Adrenal Insufficiency

Basics

Description

  • Inadequate glucocorticoid (cortisol) and/or mineralocorticoid (aldosterone) secretion to meet the body's stress requirement
  • Primary adrenal failure associated with impaired glucocorticoid and mineralocorticoid production
  • Secondary/tertiary adrenal insufficiency associated with only glucocorticoid deficiency
  • Adrenal deficiency:
    • Inadequate cortisol/aldosterone
    • Unresponsive to stimulation with adrenocorticotropic hormone (ACTH)
  • Adrenal crisis (Addisonian crisis):
    • Life-threatening emergency
    • Precipitated by:
      • Steroid-dependent patient under stress (pregnancy, surgery, trauma, infection, or dehydration)
      • Rapid steroid withdrawal
      • Acute adrenal hemorrhage
      • Recent pituitary/craniopharyngioma resection
      • Congenital adrenal hyperplasia
      • Postpartum pituitary gland necrosis (Sheehan syndrome)

Etiology

Primary Adrenal Failure: Adrenal Gland Dysfunction
  • Adrenal dysgenesis/impaired steroidogenesis:
    • Congenital hypoplasia
    • Allgrove syndrome:
      • ACTH resistance
      • Achalasia
      • Alacrima
    • Glycerol kinase deficiency:
      • Psychomotor retardation
      • Hypogonadism
      • Muscular dystrophy
  • Congenital adrenal hyperplasia:
    • 21-hydroxylase deficiency accounts for 95% of cases
  • Aldosterone synthetase deficiency
  • Mitochondrial disease
  • Adrenal destruction:
    • Autoimmune:
      • Autoimmune polyglandular syndrome types 1 and 2 (alopecia universalis, chronic mucocutaneous candidiasis, hypoparathyroid, thyroid autoimmunity, diabetes, celiac disease, pernicious anemia)
      • Adrenoleukodystrophy
    • Infectious:
      • Granulomatous: TB
      • Protozoal and fungal: Histoplasmosis, coccidioidomycosis, and candidiasis
      • Viral: Cytomegalovirus, herpes simplex virus, and HIV
      • Bacterial
      • Fungal
    • Metastatic tumors
    • Infiltration:
      • Sarcoid
      • Hemochromatosis
      • Amyloidosis
      • Iron depletion
  • Bilateral adrenalectomy
  • Hemorrhage
    • Sepsis: Particularly meningococcemia (Waterhouse–Friderichsen syndrome), Pseudomonas infection
    • Birth trauma/anoxia
    • Pregnancy
    • Seizures
    • Anticoagulants
    • Rhabdomyolysis
  • Pharmacologic inhibition:
    • Etomidate
    • Phenobarbital
    • Ketoconazole/fluconazole
    • Phenytoin
    • Rifampicin

Secondary Adrenal Failure: Pituitary Dysfunction (Corticotropin Deficiency)
  • Pituitary insufficiency
  • Sepsis
  • Head trauma
  • Hemorrhage
  • Infarction (Sheehan syndrome)
  • Infiltration: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Prader–Willi syndrome

Tertiary Adrenal Failure: Hypothalamus Dysfunction (Corticotropin-Releasing Hormone Deficiency)
  • Pharmacologic inhibition:
    • Glucocorticoid therapy
    • Mifepristone
    • Chlorpromazine
    • Imipramine
  • Sepsis
  • Infiltrative: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Head trauma (skull base fractures most common)

Diagnosis

Signs and Symptoms

  • Symptoms:
    • Depression
    • Weakness, tiredness, fatigue
    • Anorexia
    • Abdominal pain (can mimic acute abdomen)
    • Nausea or vomiting
    • Salt craving (primary only)
    • Postural dizziness
    • Muscle or joint pains
    • Dehydration (found in primary adrenal insufficiency only)
    • Dry/itchy skin (women)
    • Loss of libido (women)
  • Signs:
    • Fever or hypothermia
    • Mental status changes
    • Hypotension (<110 mm Hg systolic)
    • Tachycardia
    • Orthostatic BP changes or frank shock
    • Weight loss
    • Goiter
    • Hypogonadism
    • Hyperkalemia (primary)
    • Hypercalcemia (primary)
    • Sodium depletion
    • Azotemia
    • Eosinophilia
    • Hyperpigmentation (primary only)
    • Vitiligo
  • Addisonian crisis:
    • Hypotension and shock
    • Hyponatremia
    • Hyperkalemia
    • Hypoglycemia

Essential Workup

  • Lab confirmation of diagnosis may not be possible in ED
  • Adrenal crisis: Life-threatening condition:
    • High degree of suspicion should prompt initiation of therapy before definitive diagnosis
  • Plasma cortisol level
  • Thyroid levels
  • Chemistry panel
  • CBC with differential
  • Core temperature

