, lethargy, and cognitive impairment
Unlike adrenal insufficiency, onset is often sudden and associated with viruslike symptoms (eg, fever, sore throat, cervical lymphadenopathy); like adrenal insufficiency, condition can become chronic and disabling
Additional symptoms include musculoskeletal discomfort, sleep disturbances, headaches, and temporomandibular joint pain
Diagnosis of exclusion, based on clinical criteria
Differentiated from primary adrenal insufficiency based on laboratory testing; in chronic fatigue syndrome, cortisol levels after corticotropin stimulation testing fall within reference range
Chronic and relapsing mental disorder, characterized by pervasive sadness and reduced pleasure in most activities (anhedonia) persisting for at least 2 weeks
Major depression is formally diagnosed based on clinical history and DSM-5 criteria:
Depressed mood for most days over 2 weeks along with at least 2 characteristic symptoms
Anhedonia
Unintentional weight loss or gain
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue
Feelings of worthlessness or inappropriate guilt
Diminished ability to concentrate or indecisiveness
Suicidal ideation or attempt
Distinguished based on laboratory testing; in primary adrenal insufficiency, cortisol levels are by definition low, whereas in major depressive disorder, these levels are within reference range or high r35
Illness characterized by the following symptoms, lasting several weeks: sore throat, cervical lymphadenopathy, fatigue, and fever. Most often seen in adolescents and young adults
Fever, fatigue, and myalgias are common to both adrenal insufficiency and mononucleosis c162c163c164c165
Unlike adrenal insufficiency, most symptomatic cases of mononucleosis are associated with painful, exudative pharyngitis
Diagnosis of Epstein-Barr virus mononucleosis can be made clinically or, if necessary, established by laboratory testing r37
Serologic tests for IgM antibodies to viral capsid antigen are positive in the first 4 to 6 weeks, then return to negativity
Serologic test results for IgG antibodies to viral capsid antigen are positive after 2 to 4 weeks of infection (and positivity often persists indefinitely thereafter); for IgG antibodies to nuclear antigen, after 2 to 4 months of infection
Cortisol levels are not low in mononucleosis, and serologic test result for IgM against Epstein-Barr virus is negative in adrenal insufficiency
Inability of thyroid gland to produce sufficient thyroid hormone to meet bodily metabolic demands
Classic symptoms include fatigue, weight gain, constipation, cold intolerance, dry skin, proximal muscle weakness, and hair thinning or loss
Some symptoms that overlap with adrenal insufficiency include fatigue and poor concentration; however, patients with adrenal insufficiency usually lose weight, whereas those with hypothyroidism often gain weight
The 2 conditions are distinguished based on cortisol levels, cosyntropin testing, and thyroid function tests
Slightly elevated TSH level sometimes can occur in untreated adrenal insufficiency owing to diminished cortisol and consequent abnormalities in TSH circadian rhythm r39
In isolated adrenal insufficiency (in absence of polyglandular endocrinopathy), peripheral thyroid hormone levels (eg, free T4, total T4) fall within reference range
Persistent TSH elevation should prompt an investigation of coexisting hypothyroidism r40
Various gastrointestinal symptoms (nausea, vomiting, abdominal pain) are similar to these symptoms in the presenting stages of adrenal insufficiency r10d5
Gastric, pancreatic, and colon cancer all may present with symptoms that resemble the gastrointestinal distress typical of adrenal insufficiency d6
In both gastrointestinal malignancy and adrenal insufficiency, weight loss is unintentional and usually associated with absence of appetite
Abdominal pain is diffuse in adrenal insufficiency, whereas it may be prominent in the left upper quadrant in gastric cancer, epigastric and radiating to the back in pancreatic cancer, and segmental in colon cancer
Advanced stages of gastrointestinal cancers may exhibit signs of metastases (eg, elevated liver transaminase levels, jaundice)
Gastrointestinal malignancies are identified using endoscopy or abdominal CT
Life-threatening syndrome of organ dysfunction caused by dysregulated host response to infection
Features of sepsis that are common to adrenal insufficiency include weakness, vomiting, hypotension, and altered mental status
Differentiating features: sepsis usually arises with a very acute onset of fever (higher than 38.5 °C), often with shaking chills and rigors
Sepsis is formally confirmed by positive blood cultures or culture of an alternative source showing microbial infection, whereas primary adrenal insufficiency is verified by low cortisol response to corticotropin stimulation test and low adrenocorticotropic hormone level
Treatment
Goals
Replace glucocorticoids and mineralocorticoids in a physiologic manner; do not overreplace r1r12
Optimal glucocorticoid replacement mimics circadian rhythm of cortisol secretion
Restore and maintain blood pressure within reference range
Treatment of an adrenal crisis consists of IV administration of saline, glucose, and hydrocortisone
Adults
Rapidly infuse 1 L isotonic saline within the first hour or 5% glucose in isotonic saline, followed by continuous IV isotonic saline guided by individual patient responses (eg, blood pressure, clinical assessment of volume status) r3
