CONTENTS

• Epidemiology: at-risk populations
• Signs & symptoms
• Laboratory clues
• Evaluation of suspected adrenal crisis
• Clinical definition of adrenal crisis
• Treatment
• Prevention
• Physiology
• Related
  • Cushing syndrome
• Podcast
• Questions & discussion
• Pitfalls

---

epidemiology: at-risk populations

(back to contents)

---

Adrenal crisis is a bit like DKA. It can either be caused by chronic adrenal insufficiency plus a trigger, or it can be caused by acute adrenal insufficiency alone.

---

most common: chronic adrenal insufficiency plus acute stressor 

common causes of chronic adrenal insufficiency

• Chronic steroid therapy (the most frequent cause of adrenal insufficiency). (29075801)
• Chronic adrenal gland dysfunction:
  • Addison's disease (may be associated with other autoimmune disorders or endocrinopathies).
  • Malignancy.
  • Infection (especially tuberculosis or fungal infection).
• Chronic anterior pituitary dysfunction:
  • Granulomatous disease (e.g., tuberculosis, sarcoidosis).
  • Neoplasms (e.g., craniopharyngiomas, adenomas).
  • Iatrogenic (e.g., surgery, radiotherapy).

crisis is precipitated by any acute stressor, such as:

• Infection (especially gastroenteritis, but be careful – symptoms of adrenal crisis from other causes may mimic gastroenteritis).
• Trauma/surgery.
• Reduced steroid dose:
  • Non-adherence.
  • Steroid tapering.
• Psychological stress.
• Exercise.
• Volume depletion.
• Pregnancy.
• (Medications may also contribute, including the following)
  • Azoles (ketoconazole, fluconazole).
  • Carbamazepine.
  • Cholestyramine.
  • Etomidate.
  • Phenobarbital.
  • Phenytoin.
  • Rifampin.
  • St. John's Wort.
  • Thyroid hormone.
  • Any medication that induces cytochrome P-450 3A4 (will increase hydrocortisone metabolism).

---

less common: acute failure of the hypothalamic-pituitary-adrenal axis

acute pituitary failure

• Pituitary apoplexy 📖 (pituitary infarction, often postpartum or due to a pituitary adenoma).
• Complication of neurosurgery.

acute adrenal gland failure

• Waterhouse-Friderichsen syndrome 📖 (adrenal infarction due to disseminated intravascular coagulation).
• Checkpoint-inhibitor immunotherapy 📖 for cancer may cause acute failure of the adrenal and/or pituitary gland.

---

signs & symptoms

(back to contents)

---

central manifestations:

• Hypotension, vasodilatory shock (often refractory to fluid and vasopressors).
• Fever.
• Nausea/vomiting.
• Abdominal pain and tenderness.
• 💡 Adrenal crisis can mimic abdominal sepsis or severe pancreatitis.

other findings

• Delirium. Addison's disease may initially be misdiagnosed as a psychiatric condition or anorexia nervosa.(31888894)
• Features of the trigger of the crisis (e.g., trauma, surgery, infection).

additional clues to the presence of chronic adrenal insufficiency:

• Cutaneous hyperpigmentation or vitiligo (below).
• History of chronic fatigue, anorexia, vomiting, postural dizziness, and weight loss.

---

laboratory clues

(back to contents)

---

These laboratory abnormalities may serve as useful clues, but they cannot be used to exclude adrenal insufficiency – especially in complex patients with numerous coexisting electrolytic disorders.

electrolyte abnormalities due to mineralocorticoid deficiency

• Mineralocorticoid deficiency causes type-4 renal tubular acidosis (RTA).
  • This leads to hyperkalemia and NAGMA (non-anion gap metabolic acidosis).
  • Mineralocorticoid deficiency only occurs in primary adrenal insufficiency (e.g., Addison's disease), but not in secondary insufficiency (e.g., pituitary dysfunction).
• Glucocorticoid deficiency:
  • Hyponatremia. (25699130)
  • Hypoglycemia.
  • Hypercalcemia (rarely).
• 💡 Consider the possibility of adrenal insufficiency in any patient with unexplained hyponatremia or hypoglycemia.

differential cell count isn't behaving as expected for a critically ill patient

• Physiologic stress normally stimulates cortisol production, which decreases the eosinophil and lymphocyte counts.
• In a patient under physiologic stress (e.g., clinical shock), adrenal insufficiency is suggested by either of the following:
  • Normal or increased eosinophil counts (e.g., an absolute eosinophil count >300-400/uL).
  • Relative or absolute lymphocytosis.  A relative lymphocytosis is suggested by finding that the neutrophil/lymphocyte ratio (NLR) is lower than would be expected for a critically ill patient (e.g., NLR below ~6). 🌊

---

evaluation of suspected adrenal insufficiency

(back to contents)

---

It's important to determine whether or not the patient has underlying adrenal insufficiency, as this will impact subsequent care. One exception to this is the patient on chronic steroids (who very likely has temporary suppression of the adrenal gland by exogenous steroid).

