Primary Adrenal Insufficiency

History

• In chronic adrenal insufficiency, symptoms are nonspecific and develop over months to years
  • Nonspecific nature of symptoms can lead to delayed or missed diagnosis
  • There is often a history of steadily declining general health over weeks to months or even years ^r10r11c2
• Symptoms of chronic adrenal insufficiency include: ^r12
  • Fatigue ^c3
  • Generalized weakness ^c4c5
  • Weight loss ^c6
  • Anorexia ^c7
  • Nausea and vomiting ^c8
  • Abdominal discomfort ^c9
  • Postural dizziness ^c10
  • Salt craving ^c11
  • Arthralgia and myalgias ^{c12c13c14c15c16}
  • Depression ^c17
  • Failure to thrive (in children) ^c18c19c20c21
• Adrenal crisis may be triggered by a major stressor, such as febrile illness (higher than 38 °C), severe infection, surgery, or trauma ^r1c22c23c24
  • Symptoms can develop rapidly (within a few hours)
• Symptoms of acute adrenal crisis include:
  • Severe weakness ^c25c26
  • Abdominal pain ^c27
  • Nausea and vomiting ^c28
  • Back pain ^c29
  • Confusion ^c30
  • Fever ^c31
  • Syncope ^c32

Physical examination

• Signs of chronic primary adrenal insufficiency include: ^r11r12
  • Hyperpigmentation, particularly in skin creases, mucosal membranes, scars, knuckles, elbows, axillae, and breast areolas ^{c33c34c35c36c37c38c39c40c41}
    • Variably present and can be affected by a person's level of background pigmentation; comparison with a sibling can be helpful
  • Low blood pressure with postural drop ^c42c43
  • In females, loss of axillary and pubic hair ^c44c45
  • Fever ^c46
• Signs of adrenal crisis include:
  • Hypotension ^c47
  • Tachycardia ^c48
  • Abdominal tenderness, sometimes with guarding ^c49c50c51c52
  • Delirium ^c53
  • Reduced consciousness ^c54
  • Hypoglycemia (particularly in children) ^c55

Causes

• Autoimmunity (80%-90% of all cases) ^r12c56
  • Isolated (destruction of adrenal cortex by cell-mediated immune mechanisms)
  • Associated autoimmune diseases ^r13r14
    • Autoimmune polyendocrine syndrome type 1 (OMIM #240300) ^r15c57
    • Autoimmune polyendocrine syndrome type 2 (OMIM %269200) ^r16c58
• Infectious adrenalitis ^c59
  • Tuberculosis ^c60
  • Cytomegalovirus ^c61
  • HIV/AIDS ^c62c63c64
  • Fungal infection (eg, candidiasis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis) ^{c65c66c67c68c69}
  • Histoplasmosis ^c70
  • African trypanosomiasis ^c71
  • Syphilis ^c72
• Adrenal hemorrhage ^c73
  • Trauma (eg, direct body blows, motor vehicle crash) ^{c74c75c76c77c78}
  • Anticoagulant medication ^c79
  • Meningococcal sepsis (Waterhouse-Friderichsen syndrome) ^c80c81
  • Antiphospholipid syndrome ^c82
    • Characterized by recurrent arterial and venous thrombosis and complications during pregnancy ^c83c84c85
    • Can be isolated or manifest in context of connective tissue disorders or malignancy ^c86c87
• Adrenal infiltration
  • Primary amyloidosis ^c88
  • Metastases (primarily lung, breast, colon, and lymphomatous tumors) ^{c89c90c91c92c93c94}
  • Hemochromatosis ^c95
• Bilateral adrenalectomy (indicated for intractable Cushing syndrome or bilateral pheochromocytomas) ^c96
• Medication
  • Adrenal enzyme inhibitors of cortisol synthesis ^c97
    • Aminoglutethimide ^c98
    • Etomidate ^c99
    • Ketoconazole ^c100
    • Mitotane ^c101
    • Metyrapone ^c102
  • Medication adverse effects
    • Immune checkpoint inhibitors ^r17r18c103
    • Bleeding from anticoagulant use ^r17c104
• Adrenoleukodystrophy in males ^r19c105
  • 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 children^r1) ^r20c107
  • Adrenal hypoplasia congenita ^c108c109
  • Adrenocorticotropic hormone insensitivity syndromes ^c110
    • 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

