As patients often present critically ill in shock and unable to assist with the interview, it is important for the healthcare team to know if the patient has a history of adrenal insufficiency, which helps narrow the differential diagnosis and provide prompt treatment. 

If the patient is on chronic steroid therapy, compliance with medication is important, as an Addisonian crisis can be precipitated by both the abrupt cessation of steroids, or the opposite - if the patient had an acute stress event and did not increase their steroid dose enough. Other useful elements of history include any recent illnesses such as gastroenteritis, surgeries, traumatic injuries or other stressors. Family history, or a personal history of autoimmune diseases such as hypothyroidism or diabetes mellitus raises the likelihood of another concurrent autoimmune diseases such as undiagnosed Addison's disease. 

Initial signs and symptoms are nonspecific such as nausea, vomiting, fever and lower chest/abdominal pain along with hypotension, altered mental status, and obtundation. The physical exam may show hyperpigmentation of the dorsum of the hands in those with primary adrenal insufficiency (Addison's disease) or Cushingoid symptoms such as facial fullness, dorsocervical fat pad, truncal obesity with striae, hirsutism in those who take chronic steroids. Abdominal symptoms may take on features of acute abdomen[16]. Patients may have hyperpyrexia, with temperatures reaching 105 F or higher. [1][3][11]. As the patient's cortisol stores are depleted, they will eventually develop circulatory collapse with cyanosis and shock and eventual coma and death if not treated.  

Initial laboratory testing should include serum chemistry (particularly sodium, potassium, glucose, and calcium), complete blood count with differential, cortisol level, adrenocorticotropic hormone (ACTH), aldosterone, renin, and thyroid function[16]. Pertinent electrolyte abnormalities may include hyponatremia, hyperkalemia, hypoglycemia, acute renal injury, non-anion gap metabolic acidosis, and eosinophilia. The electrolytes reflect a state of dehydration and hypoperfusion in addition to mineralocorticoid deficiency. Normally an acute stress event such as sepsis will stimulate cortisol production, which usually decreases eosinophil counts,  however in patients with adrenal insufficiency they will unable to increase their cortisol reserves, and thus normal or increased eosinophil counts in an unstable patient raises the possibility of an adrenal etiology. Hypoglycemia is sometimes seen, however it is more prevalent in children. 

Although a reliable diagnosis of underlying adrenal insufficiency is not possible during the initial period of fulminant adrenal crisis, a measurement of blood ACTH and cortisol during the crisis (before treatment with corticosteroids is given)  is often enough to make a preliminary diagnosis. Providers should not delay treatment pending these results. Primary adrenal insufficiency (Addison Disease) is characterized by low cortisol and high ACTH. Secondary adrenal insufficiency is characterized by low cortisol and low to normal ACTH. Workup and treatment for other suspected underlying etiologies on the differential should happen simultaneously. [17]

An EKG may show peaked T waves from hyperkalemia or short QT interval from hypercalcemia[18]. A chest radiograph, urine studies, and blood cultures should be ordered to evaluate for any infection. A CT scan of the abdomen may show hemorrhage in the adrenals, calcification of the adrenals (seen with tuberculosis) or metastasis. In cases of secondary adrenal insufficiency, a head CT scan may show the destruction of the pituitary (i.e., empty sella syndrome) or a pituitary mass lesion.

This diagnosis requires quick identification and treatment. It is a medical emergency requiring maximal supportive care and monitoring in the ICU.

Fluids and glucocorticoid replacement are the mainstays of emergent therapy. Two to three liters of normal saline or 5% dextrose in normal saline should be infused in the first 12 to 24 hours[19]. The dextrose-containing solution should be used in the setting of hypoglycemia. Volume status and urine output should be used to guide resuscitation. A bolus of steroids, with Hydrocortisone (100 mg IV bolus) or an equivalent such as Dexamethasone (4 mg IV bolus) can be used. [14][16]. In patients without known adrenal insufficiency, dexamethasone is preferred because it does not interfere with the diagnostic testing, unlike hydrocortisone. Maintenance steroid replacement is required - dexamethasone 4 mg IV every 12 hours or hydrocortisone 50 mg IV every 6 hours until vital signs have stabilized and the patient can take medication orally[14]. Critically ill patients who fail to respond with the initial IVF bolus will need to be started on vasopressors to maintain a MAP above 65 for adequate organ perfusion and may need elective intubation to protect the airway if comatose. If the etiology is primarily adrenal insufficiency, the patient should stabilize quickly with the resolution of symptoms and hypotension within hours of steroid administration. The healthcare team will need to do a complete work-up to identify the triggering stress event, and address the underlying etiology (I.e. Myocardial infarction, gastroenteritis, acute adrenal hemorrhage, etc.)