#1. start with random cortisol level

• Cortisol >20 ug/dL excludes adrenal insufficiency.
• Cortisol <20 ug/dL is nonspecific, requiring an ACTH stimulation test.
  • <5-7 ug/dL in the context of physiologic stress strongly suggests adrenal insufficiency.

#2. ACTH stimulation test

• Give 250 micrograms of intravenous ACTH (trade names COSYNTROPIN or SYNACTHEN).
• Check cortisol at baseline and 60 minutes after ACTH administration.(29444197)
• If cortisol level doesn't rise above >20-25 ug/dL, this confirms the diagnosis of adrenal insufficiency.
• This test can be done if the patient is receiving dexamethasone, but administration of other types of steroid renders the results meaningless.
• ⚠️ This test may fail to identify acute pituitary dysfunction (e.g., pituitary apoplexy) that is causing acute secondary adrenal insufficiency.
  • Chronic secondary adrenal insufficiency will cause adrenal atrophy, leading to an inadequate response to ACTH.  However, immediately after a pituitary injury, the ACTH stimulation test will be normal.

---

clinical definition of adrenal crisis

(back to contents)

---

There is no established, formal definition of adrenal crisis.(31223468) One reasonable definition might be as follows.(31461595)

1. Acute deterioration with absolute hypotension (systolic pressure <100 mm) or relative hypotension (fall in systolic pressure by >20 mm).
2. Resolution within 1-2 hours of intravenous steroid administration.

This definition reveals that steroid may play both a diagnostic and therapeutic role. When in doubt, patients should be trialed with steroid therapy. If hemodynamic instability persists, then alternative etiologies should be sought (see #4 below).

---

treatment

(back to contents)

---

#1 investigation & treatment of trigger

• The trigger of the crisis should be sought and treated.
• For patients with possible infection, it may be reasonable to obtain cultures and start empiric antibiotic.

#2 steroid

• For patient with known adrenal insufficiency:
  • 100 mg hydrocortisone IV STAT as a loading dose. This is followed by 50 mg IV hydrocortisone IV q6hr as a maintenance dose.
  • If hydrocortisone isn't immediately available, may substitute 40 mg IV methylprednisolone daily.
  • Once the patient has recovered, steroid may be tapered over three days to the patient's baseline regimen.(31461595)
• For patient with suspected adrenal insufficiency:
  • Don't delay steroid administration in suspected adrenal crisis. Give dexamethasone 4-6 mg IV once. Dexamethasone is useful because it doesn't interfere with measurement of cortisol levels (unlike most other steroids).
    • Dexamethasone has no mineralocorticoid effects, but that generally isn't important (these patients will be receiving lots of IV crystalloid, so increased renal sodium excretion isn't a big deal). For patients with hyperkalemia, supplemental mineralocorticoid may be beneficial (fludrocortisone 0.2 mg orally).
  • Test for adrenal insufficiency as described above. 📖
  • Cortisol levels should be available within a few hours. If they reveal adrenal insufficiency then initiate standard therapy with hydrocortisone 50 mg IV q6hr.

#3 resuscitation

• The overall resuscitative strategy here is similar to a sepsis resuscitation (another type of distributive shock).
  • Provide volume resuscitation based on hemodynamic assessment (patients often depleted due to poor oral intake, vomiting, and renal sodium wasting).
  • Early use of vasopressors should be considered, with subsequent weaning based on clinical parameters.
• Treat hypoglycemia with IV glucose as needed.

#4 re-evaluation

• Patients with adrenal crisis should improve rapidly with aggressive resuscitation and steroid.
• Failure to improve suggests missed injury (e.g., occult focus of infection) or possible takotsubo cardiomyopathy (which can be associated with adrenal crisis). Re-evaluate and consider further imaging studies.

---

prevention

(back to contents)

---

For patients with known adrenal insufficiency, steroid dose should be increased when undergoing physiologic stress to prevent the development of adrenal crisis.

• Severe stress (e.g., major surgery, severe infection) ➡ 50 mg IV hydrocortisone Q6hr may be reasonable. This represents roughly eight times the normal physiologic output of steroid.(31461595)
• Moderate stress ➡ may double or triple the patient's maintenance dose of steroid (this will be ~50-75 mg/day hydrocortisone in two or three divided doses). (25288693)
• As a reference point, common maintenance steroid regimens in adrenal insufficiency are as follows:(Vincent 2023)
  • Hydrocortisone: 20 mg qAM and 10 mg QHS, plus fludrocortisone 50-100 mcg/day.
  • Prednisone: 5 mg qAM and 2.5 mg QHS, plus fludrocortisone 50-100 mcg/day.