Treat with hydrocortisone 100 mg IV bolus, followed by 200 mg IV over 24 hours as a continuous infusion or in divided doses every 6 hours r3
Reduce hydrocortisone to 100 mg/day as a continuous infusion the following day
Mineralocorticoids are not needed when supraphysiologic doses of glucocorticoids are given r4
No additional mineralocorticoids are necessary if total daily dose of hydrocortisone is higher than 50 mg r4
Administering IV saline along with large doses of hydrocortisone is almost always sufficient to normalize blood pressure and electrolyte levels; mineralocorticoids are usually unnecessary in the first phase of treatment
Children
Give rapid IV bolus of normal saline (0.9%) 20 mL/kg; can repeat up to a total of 60 mL/kg within 1 hour for shock r3
Administer IV glucocorticoids using age- and BSA-appropriate dosing (required in children)
Treat with hydrocortisone 50 mg/m² (Max: 100 mg) IV bolus, followed by 50 to 100 mg/m² (Max: 200 mg) IV over 24 hours as a continuous infusion or in divided doses every 6 hours r3
Do not use prednisone to treat adrenal crisis, owing to its first-pass metabolism in the liver r1
If child is hypoglycemic, administer dextrose 0.5 to 1 g/kg or 2 to 4 mL/kg of D25W (maximum single dose: 25 g) infused slowly at a rate of 2 to 3 mL/minute. Alternatively, administer 5 to 10 mL/kg of D10W to children younger than 12 years r3
Prescribe hydrocortisone or cortisone acetate in 2 or 3 divided oral doses per day r22
Highest dose is taken immediately upon waking in the morning
Twice-daily dose regimen (most commonly used): give second dose in early afternoon
Thrice-daily dose regimen: give second dose at lunch and third in afternoon
Thrice-daily dosing induces cortisol profiles that more closely mimic physiologic profiles than twice-daily dosing,r42 but less-frequent dosing may be associated with greater adherencer43
Alternative formulations and preparations for once-daily dosing are available and are more convenient
Prednisolone 3 to 5 mg/day can be used, but adverse metabolic consequences (eg, weight gain, dyslipidemia) tend to occur
Once-daily dual release hydrocortisone tablet (Plenadren) is in development and has orphan drug designation in the United States; it has been shown to have more favorable metabolic profiles, improve quality of life, and reduce fatiguer44r45
Do not use dexamethasone; it has greater likelihood of inducing cushingoid adverse events
For patients with confirmed aldosterone deficiency, prescribe once daily dosing of fludrocortisone
Begin mineralocorticoid replacement as soon as total daily dose of hydrocortisone is less than 50 mg per 24 hours r2
Titrate dosing to achieve blood pressure and blood electrolyte levels within reference range and to eliminate edema and salt cravings
Generally, use clinical measures to assess adequacy of mineralocorticoid replacement; however, if there is any uncertainty, one can ensure proper dosing by targeting plasma renin level to upper end of reference range r5
Reduce fludrocortisone dose if hypertension develops
Higher doses of fludrocortisone may be needed if prednisolone is prescribed (in place of hydrocortisone) because of its lower mineralocorticoid activity
Temporary increases in fludrocortisone (50%-100%) may be needed for hot weather or situations that lead to heavy sweating r3
Dehydroepiandrosterone replacement
Controversial owing to inconsistent data about any benefits r46r47
Some experts suggest that after optimizing glucocorticoid and mineralocorticoid replacement, clinician should consider a trial of dehydroepiandrosterone in females with low libido, depression, and fatigue r3
If given, limit dehydroepiandrosterone trial to 6 months; if beneficial responses do not occur, discontinue r3
Monitor clinical signs of androgen action (eg, acne, hirsutism), and obtain serum dehydroepiandrosterone sulfate levels with aim to achieve a value in middle of reference range r46
Treat with hydrocortisone in 3 or 4 divided doses throughout the day
Prescribe first dose (slightly higher than other doses) to be taken upon waking in the morning; last dose is taken 4 to 6 hours before bedtime
Avoid synthetic long-acting glucocorticoids (eg, prednisolone, dexamethasone) in children because these medications have potent suppressor effects on growth
Hydrocortisone Oral tablet; Children: Initially, 8 mg/m²/day PO given in 3 to 4 divided doses. Doses are not evenly divided; a higher dose should be given in the morning at awakening and lower doses in the afternoon. Individualize doses to minimize symptoms of adrenal insufficiency while avoiding growth restriction/cushingoid symptoms that occur with overdosage. r3
Hydrocortisone Oral tablet; Adults: 15 to 25 mg/day PO given in 2 to 3 divided doses. Doses are not evenly divided; a higher dose should be given in the morning at awakening, and lower doses in the afternoon. r3
Fludrocortisone Acetate Oral tablet; Children† and Infants†: As a supplement to hydrocortisone or cortisone, 0.05—0.3 mg PO once daily in early infancy; typical maintenance doses are 0.05—0.2 mg/day depending on the sodium intake. Sodium chloride supplements (1—3 g/day or 17—51 mEq/day distributed in several feedings) are often needed, as the sodium content of breast milk and most infant formulas is insufficient to meet the requirements of aldosterone deficient children. Fludrocortisone receipt will reduce vasopressin and ACTH concentrations and lower the dosage of glucocorticoid required. Assess the need for continuing mineralocorticoids on plasma renin activity and blood pressure.