Once the crisis is controlled, an ACTH stimulation test can be performed to diagnose the etiology of the adrenal insufficiency in those patients with no prior history of adrenal disorders. [16]. After the initial stabilization of the patient using the above measures, the underlying cause of the crisis should be identified and treated[16].

Current Guidelines for Addisonian crisis

1. In acutely ill patients with signs and symptoms suggestive of acute adrenal insufficiency, one should rule of Addisonian crisis
2. Assess blood pressure and perform orthostasis
3. Determine the history of steroid use
4. Perform appropriate tests like sodium, potassium, creatinine, urea, TSH, cortisol and plasma ACTH levels
5. In stable patients, consider performing a short Synacthen test.
6. Never delay treatment because of testing
7. If in doubt and suspicion is high, administer IV hydrocortisone and hydrate patient.

Addisonian crisis secondary to adrenal insufficiency can be difficult to diagnose in acutely ill patients as the initial presentation is usually nonspecific with symptoms of fatigue, weakness, nausea, vomiting, abdominal pain, back pain, diarrhea, dizziness, hypotension, syncope, and if not treated, progression to obtundation, coma, and shock. Usually, the Addisonian crisis is not at the top of the differential compared to other more common diagnoses, and more education is needed to ensure healthcare providers are aware of this diagnosis. 

If the patient has a known history of adrenal insufficiency, the Addisonian crisis is near the top of the differential and immediately care can be initiated. The diagnosis is often multifactorial; the difficulty in diagnosing the Addisonian crisis is due to identifying the underlying event that triggered the crisis while simultaneously treating and providing supportive care. The stress event may be secondary to recent surgery, cardiac event, infection, malignancy, medication, or physical and mental stress.  Treatment will need to address this underlying cause for full resolution. The differential diagnoses are broad and include: 

• Shock
  • Cardiogenic
  • Obstructive
  • Distributive
  • Hypovolemic
  • Septic
• Cardiac
  • Acute myocardial infarction
• Endocrine
  • Thyrotoxicosis
  • Diabetic Ketoacidosis
  • Hyperosmolar Hyperglycemic state
  • Myxedema coma
  • Pituitary adenoma
• Gastrointestinal
  • Dehydration
  • Gastroenteritis
  • Poor oral intake
  • Acute Abdomen (such as appendicitis, diverticulitis, obstruction)
• Heme/Onc
  • history of melanoma, breast cancers, on Immunotherapy with a checkpoint inhibitor
  • Malignancy
• OBGYN
  • Pregnancy
  • Hyperemesis gravidarum
• Infectious
  • Acute localized or systemic infection
• Other:
  • Trauma 

In any acute adrenal crisis, immediate first-line treatment is to give IVF with glucocorticoids. Studies suggest a 100mg IV bolus of hydrocortisone is the  first-line for glucocorticoid replacement. If that is not available, another glucocorticoid such as dexamethasone can be substituted, but dexamethasone does not have a secondary mineralocorticoid action as hydrocortisone does. Oral glucocorticoids are not recommended, as patients are too acutely ill, not able to eat or drink, have nausea and vomiting, or are obtunded and cannot swallow.

Upon discharge, the patient will need to have a prescription for long-term glucocorticoid therapy, as well as close followup with a primary care provider or endocrinologist. 

Without prompt treatment, there is a high chance of mortality or irreversible complications. Each year roughly 8% of those with known adrenal insufficiency have an adrenal crisis, and the rate of death is around 6%. If the Addisonian crisis is quickly identified and given prompt treatment with IVF and steroids, patients have a good prognosis and recovery. Those who present critically ill with significantly altered mental status or had advanced endocrinopathies (severe diabetes, uncontrolled thyroid disease) or multiple comorbidities had increased mortality and residual disability. The patient may need physical or occupational therapy and rehabilitation to regain independent function. 

If left untreated, an Addisonian crisis can lead to complications such as:

• Cardiac arrhythmias from multiple electrolyte abnormalities
• Cardiac arrest
• Hypotension can lead to orthostatic hypotension and syncope, with progression to a shock state with hypoperfusion to the organs causing sequelae such as elevated transaminitis (shock liver), bradycardia and myocardial infarction, respiratory failure, ileus, hypoxic brain injury
• Hypoglycemia and hypoglycemic coma 

Addisonian Crisis is a medical emergency, requiring hospital admission. In most cases, patients will require close monitoring in the ICU with a critical care consultation due to the high risk of decompensation from multifactorial etiologies. Once stable, Endocrinology should be consulted to help manage the dosing for long-term steroid therapy, if the underlying cause is adrenal insufficiency. Other specialists such as Cardiology, Gastroenterology, Infectious Disease should be consulted as needed to help address and manage the underlying cause of what precipitated the Addisonian Crisis. 

