Synonym: Addisonian crisis

This is a potentially fatal condition associated mainly with an acute deficiency of the glucocorticoid cortisol and, to a lesser extent, the mineralocorticoid aldosterone.

See separate related article Adrenal Insufficiency and Addison's Disease.

Aetiology

Crisis occurs when the physiological demand for these hormones exceeds the ability of adrenal glands to produce them, i.e. in patients with chronic adrenal insufficiency when subject to an intercurrent illness or stress:¹

• Major or minor infections
• Injury
• Surgery
• Burns
• Pregnancy
• General anaesthesia
• Hypermetabolic states

The most common cause is abrupt withdrawal of steroids; secondary adrenocortical insufficiency occurs when steroids given as therapy have suppressed the hypothalamic-pituitary-adrenal axis.

Bilateral adrenal gland haemorrhage can produce adrenal crisis due to severe physiological stressors such as myocardial infarction, septic shock or complicated pregnancy, or with concomitant coagulopathy or thromboembolic disorders.

Other causes include autoimmune Addison's disease, tuberculosis, HIV, adrenoleukodystrophy, congenital adrenal hypoplasia and syndromes including Triple A (Allgrove syndrome) and IMAGe (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, Genital abnormalities - see 'Internet and further reading' below for more detail on these).

Risk factors

• Long-term steroids:
  • There have been a few cases associated with high-dose inhaled fluticasone and it may cause suppression at lower doses also.²
  • A case has been documented following intra-articular steroid injection.³
• There have also been cases after ketoconazole,⁴ phenytoin and rifampicin.

Presentation

• The patient is acutely ill with hypotension, especially postural. They may also be very weak and confused.
• Circulatory collapse may be severe with feeble rapid pulse and soft heart sounds.
• Pyrexia is common and may be due to underlying infection.
• Anorexia, nausea, vomiting and severe abdominal pain occur very frequently. This may be severe and present as an apparent acute abdomen.
• The patient may show increased motor activity progressing to delirium or seizures.

Investigations

• Sodium is usually moderately decreased, but may be normal.
• Potassium is usually slightly increased or normal - rarely, markedly increased (risk of arrhythmias).
• Hypoglycaemia, possibly severe, is characteristic.
• Serum cortisol concentrations are normally highest in the early morning hours (04:00 hours-08:00 hours) and increase further with stress. Serum cortisol concentrations at this time of less than 80 nmol/L are strongly suggestive of adrenal insufficiency.
• A short ACTH stimulation test should be performed in all patients suspected of having adrenal insufficiency:
  • Determine the baseline serum cortisol, then administer ACTH 250 mcg intravenously.
  • Serum cortisol measurements are taken at 30 and 60 minutes after ACTH administration.
  • A rise in serum cortisol concentration after 30 or 60 minutes to a peak of 500 to 550 nmol/L or more is considered a normal response.
• ECG may show prolonged QT interval:
  • This may induce ventricular arrhythmias.
  • Deep negative T waves have been described in acute adrenal crisis.⁵

Management

General principles

• Start treatment immediately based on clinical features and not delayed for confirmation of adrenal function.
• Administration of glucocorticoids in supraphysiological or stress doses is the only definitive therapy.
• Dexamethasone does not interfere with serum cortisol assay and may therefore be the initial drug of choice.
• However, because dexamethasone has little mineralocorticoid activity, fluid and electrolyte replacement is essential.