Fludrocortisone Acetate Oral tablet; Adults: As a supplement to hydrocortisone or cortisone, 0.1 mg PO once daily with a dose range of 0.1 mg PO 3 times per week to 0.2 mg PO once daily. Reduce the dose to 0.05 mg PO once daily if transient hypertension due to therapy develops.
Consider dehydroepiandrosterone replacement trial on a case-by-case basis, depending on patient's symptoms. Inform patients that it is not considered a standard part of chronic adrenal insufficiency treatment r46
Beneficial effects of dehydroepiandrosterone therapy show high interindividual variation r46
May, in part, be due to its FDA designation as a dietary supplement (content is not regulated or verified)
Dehydroepiandrosterone Oral capsule; Adult females: 25 to 50 mg PO as a single dose in the morning. r3
A dose of 25 mg dehydroepiandrosterone PO usually suffices to normalize serum dehydroepiandrosterone and dehydroepiandrosterone sulfate levels and, in females, serum androgen levels, within the reference range of young adults r46
Provide information about how to manage sick days and how to identify situations that require emergency glucocorticoids to be administered parenterally
Increase dosage of glucocorticoids during intercurrent illness, fever, and stress
Double usual hydrocortisone dose if fever is higher than 38 °C, or triple dose if fever is higher than 39 °C, until recovery r3
Increase consumption of electrolyte-containing fluids as tolerated
Teach patients how to self-inject glucocorticoids for impending crisis c176
Provide patient with a hydrocortisone emergency injection kit, which contains 100 mg hydrocortisone sodium succinate for injection (can be given by self or other layperson) r10
Advise patients to go to the emergency department if unable to self-inject intramuscular glucocorticoids at home
First, optimize glucocorticoid replacement, and consider reducing dose if there are clinical signs of excessive dosing
Next, consider slightly reducing fludrocortisone dose if there are signs of mineralocorticoid excess (eg, edema, hypokalemia)
Plasma renin measurement can help determine proper mineralocorticoid replacement, if needed; plasma renin level is ideally toward the upper end of or above reference range r5
If hypertension persists, begin antihypertensive therapy r48
ACE inhibitor or angiotensin II receptor antagonist are preferred
Dihydropyridine calcium channel blockers are clinically useful as second line agents
Avoid diuretics and aldosterone antagonists (eg, spironolactone, eplerenone)
Monitor pregnant patients with primary adrenal insufficiency at least once per trimester for symptoms and signs of glucocorticoid under- and overreplacement
Monitoring parameters include gestational weight gain, orthostatic blood pressure, and blood glucose levels
Increase hydrocortisone dose in third trimester if patient develops signs of adrenal insufficiency
Give hydrocortisone stress dose during active labor
Labor and delivery dosing, beginning at the onset of labor: hydrocortisone, 100 mg per IV bolus followed by continuous infusion of 200 mg hydrocortisone per 24 hours (alternatively, 50 mg every 6 hours IV or intramuscularly)
Postpartum dosing: double usual oral dose for 24 to 48 hours after delivery, then taper to normal dose
Use hydrocortisone preferentially over other glucocorticoid preparations (eg, cortisone acetate, prednisolone, prednisone); do not use dexamethasone, because it is not inactivated in the placenta
Adult: hydrocortisone, 25 to 75 mg per 24 hours (usually 1-2 days)
Children: children, intramuscular hydrocortisone 50 mg/m² or hydrocortisone replacement doses doubled or tripled
Postoperatively, double the oral dose for 24 hours, then return to normal dose
Major surgery with general anesthesia, trauma, delivery, or disease that requires intensive care
Adults and children: administer weight-appropriate continuous IV fluids with 5% dextrose and 0.45% sodium chloride
Adult: hydrocortisone 100 mg per IV injection followed by continuous IV infusion of 200 mg hydrocortisone per 24 hours (alternatively 50 mg every 6 hours IV or intramuscularly)
Children: hydrocortisone 50 mg/m² IV hydrocortisone, followed by hydrocortisone (total 50-100 mg/m²/day divided every 6 hours)
Postoperatively, continue hydrocortisone infusion until patient is able to eat and drink. Then double oral dose for 48 or more hours, then taper to normal dose