A Polish retroactive study showed that over 44% of patients who had adrenal insufficiency were diagnosed only after they had presented in an acute adrenal crisis. [20] These patients primarily presented with vague signs, and were misdiagnosed with other conditions such as chronic gastritis. Upon diagnosis, patients will need to be counseled on the nature of their disease and how their body produces fewer glucocorticoids than others and will need to remain on lifelong therapy. These patients are often diagnosed with adrenal insufficiency years after the initial presenting symptoms, and many are dissatisfied with the rigorous glucocorticoid replacement schedules. Many report a decrease in quality of life due to chronic weakness and fatigue, and inability to perform their usual activities of daily living and fear of their next Addisonian crisis. 

Prevention strategies to avoid Addisonian crisis include

• Close routine followup with the physician managing their adrenal insufficiency
• Individualized care plans 
• Educating the patient in the event of acute illness; for example to increase their usual steroid dose by 2-3x
• Those who plan for elective surgeries should be aware that they may need post-operative stress-dose steroids and to notify the operating surgeon or anesthesiologist
• An emergency dose of parenteral hydrocortisone at home when the patient cannot tolerate oral steroids, but still need the cortisol replacement. The family should be taught how to give an emergency steroid injection via IV administration. 
• Having some type of identification detailing the patient having adrenal insufficiency or a history of Addisonian crisis, such as a bracelet or ID card

• Overall, Addisonian crisis is a life-threatening emergency requiring the healthcare providers to recognize the underlying adrenal insufficiency and to treat with IVF resuscitation and IV hydrocortisone promptly while simultaneously working up the etiology which triggered the acute decompensation. 
• In the setting of shock, oftentimes adrenal insufficiency is low on the differential. A key to diagnosis is hypotension resistant to vasopressor and IV fluid support. 
• Severe cortisol deficiency is the main driver of acute adrenal insufficiency. It is usually released during times of stress to assist with homeostasis, vasoconstriction, and immune function. Aldosterone deficiency is also present, contributing to electrolyte imbalances such as hyperkalemia, hyponatremia, and hypercalcemia.
• The most common triggering event is GI infection. Any other condition that can cause stress on the body can lead to an acute crisis. 
• Addisonian crisis can occur both in those previously undiagnosed, or those diagnosed with adrenal insufficiency.
• Primary adrenal insufficiency (Addison Disease) is characterized by low cortisol and high ACTH from the destruction of the adrenal glands. Secondary adrenal insufficiency is characterized by low cortisol and low to normal ACTH caused by decreased ACTH secretion from the pituitary
• An ACTH stimulation test can be performed to diagnose adrenal insufficiency. Those with concurrent endocrinopathies or auto-immune disease, or have a family history of such diseases are at high risk for adrenal insufficiency.
• Patients and their families will need to be educated on strategies to prevent acute decompensation, and how any triggering event will require an adjustment of their steroid doses.
• A team-based approach between healthcare providers and the patient is essential in maintaining control of this condition. 

The diagnosis and management of Addisonian crises require an interprofessional team because the disorder is difficult to diagnose, has non-specific clinical features and is associated with nearly 100% mortality if treatment is delayed. Most patients present to the emergency department and the triage nurse should be familiar with the signs and symptoms of this life-threatening disorder. Prompt admission and communication should be made to the emergency department physician. While the endocrine consult is made, laboratory workup and imaging tests should be ordered. At the same time, nurses should have two large-bore IVs with fluids running and have the patient hooked up to a monitor. The pharmacist should determine if the patient has been on prior corticosteroids.

The radiologist should be informed about an urgent CT scan to determine if there is an adrenal hemorrhage. However, good clinical acumen is needed before sending an unstable patient to an unmonitored radiology suite. If the patient is unstable, a mobile team should monitor the patient while being transported to the radiology department.

The endocrinologist, internist intensivist, infectious disease expert, and nephrologist should play an active role in the management. After the initial stabilization of the patient using the above measures, the underlying cause of the crisis should be identified and treated[16]. Once the patient has been managed as an inpatient, he or she can be followed by the primary care provider or nurse practitioner.  The pharmacist has to educate the patient on medication compliance to prevent a recurrence. Untreated cases have mortality in excess of 90%.[21]

Finally, the interprofessional team should urge the patient to wear an ID bracelet detailing the Addisonian crisis. (Level 5)