Resuscitation

• ABCDs which may include:
  • Oxygen.
  • IV Normal saline fluid boluses (500-1000 mL for adult, 10-20 mL/kg for a child).
  • IV dextrose (25-50 mL 50% dextrose for an adult, 2-5 mL/kg 10% dextrose for a child) as required.
• Continued intravenous replacement of estimated dehydration:
  • Usually 5%+ over 8+ hours.
  • Using 5% dextrose in normal saline.
  • Take into account age, volume, cardiac and renal function.
  • Unlikely to require added potassium initially.
• 200 mg hydrocortisone - 100 mg/m² or approximately 4 mg/kg for a child - IV stat:
  • Then 100 mg hydrocortisone (2 mg/kg for a child) IV every 6 hours during the first 24 hours.
  • Thereafter, the hydrocortisone dose can usually be halved again.
  • With such high doses of glucocorticoid, mineralocorticoids are not required.
  • When dosage is reduced further, add fludrocortisone 0.05-0.2 mg/day, aiming at normotension, normokalaemia and a plasma renin activity in the upper normal range.⁶
• If hypotension persists, give additional corticosteroids and consider vasopressors, e.g. dopamine.
  • Investigate adrenal haemorrhage, especially if the patient is receiving anticoagulants.
  • Reversal of coagulopathy should be attempted with fresh frozen plasma.
• Treat the underlying precipitating disorder, e.g. infection, with antibiotics.
• When testing for adrenal insufficiency and treating at the same time, replace hydrocortisone with dexamethasone added to the infusion together with corticotropin.
• Collect blood and urine for analysis of cortisol and urinary-OHCS levels.

Prevention

• Early dose adjustments (e.g. doubling the usual maintenance dose) are required to cover the increased glucocorticoid demand in stress.
• Careful and repeated education of patients and their partners is the best strategy to avoid this life-threatening emergency.
• Avoid exposure to chickenpox or measles. If exposed, seek medical advice without delay.
• Patients do not require cover for routine dentistry. Patients undergoing general anaesthesia for procedures may require supplementary steroids depending on the dose and duration of steroid treatment.⁷

Associations

Other underlying associated endocrinopathies, which should be excluded:

• Hypothyroidism may mask the Addison's disease and the thyroxine replacement may precipitate an acute adrenal crisis.
• On steroid replacement therapy the 'hypothyroidism' will resolve.⁸

Complications

Death may be caused by circulatory collapse and arrhythmias with hypoglycaemia contributing.
Prognosis is the same as for patients without adrenal insufficiency if the precipitating condition is diagnosed and treated appropriately.

Document references

1. Adrenal Physiology and Diseases, Editor George Chrousos. From online textbook 'Endotext.com'
2. Todd GR, Acerini CL, Ross-Russell R, et al; Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child. 2002 Dec;87(6):457-61. [abstract]
3. Wicki J, Droz M, Cirafici L, et al; Acute adrenal crisis in a patient treated with intraarticular steroid therapy. J Rheumatol. 2000 Feb;27(2):510-1. [abstract]
4. Khosla S, Wolfson JS, Demerjian Z, et al; Adrenal crisis in the setting of high-dose ketoconazole therapy. Arch Intern Med. 1989 Apr;149(4):802-4. [abstract]
5. Iga K, Hori K, Gen H; Deep negative T waves associated with reversible left ventricular dysfunction in acute adrenal crisis. Heart Vessels. 1992;7(2):107-11. [abstract]
6. Hahner S, Allolio B; Management of adrenal insufficiency in different clinical settings. Expert Opin Pharmacother. 2005 Nov;6(14):2407-17. [abstract]
7. Gibson N, Ferguson JW; Steroid cover for dental patients on long-term steroid medication: proposed clinical guidelines based upon a critical review of the literature. Br Dent J. 2004 Dec 11;197(11):681-5. [abstract]
8. Shaikh MG, Lewis P, Kirk JM; Thyroxine unmasks Addison's disease. Acta Paediatr. 2004 Dec;93(12):1663-5. [abstract]

Internet and further reading

• Kirkland L; Adrenal crisis, eMedicine, Mar 2010
• Addison's Disease Self Help Group. Website
• Boston BA; Allgrove (AAA) Syndrome, eMedicine, Feb 2009
• Pedreira CC, Savarirayan R, Zacharin MR; IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development. J Pediatr. 2004 Feb;144(2):274-7. [abstract]
• Living with Addisons Disease, The Addison's Disease Self Help Group

Acknowledgements