Adrenal Crisis, by Dr Nilesh Patel

-Also known as acute adrenal insufficiency or Addisonian crisis
-No universally accepted definition.

Proposed Definition:
Acute deterioration in health status associated with hypotension (SBP < 100) or relative hypotension (drop in 20 mmHg from baseline) that resolve in 1-2 hours after glucocorticoid therapy. Generally this occurs in patients with a hx of hypoadrenalism or primary or secondary adrenal insufficiency; the prototype is Addison’s disease.

-Pediatrics:  Acute deterioration in health status associated with hemodynamic disturbance (hypotension or sinus tach or other markers of perfusion related deficits adjusted to age) or a marked electrolyte abnormality—hyponatremia, hypokalemia, or hypoglycemia—that is not attributable to another illness that resolves after parenteral glucocorticoid treatment

-Acute abdominal symptoms (n/v, loss of appetite), abdominal pain, back pain
-Altered mental status (delirium, confusion, obtundation)
-Severe fatigue, weakness
-Postural dizziness, syncope
-Hypotension, fever
-Abdominal tenderness
-Hyper pigmentation (if primary adrenal insufficiency)
-Hyponatremia, Hyperkalemia, Hypoglycemia (more common in kids). These electrolyte abnormalities are seen more with Addison’s disease or Congenital adrenal hyperplasia.

-If hypotension does not respond to steroids, consider another dx or concomitant dx.
-An acute illness without hypotension in a patient with adrenal insufficiency is distinct from an adrenal crisis. It is termed symptomatic adrenal insufficiency or a  precursor to adrenal crisis—if marked symptoms, treatment with IVF and steroids may avert an adrenal crisis.

—Absolute or relative deficiency in cortisol. Insufficient tissue glucocorticoid activity to maintain homeostasis. Cortisol short half life (90 minutes) so tissue becomes deplete.
—Cortisol suppresses cytokines and inflammatory mediators:  cortisol deficiency results in increased cytokines which leads to fever, weakness, body pain, etc.
—Cortisol interacts with catecholamines to maintain vascular permeability:  cortisol deficiency results in increased vascular permeability, vasodilation, and hypotension.
—Cortisol works on the liver; cortisol deficiency results in decreased gluconeogenesis and hypoglycemia.
—Cortisol direct effects on kidneys reduced Na resorption to lead to hypoNa and increase K resorption from tissues leads to hyperK
—Mineralocorticoid deficiency:  prominent in primary but not secondary adrenal insufficiency exacerbates adrenal insufficiency particularly hypoNa and hyperK

-Annually 6-8% of patients with adrenal insufficiency will develop adrenal crisis.
-More common in primary adrenal insufficiency vs secondary—probably due to absolute cortisol deficiency and lack of mineralocorticoid activity.
-Uncommon in those with hypoadrenalism on long term glucocorticoid therapy.
-Risk factors for adrenal crisis: Older age, Hx of adrenal crisis, Presence of autoimmune polyglandular syndrome, Type I DM, Hx of asthma, Hx of cardiac dz.
-Unclear as to why some of these are risk factors for adrenal crisis.

-Up to 6%.
-Increase mortality if occurs in conjunction with other illness such as sepsis.

-Infection (bacterial infections in the elderly, viral infections in kids)
-Gastroenteritis (plus leads to misdiagnosis, vomiting exacerbates dehydration, and inability to tolerate meds).
-Other conditions if body cannot mount response or replacement therapy not increased:
—Major trauma
—Emotional upset
—10% of episodes adrenal insufficiency no precipitant identified
—Certain treatments like chemotherapy and immune check point therapy may cause adnreal insufficiency and precipitate crisis.  May need to give glucocorticoid replacement.
—Non adherence to glucocorticoid therapy.
—Undiagnosed thyrotoxicosis or initiation of thyroxine in patient with hypoadrenalism may precipitate a crisis.
—Certain meds (phenytoin, St. Joh’s wort)—cytochrome 450 inducers—may increase glucocorticoid (hydrocortisone) metabolism—may necessitate increase in dosing or uncover adrenal insuff and precipitate crisis
—Cytochrome P450 inhibitors may precipitate crisis once they are withdrawn b/c increased cortisol levels, suppression of  adrenals.

-Prompt administration of hydrocortisone!
-100 mg bolus, 200 mg every 24 hours—continuous infusion or 50 mg q6—then tailor dose to clinical response.
-If hydrocortisone is unavailable, then can use Dex or Solumedrol.
-Dosing is based on their glucocorticoid potency relative to hydrocortisone.
-Peds hydrocortisone weight based dosing—50 mg per m2 BSA for bolus, then maintenance
-Hydrocortisone (cortisol) is the
preferred drug for treatment of an adrenal crisis
because of its physiological glucocorticoid pharmacokinetics, plasma protein binding, tissue distribution, and balanced glucocorticoid–mineralocorticoid effects.
-Fludrocortisone not needed if Hydrocortisone dose exceeds 50 mg in 24 hours. Can resume Start fludrocoristone once adrenal crisis is over.
-IVF—crystalloids, glucose as needed—judicious.
—Search for and treat underlying causes.
—After successful management of adrenal crisis, hydrocortisone tapered over 3 days to the patient’s maintenance dose.

Rushworth, RL, et al. Adrenal Crisis. NEJM 2019 Aug;381;9:852-861.