Primary diagnostic tools

• 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
• Adrenal insufficiency diagnosis entirely depends on demonstrating inappropriately low cortisol secretion ^r12r23
• Optimal diagnostic strategy ^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 ^r5r17
• 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 ^r5r17
  • 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
    • For infants: consider rare genetic syndromes (ie, adrenal hypoplasia congenita) ^c130
    • For adults: consider adrenal infiltrative or destructive processes and order CT or MRI of the adrenals ^c131c132
    • For males: consider adrenoleukodystrophy and order testing for plasma concentrations of very-long-chain fatty acids ^c133c134
• Additional investigations to provide supporting evidence for diagnosis or to guide management ^r12r17
  • Serum chemistry panel and CBC ^c135c136

Laboratory

• Serum or plasma cortisol level (reference ranges apply to both) ^c137c138
  • Cortisol levels are highest in early morning and lowest 1 hour after usual time of sleep onset
  • Basal morning (8:00 AM) cortisol level lower than 5 mcg/dL is suggestive, but not diagnostic, of adrenal insufficiency ^r1r17
  • Usually, primary adrenal insufficiency is highly unlikely if a basal morning cortisol level is higher than 18 mcg/dL ^r17
  • Do not use random serum cortisol levels to exclude adrenal insufficiency
  • Reported cortisol levels are assay dependent ^r1
    • 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
• Plasma corticotropin (or adrenocorticotropic hormone) ^c139
  • 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
• Plasma renin and serum aldosterone ^{r23c140c141c142}
  • Reference ranges are laboratory specific
  • 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 ^r13
• Autoantibodies against 21-hydroxylase ^c143
  • 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
• Serum chemistry panel ^{c144c145c146c147}
  • Hallmark values include hyponatremia and hyperkalemia, owing to both mineralocorticoid deficiency and glucocorticoid deficiency ^r12
  • Hypoglycemia can occur, especially in children ^r12
  • BUN and creatinine levels may be increased due to hypovolemia
• CBC ^{c148c149c150c151c152c153c154}
  • Normocytic anemia, eosinophilia, and lymphocytosis can occur and reflect glucocorticoid deficiency ^r12

Imaging

• CT of adrenals ^c155
  • 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
• MRI of adrenals ^c156
  • 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

Functional testing

• Corticotropin stimulation test ^c157
  • In most cases, used to confirm primary adrenal insufficiency diagnosis,^r3 unless basal cortisol level result is unequivocally low (ie, lower than 3 mcg/dL^r12) 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

Most common

• Chronic fatigue syndrome ^r32c158
  • 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
• Major depressive disorder ^r33r34c159d1
  • 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
• Infectious mononucleosis ^r36c160d2
  • Illness characterized by the following symptoms, lasting several weeks: sore throat, cervical lymphadenopathy, fatigue, and fever. Most often seen in adolescents and young adults
    • Most often caused by Epstein-Barr virus ^c161
  • 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
• Hypothyroidism ^r20r38c166d3
  • 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
• Gastrointestinal malignancy ^c167d4
  • 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
• Sepsis ^r41c168d7
  • 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

Admission criteria

Acute adrenal crisis

Recommendations for specialist referral

• Consult endocrinologist for interpretation of diagnostic test results and management of corticosteroid replacement

Drug therapy

• Glucocorticoids ^c169
  • Hydrocortisone ^c170
    • 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
• Mineralocorticoids ^c171
  • Fludrocortisone ^r23c172
    • 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.
• Androgen precursor ^c173
  • Dehydroepiandrosterone ^c174
    • 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

Nondrug and supportive care

• Patient education ^c175
  • 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
• Medical emergency monitoring and call systems ^{c177c178c179c180}
  • Arrange for patients to obtain a medical call bracelet ^c181c182

Special populations

• Patients with hypertension ^r48
  • 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)
• Pregnant patients ^r3
  • 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
• Surgical or ICU patients ^r10
  • Minor to moderate surgical stress
    • 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 humidity^r49
• 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