Cristina Cunanan, MD Anahat Dhillon, MD
BASICS
DESCRIPTION
• Also called adrenal crisis, acute adrenal insufficiency is a life-threatening condition secondary to inadequate adrenal steroid production not matching increased demands during stress (e.g., infection, surgery) (1).
• Manifestations result from mineralocorticoid deficiency, in association with prostaglandin excess, and decreased responsiveness to norepinephrine and angiotensin II (2):
– Severe hypotension – Circulatory collapse – Hypothermia
– Altered mental status – Hypoglycemia
• Primary adrenal insufficiency (PAI) (3):
– All 3 layers of the adrenal cortex are affected.
– Involves glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies
– Seen with autoimmune adrenalitis, adrenal hemorrhage, adrenalectomy, AIDS, and tuberculosis
• Secondary adrenal insufficiency (SAI) (2):
– Results from disorders of the hypothalamic–pituitary–adrenal (HPA) axis that may involve tumors, irradiation, trauma, surgery, exogenous glucocorticoid therapy (most common), enzyme inducers that enhance the clearance of synthetic glucocorticoids (rifampin and carbamazepine), or drugs that inhibit cortisol synthesis (ketoconazole, etomidate) (3)
– These conditions can cause a deficiency in adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH), leading to atrophy of the adrenal zona fasciculata where glucocorticoids are synthesized.
– Mineralocorticoid function is better maintained, and hence, less likely to cause an adrenal crisis.
• Initiation of thyroxine replacement in patients with hypothyroidism may induce adrenal crisis due to increased cortisol metabolism (4).
EPIDEMIOLOGY Incidence
3.3–6.3 adrenal crisis per 100 patient years (4,5) Prevalence
• Of PAI, 93–140 per million; age of diagnosis peaks in the 4th decade of life; women more frequently than men (5).
• Of SAI, 150–280 per million; age of diagnosis peaks in the 6th decade of life; women more
• In SAI patients, there is a higher risk of adrenal crisis in female patients and with the presence of diabetes insipidus.
• Adrenal cortex produces glucocorticoids (mainly cortisol) and mineralocorticoids (mainly aldosterone); these hormones are required for the maintenance of metabolic control, blood
– Facilitates sodium and potassium homeostasis and the maintenance of intravascular volume
– Increased angiotensin synthesis by the liver
• Glucocorticoid deficiency, therefore, results in decreased vascular responsiveness to angiotensin II and norepinephrine, decreased synthesis of renin substrate, and increased prostacyclin production which can aggravate the circulatory collapse seen in mineralocorticoid deficiency.
• Chronic use of exogenous corticosteroids given in supraphysiologic doses leads to the development of SAI, and the amount of adrenal suppression depends on the dose, duration, frequency, time and route of administration and can occur as early as 1 week after commencing therapy (3).
PREVENTATIVE MEASURES
• Anesthetic plan should avoid the use of drugs that inhibit cortisol synthesis (e.g., etomidate) in patients at risk.
• Controversy remains over whether supplemental perioperative steroids are required for patients on maintenance doses of corticosteroids who undergo surgery (9). A 2009 Cochrane review of randomized controlled trials of supplemental perioperative steroids concluded that there is inadequate evidence to support or refute the use of supplemental perioperative steroids, but it is likely that the administration of daily maintenance steroid dose may be sufficient and supplemental doses are not required.
• While this topic is controversial and the optimal dose and duration of perioperative glucocorticoid coverage have also not been established, the following recommendations are based on a review of expert opinion and clinical experience (3):
– For minimal stress procedures (<1 hour under local anesthesia), continue usual replacement corticosteroid dose.
– For minor stress procedures (colonoscopy, inguinal hernia repair), administer IV hydrocortisone 25 mg or equivalent at the start of the procedure, followed by usual replacement doses after the procedure.
– For moderate stress procedures (open cholecystectomy, joint replacement, lower limb revascularization, abdominal hysterectomy), administer IV hydrocortisone 75 mg/d on the day of the procedure (25 mg q8h), then taper over the next 1–2 days to usual replacement doses.
– For severe stress procedures (cardiothoracic, Whipple, liver resection), administer IV hydrocortisone 150 mg/d (50 mg q8h), then taper over the next 2–3 days to the usual replacement dose.