Diagnostic Tests and Interpretation

Lab
  • CBC with differential:
    • Anemia
    • Eosinophilia
    • Lymphocytosis
  • Arterial blood gases/chemistry:
    • Hypoxemia
    • Acidosis
    • Hyperkalemia (primary insufficiency only)
    • Hyponatremia
    • Elevated creatinine (primary only)
    • Decreased glucose
    • Hypercalcemia (primary only)
  • Cortisol levels in critically ill patients:
    • Baseline AM cortisol <3 mcg/dL diagnostic for adrenal deficiency but impractical in the ED
    • Consensus critical care recommendation to diagnose acute adrenal deficiency:
      • Random serum cortisol <10 mcg/dL (while under physiologic stress)
      • A change in cortisol <9 mcg/dL after cosyntropin (250 mcg) administration at 60 min
  • Cosyntropin stim test also suggestive if cortisol level at 60 min <18 mcg/dL
  • Search for underlying infection

Imaging
CXR:
  • Look for infection or pulmonary edema

Diagnostic Procedures/Other
ECG:
  • Evaluate for signs electrolyte disturbances

Differential Diagnosis

  • Sepsis
  • Shock
  • Hypoglycemia
  • Hypothermia
  • Acute abdominal process

Treatment

Initial Stabilization/Therapy

  • Airway, breathing, and circulation management (ABCs)
  • Cardiac monitor
  • BP support for hypotension:
    • Normal saline (0.9%) IV fluids 500 mL–1 L (peds: 20 mL/kg) bolus
  • Supplemental oxygen to meet metabolic needs
  • Correct hyperthermia/hypothermia

Ed Treatment/Procedures

  • Glucocorticoid/mineralocorticoid replacement:
    • IV hydrocortisone or dexamethasone immediately
    • Use IM route if no IV access
    • Dexamethasone will not interfere with results of cosyntropin stimulation tests
    • Hydrocortisone at doses >50 mg provide adequate mineralocorticoid coverage, dexamethasone does not
    • Fludrocortisone (oral only) can be given for isolated mineralocorticoid deficiency
  • Volume expansion:
    • NS (0.9%) or D5NS at rate of 500–1,000 mL/hr for first 3–4 hr
    • Care should be taken to note patient's age, volume, and cardiac and renal function
  • For hypoglycemia:
    • D50W
  • Treat life-threatening dysrhythmias secondary to hyperkalemia with calcium, bicarbonate, and insulin/glucose
  • Identification and correction of underlying precipitant
  • Should see BP improvement within 4–6 hr of therapy

Medication

  • Dexamethasone: 6–10 mg (peds: 0.15 mg/kg per dose) q12h
  • Hydrocortisone: 50–100 mg (peds: 1–2 mg/kg per dose) IV q6h, doses >50 mg adequately treats mineralocorticoid deficiency
  • Fludrocortisone (50–100 mcg) oral formulation only in patients with isolated mineralocorticoid deficiency

Ongoing Care

Disposition

Admission Criteria
  • All patients with acute adrenal insufficiency
  • ICU admission for patients with unstable or potentially unstable cases

Discharge Criteria
  • Normal lab evaluation with treated adrenal insufficiency
  • Should speak with endocrinologist before discharge in patients with chronic adrenal insufficiency

Follow-Up Recommendations

  • Should have primary care physician follow-up within a few weeks depending on symptoms
  • May benefit from endocrinology referral

Pearls and Pitfalls

  • Acute adrenal insufficiency is a life-threatening emergency, and treatment should not be delayed in the ED while waiting for definite lab diagnosis
  • Patients with primary adrenal insufficiency are lacking both glucocorticoids and mineralocorticoids
  • Patients with secondary and tertiary adrenal insufficiency are deficient only in glucocorticoids
  • Morning cortisol levels are not practical in the ED, but a random cortisol <10 mcg/dL in a patient under physiologic stress is suggestive of adrenal insufficiency
  • An increase of cortisol <9 mcg/dL 1 hr after cosyntropin administration or a cortisol level <18 mcg/dL 1 hr after cosyntropin administration is also suggestive of adrenal insufficiency
  • Hydrocortisone doses greater than 50 mg provide adequate mineralocorticoid coverage
  • Dexamethasone can be used to treat glucocorticoid deficiency and will not interfere with the cosyntropin stim test. Dexamethasone has minimal mineralocorticoid effects
  • Patients using chronic steroids may need increased doses during times of critical illness
  • Steroids in septic shock is controversial but still recommended in shock refractory to vasopressors or in patients using chronic corticosteroids
  • The clinical consequence of a single dose of etomidate for rapid sequence intubation is controversial. Studies do show biochemical adrenal suppression which must be weighed against agents with other undesirable properties while performing a critical, life-saving procedure

Additional Reading

  • Bancos I, Hahner S, Tomlinson JT, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes and Endocrinol. 2015;3(3):216–226.
  • Bornstein SR, Allolio B, Arit W, et al. Diagnosis and treatment of primary adrenal insufficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389.
  • Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383:2152–2167.
  • Chou SH. Adrenal insufficiency. Hosp Med Clin. 2012;1(1):e97–e108.
  • Gibbison B, Lopez JA, Higgins JP, et al. Corticosteroids in septic shock: A systematic review and network meta-analysis. Crit Care. 2017;21:78.
  • Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937–1949.
  • UVar A, Baş F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr. 2016;12(3):261–274.

See Also

Cushing Syndrome
The authors gratefully acknowledge Rita K. Cydulka and Joseph P. Tagliaferro for their contribution to the previous edition of this chapter.

Authors

Terry Singhapricha
Todd A. Taylor


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