---

physiology

(back to contents)

---

impaired suppression of inflammation

• Normally, cortisol inhibits pro-inflammatory cytokines (via mechanisms including depression of nuclear factor kappa b, i.e. NF-kB).
• Release of this inhibition increases systemic inflammation.
• Clinical manifestations may include fever, malaise, and anorexia.(31461595)

hemodynamic effects

• Cortisol normally functions synergistically with catecholamines to cause vasoconstriction.

metabolic effects

• Cortisol is generally a catabolic hormone, which stimulates the production of numerous fuels in times of stress:
  • (a) Cortisol stimulates gluconeogenesis in the liver
  • (b) Cortisol promotes production of free fatty acids
  • (c) Cortisol promotes the release of amino acids
• Adrenal crisis may lead to low levels of these fuels (particularly hypoglycemia, which can be detected clinically).

renal effects

• Aldosterone is deficient only in cases involving failure of the entire adrenal gland (e.g. Addison's disease).
• Deficiency of aldosterone causes wasting of sodium, with retention of positively charged ions (K+ and H+). This leads to hyperkalemia and non-anion-gap metabolic acidosis (NAGMA).

---

Cushing syndrome

(back to contents)

---

definitions

• Cushing syndrome: symptomatic hypercortisolism of any etiology.
• Cushing disease: ACTH-secreting pituitary adenoma.

clinical manifestations

• Asthenia (~90%).
• Weight gain (truncal obesity, buffalo hump, Cushingoid facies, frontal balding).
• Dermatologic (atrophic skin, easy bruising, violaceous striae, acne).
• Cardiovascular:
  • Hypertension.
  • Edema due to sodium retention.
• Proximal muscle weakness.
• Neuropsychiatric:
  • Depression.
  • Confusion.
  • Psychosis, emotional lability (“roid rage”).

laboratory findings can include

• Hyperglycemia/diabetes.
• Hypokalemia.
• Metabolic alkalosis.
• CBC: leukocytosis, lymphopenia, eosinopenia.

evaluation

• 24-hour urine free cortisol:
  • Normal: 20-80 ug/day.
  • >250-300 may be diagnostic of Cushing syndrome.
• Dexamethasone suppression test:
  • 1 mg PO dexamethasone QHS.
  • Check plasma cortisol at 8-9 AM tomorrow.
  • Normally, cortisol should be suppressed <1.8 ug/dL.  Higher values suggest hypercortisolism.
  • Sensitivity and specificity are ~80-95%. (37432427) False-positive may be caused by drugs that induce the metabolism of dexamethasone (e.g., phenobarbital, phenytoin, or recent use of oral contraceptives).

causes of hypercortisolism

• Exogenous glucocorticoids are the most common cause (including inhaled or topical steroids).
• Endogenous:
  • 65% Cushing syndrome (benign pituitary adenoma).
  • 30% Adrenal tumors.
    • Cortisol-producing adenoma (22%).
    • Primary bilateral macronodular adrenocortical hyperplasia (5%).
    • Primary pigmented nodular adrenocortical disease (2%).
    • Adrenocortical carcinoma (1%).
  • 6% Ectopic ACTH syndrome (e.g., SCLC, bronchial carcinoid, thymic carcinoid or thymoma, pancreatic islet cell tumors, medullary thyroid neuroendocrine tumors).
  • <1% Ectopic CRH (corticotropin-releasing hormone) syndrome. (37432427)

differential diagnosis: pseudo-Cushing syndrome (nonneoplastic endogenous hypercortisolism)

• This involves conditions wherein endogenous stress stimulates high levels of cortisol. Differentiating pseudo-Cushing syndrome from Cushing syndrome can be difficult. (37432427)
• Includes:
  • Depression.
  • Alcoholism.
  • Obesity.
  • Diabetes.
  • Pregnancy.
  • Malnutrition.
  • Acute stress.

management

• Resection of the lesion:
  • Most often, this will involve resection of a pituitary adenoma. However, in rare cases, such as ectopic ACTH secretion, it may be necessary to perform a bilateral adrenalectomy.
  • Postoperatively, patients may have adrenal insufficiency and require adrenal replacement therapy.
• Medical therapy may be used for inoperable disease or to stabilize the patient before surgery:
  • Adrenal steroid inhibitors may work in any form of endogenous hypercortisolism:
    • Ketoconazole (inhibits cholesterol desmolase, the first step in the biosynthesis of adrenocortical steroids).
    • Metyrapone (11-beta hydroxylase inhibitor).
    • Low-dose etomidate infusion works more rapidly and has greater efficacy than ketoconazole.
    • Osilodrostat is very potent but may induce adrenal insufficiency.
  • Mifepristone acts as a peripheral glucocorticoid receptor antagonist.
  • Cushing disease may be treated by medications (e.g., pasireotide and cabergoline). These are less effective at inhibiting steroidogenesis but could be helpful in patients with macroadenomas exerting mass effects on nearby structures. (37432427)

---

podcast

(back to contents)

---

Follow us on iTunes

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Adrenal insufficiency should be considered in any patient with known chronic steroid use plus acute illness.
• For patients without a known diagnosis of adrenal insufficiency, it is important to make a firm diagnosis up-front (e.g., with an ACTH stimulation test).
• Don't forget that chronic steroid use is the most common cause of adrenal insufficiency, leaving these patients at risk for adrenal crisis due to acute stress (e.g., severe infection).
• Adrenal crisis should be considered in any patient who appears to be septic, but doesn't have an obvious source of infection. This is a classic sepsis-mimic.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.