DIAGNOSIS
• History/physical exam
– If PAI is undiagnosed and suspected, elicit symptoms such as chronic fatigue, weakness, lethargy, anorexia, weight loss, postural hypotension, recurring abdominal pain, loss of
libido, loss of axillary and pubic hair, and hyperpigmentation (2).
– All of the above may be present in SAI, except for hyperpigmentation, and hypotension may be less prominent (2).
– Any patient who has received the equivalent of 20 mg/d of prednisone for >5 days is at risk for suppression of the HPA axis; if on therapy for 1 month, HPA axis suppression can last up to 6–12 months after cessation of therapy (10).
– Other modes of steroid administration should be noted, such as topical, inhaled, and regional (10).
• Maintain a high level of suspicion for adrenal crisis in cases of unexplained hypotension refractory to catecholamines, especially in patients with increased risk (e.g., prior glucocorticoid therapy, autoimmune disease, AIDS) (2).
• ACTH stimulation test involves the administration of cosyntropin 250 mcg IV (synthetic ACTH hormone), followed by serum cortisol measurements at 30 minutes and 60 minutes.
Plasma cortisol values:
– <3 mcg/dL (80 nmol/L) is highly suggestive of adrenal insufficiency.
– <10 mcg/dL (275 nmol/L) requires further adrenal evaluation.
– >20 mcg/dL (550 nmol/L) makes adrenal insufficiency highly unlikely (2).
• Morning plasma cortisol levels – 10–20 mcg/dL is normal.
– <3 mcg/dL is highly suggestive of adrenal insufficiency (2).
• Other tests:
– Elevated plasma corticotropin levels in PAI – Decreased aldosterone levels
– Hyperreninemia – Hyponatremia – Hyperkalemia – Hypoglycemia – Eosinophilia – TSH
DIFFERENTIAL DIAGNOSIS
• Cardiogenic shock
• Anaphylactic shock
• Hypovolemic shock
TREATMENT
• Immediate administration of hydrocortisone 100 mg IV followed by 100–200 mg IV per 24 hours
• IV fluids
• Electrolyte replacement
• Improvement in response to glucocorticoids is usually seen within 12 hours (2).
• If diagnostic screening demonstrates basal or post-ACTH cortisol levels >20 mcg/dL, stop further hydrocortisone therapy unless the patient is still critically ill.
FOLLOW-UP
• If hemodynamic stability is recovered after administration of glucocorticoid, may consider continuing with surgical procedure.
• Final confirmation of adrenal insufficiency and evaluation of its etiology, if unknown, may be appropriate after resolution of the acute crisis.
REFERENCES
1. Hahner S, Allolio B. Therapeutic management of adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009;23(2):167–179.
2. Bouillon R. Acute adrenal insufficiency. Endocrinol Metab Clin North Am. 2006;35(4):767–
775.
3. Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust. 2008;188(7):409–413.
4. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: The need for new prevention strategies. Eur J Endocrinol. 2010;162(3):597–
602.
5. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361:1881–1893.
6. Schulman D, Palmert MR, Kemp SF, et al. Adrenal insufficiency: Still a cause of morbidity in childhood. Pediatrics. 2007;119:e484–e494.
7. Bergthorsdottir R, Leonsson-Zachrisson, M, Oden A, et al. Premature mortality in patients with Addison’s disease: A population-based study. J Clin Endocrin Metab. 2006;91:4849–
4853.
8. Erichsen M, Løvås K, Fougner KJ, et al. Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. Eur J Endocrinol. 2009;160:233–237.
9. Yong SL, Marik P, Esposito M, et al. Supplemental perioperative steroids for surgical patients with adrenal insufficiency. Cochrane Database Syst Rev. 2009;7(4).
10. Kohl B, Schwartz S. Surgery in the patient with endocrine dysfunction. Anesthesiol Clin.
2009;27:687–703.
See Also (Topic, Algorithm, Electronic Media Element)
• Cortisol
• Ulcerative colitis
• Rheumatoid arthritis
CODES
ICD9
255.41 Glucocorticoid deficiency ICD10
• E27.2 Addisonian crisis
• E27.40 Unspecified adrenocortical insufficiency
CLINICAL PEARLS
• Risk of adrenal crisis is significantly higher in PAI than in SAI.
• The body makes approximately 10 mg/d of cortisol. During extreme stress 75–150 mg/d can be made.
• Any patient who receives >20 mg/d of prednisone equivalent for >5 days is at risk for SAI.
• There is inadequate evidence to support empiric use of supplemental corticosteroids in patients with risk factors for SAI.