Shift workers
Change timing of glucocorticoid dosing so that larger dose of hydrocortisone is taken upon waking (eg, in the evening if patient sleeps during normal daytime hours) r6
Athletes
For very-long-duration endurance events, consider slightly increasing dose of corticosteroids
For example, during a marathon or triathlon, consider a 2.5- to 5-mg increase in hydrocortisone and 50- to 100-mcg increase in fludrocortisone, depending on environmental temperature and humidityr49
Patients with thyroid disease
Thyroid hormone increases metabolism and cortisol clearance r40
Patients with thyrotoxicosis who have adrenal insufficiency require higher replacement doses of glucocorticoids r40
Initiating thyroid hormone in patient with newly diagnosed hypothyroidism may induce adrenal crisis r5
Monitoring
Monitor patients carefully throughout their lives to avoid over- or undertreating with glucocorticoids and mineralocorticoids
Monitor the following parameters at least annually in adults and children to ensure appropriate corticosteroid dosing r3
Do not measure blood steroid hormone levels or use these levels to adjust glucocorticoid or mineralocorticoid dosing r6
There are no reliable hormonal markers to assess appropriate dosing of glucocorticoids
Adrenocorticotropic hormone level cannot be used to guide glucocorticoid dose adjustments, because targeting levels within the reference range leads to chronic overreplacement r1
Fludrocortisone requirements can be monitored periodically with serum sodium and potassium levels and plasma renin levels (in addition to clinical measures stated earlier) r6
Do measure morning serum dehydroepiandrosterone sulfate levels to monitor dehydroepiandrosterone replacement (if used) r3c196
At least annually, monitor patient for development of associated autoimmune diseases, particularly autoimmune thyroid disease r3c197c198
Watch for the following conditions: thyroid disease, diabetes mellitus, premature ovarian failure, celiac disease, and autoimmune gastritis with vitamin B₁₂ deficiency c199c200c201c202c203c204c205c206c207c208c209c210
Screening laboratory tests to perform annually include CBC plus TSH, free T₄, and hemoglobin A1C levels r3
Patients receiving fludrocortisone should be monitored for: r23
Blood electrolyte levels
Symptoms of salt craving, light-headedness, blood pressure changes, and swelling of legs and feet
Complications and Prognosis
Complications
Chronic overtreatment with glucocorticoids leads to several undesirable health outcomes, including: r1
Delayed treatment of hypoglycemia can lead to long-term neurologic deficits
Prognosis
Chronic adrenal insufficiency
Increased mortality
Standardized mortality ratio in primary adrenal insufficiency is more than 2-fold, mainly owing to infections, cancer, and cardiovascular causes r51r52
Health-related quality of life is reduced, even in patients who receive standard corticosteroid replacement r43
Acute episodes of adrenal crisis
In most patients, treatment with parenteral glucocorticoids and correction of hypovolemia with isotonic saline is uniformly successful and leads to clinical recovery within 24 hours r10
For patients with long-standing untreated adrenal insufficiency presenting with confusion and somnolence, full recovery can take from several days to 1 week r10
Estimated mortality rate for adrenal crisis is 0.5% to 2% r4
Screening and Prevention
Prevention
Prevention of adrenal crisis in patients with known adrenal insufficiency
Monitor patient regularly (eg, every 6-12 months) for symptoms and signs of undertreatment c215c216
Educate patients and caregivers regarding symptom awareness and situations requiring adjustment of glucocorticoid replacement level c217
Adjust glucocorticoids according to illness severity or stressor magnitude c218c219
Provide patient with medical information card identifying the patient as requiring daily steroid replacement (a so-called steroid replacement card) c220
Provide patient with a hydrocortisone emergency injection kit, which contains hydrocortisone sodium succinate for injection that can be self-injected or given by another layperson c221c222c223
Encourage patients with adrenal insufficiency to wear medical call bracelet c224c225
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