Adrenal Insufficiency

Adrenal insufficiency is a clinical syndrome of cortisol and aldosterone deficiency and may be divided into:

Primary adrenal insufficiency is rare overall, and vanishingly rare as the cause in an ICU patient.

Acute adrenal insufficiency, or Addisonian crisis, occurs when there is an rapid fall in adrenal hormones from any cause.

Epidemiology and Risk Factors

  • ~5-10 crises per 100 patient-years

Pathophysiology

In health, the adrenal cortex is responsible for production of steroid hormones:

  • Under the control of the HPA axis
    • CRH release from the hypothalamus stimulates ACTH release from the pituitary
    • Stimulation is ↑ during critical illness, resulting in ↑ plasma cortisol
  • Including:
    • Cortisol
      Usually secreted:
      • In pulses
      • With a diurnal pattern
        • Peak at ~0800 hours
        • Trough at ~0100
      • Under the influence of ACTH
        Negative feedback mechanism exists.
      • At 15-30mg/day
    • Aldosterone
    • Sex steroids
      Relatively unimportant in critical illness.

Aetiology

Primary adrenal insufficiency:

Adrenal crisis generally occurs in a patient with known adrenal insufficiency who experience physiological stress without adequate stress-dose steroid supplementation.

About half of patients presenting with adrenal crisis have undiagnosed primary adrenal insufficiency.

  • Autoimmune
    Most common in Western world.
  • Infections
    • TB
      Most common worldwide.
    • CMV
    • Histoplasmosis
    • Coccidiomycosis
  • Adrenal haemorrhage
    Waterhouse-Friderichsen syndrome.
    • Sepsis
      Meningococcal septicaemia, also known as Waterhouse-Friderichsen syndrome.
    • APS
    • Trauma
    • Surgery
  • Infiltrative
    • Tumour
    • Amyloid
    • Sarcoid
    • Haemachromatosis
  • Drug related
    • Inhibition of cortisol synthesis
      • Etomidate
      • Fluconazole
    • Induce cortisol metabolism
      • Rifampicin
      • Phenytoin
  • Congenital
    • Adrenal dysgenesis

Secondary adrenal insufficiency:

  • Cessation of exogenous glucocorticoid
  • Pituitary disease
    • Surgery
    • Infarction
      • Sheehan’s syndrome
    • Pituitary tumour

Clinical Features

Adrenal crisis is a catastrophic syndrome characterised by:

  • Refractory shock
  • Poor response to vasopressors

Many patients with primary deficiency will present with an adrenal crisis, due to the vague symptomatology of evolving disease.

Presentation without an adrenal crisis is usually non-specific and ill-defined. Subtypes of adrenal insufficiency vary with their features:

  • Primary adrenal insufficiency is the only cause that produces hyperpigmentation
    Only form with ↑ ACTH production.
  • Secondary adrenal insufficiency typically does not result in substantial mineralocorticoid deficiency, and remains a primarily cortisone-deficient state
Features of Adrenal Insufficiency
Specific to Cortisone Deficiency Specific to Aldosterone Deficiency Non-specific
  • Hypotension
    Refractory to fluids and vasopressors.
  • Hypoglycaemia
  • Eosinophilia
  • Hyperpigmentation
    Due to ↑ ACTH, which stimulates melanogenesis. First evident on mucous membranes, then non-sun exposed areas, followed by normal skin.
  • Hyponatraemia
  • Hyperkalaemia
  • NAGMA
    Type 4 RTA.
  • Weakness
  • Weight loss
  • Anorexia
  • Diarrhoea
  • Abdominal pain
  • Nausea
  • Normocytic anaemia
  • Postural hypotension

Diagnostic Approach and DDx

Investigations

Bedside:

  • ABG
    • NAGMA
    • Hyponatraemia
    • Hyperkalaemia

Laboratory:

  • Blood
    • FBE
      • Anaemia
    • UEC
      • Hyponatraemia
      • Hyperkalaemia
    • Random cortisol
      In adrenal crisis would be expected to be <80nmol/L; ACTH stimulation testing is not required.
    • ACTH stimulation test
      In a stable patient:
      • Administer 250μg of tetracosactrin (Synacthen)
      • Measure cortisol at 0 and 30 minutes
      • Appropriate elevation in peak cortisol should be seen
        Threshold varies depending on the laboratory.
        • Hydrocortisone interacts with many assays and so cannot be used
        • Dexamethasone can be used as an alternative steroid if planning the test

Imaging:

  • MRI
    • Adrenal glands

Other:

Management

  • Steroid supplementation
  • Correct hypovolaemia and electrolyte abnormalities

Specific therapy:

  • Pharmacological
    • Glucocorticoids
      • 100mg hydrocortisone IV Q6H
        This provides adequate mineralocorticoid replacement.
  • Procedural
  • Physical

Supportive care:

  • C
    • Volume resuscitation
      Normal saline ideal.
    • Vasopressors
  • E
    • Correct BSL
  • F
    • Electrolyte correction

Disposition:

  • Endocrinology involvement
  • Long-term glucocorticoid therapy

Preventative:

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

Prognosis

Key Studies

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  2. Rathbun KM, Nguyen M, Singhal M. Addisonian Crisis. In: StatPearls. StatPearls Publishing; 2023. Accessed August 2, 2023.