Obtaining an extensive history is the initial step in the evaluation in patients with suspected adrenal crisis. A review of the patient's past medical history and past surgical history is mandatory. The physicians should review the list of home medications. Identifying the precipitating factors and confirming if there is any history of long-term steroid use is required as abrupt cessation or an acute process can precipitate adrenal crises in these patients. Inquiring about other autoimmune diseases is also important while obtaining history since a patient with autoimmune polyglandular endocrinopathy can present with multiple autoimmune diseases. Note that recurrent hypoglycemia can be a sign of adrenal insufficiency in patients with type 1 diabetes on insulin therapy. Patients with adrenal crisis usually present with an unexplained shock which is refractory to vasopressors and fluids. Classical manifestations are weakness and fatigue (74–100%) and weight loss (78–100%) with decreased appetite. In children, weight loss with failure to thrive can be seen in 61–100% and other manifestations can be hypoglycemic crises with seizures. Additional manifestations as anorexia, orthostatic hypotension and tachycardia can be seen in 88–94% of the patients while skin and mucosal hyperpigmentation in 80–94%. The gastrointestinal manifestations can be either nausea, vomiting, and diarrhea which occur in 75–86% or recurrent abdominal pain which occur in 31% of the patients. The less common presentation are a surgical emergency, amenorrhea, libido reduction, depression in less than 40% of the patients and the least common presentation is salt-craving which is only seen in 9–16% of the patients. Pregnant patients, patients with meningitis and patients with a headache and vision changes represent a small subset of patients that may present with occult adrenal crisis secondary to Sheehan syndrome, Waterhouse-Friedrichsen syndrome, and pituitary apoplexy respectively. Patients with pituitary apoplexy may present with a headache and bitemporal hemianopsia in addition to signs of adrenal crisis.[7][5][28][29][30]

There are multiple laboratory abnormalities are expected in the setting of adrenal crisis. The Classic laboratory features may reveal:

• Hyponatremia( due to mineralocorticoid deficiency)
• Hyperkalemia ( due to mineralocorticoid deficiency)
• Hypoglycemia( due to decreased gluconeogenesis and glycogenolysis)
• Low or low normal ACTH level in secondary adrenal insufficiency and high or high normal ACTH level in primary adrenal insufficiency
• Hypercalcemia(due to increased intestinal absorption and decreased renal excretion of calcium)
• Prerenal failure with elevated creatinine level
• Low aldosterone ( due to mineralocorticoid deficiency)
• High renin is expected in primary adrenal insufficiency as there is an increase in urinary sodium loss and decreases in the blood volume)
• Normocytic normochromic Anemia, lymphocytosis, and eosinophilia 
• TSH levels may be increased, usually between 4 and 10 IU/L( due to coexisting hypothyroidism in autoimmune polyglandular endocrinopathy or due to the lack of the inhibitory effect of cortisol on TSH production)

Other lab tests may also help to reveal the underlying cause of the concomitant adrenal crisis. In patients with known adrenal insufficiency, you may be able to use laboratory findings to distinguish between primary and secondary causes. Patients with secondary adrenal insufficiency may only be hypoglycemic due to impaired gluconeogenesis, but there is some variability overall as this is rare. The mineralocorticoid axis is usually intact and it is not expected to see hyponatremia or hypokalemia in the laboratory testing. In patients where the diagnosis of adrenal crisis is not clear, there are confirmatory tests that may be done, but this should not take precedence over empiric treatment in suspected cases. An ACTH stimulation test would confirm the diagnosis but should not be done in the acute setting. Several labs such as ACTH, serum cortisol, aldosterone, dehydroepiandrosterone sulfate, and renin should be drawn before the administration of hydrocortisone for review at a later time. In some cases a random cortisol level before administration may exclude or support the diagnosis of adrenal insufficiency and crisis; however, this should not prevent the administration of glucocorticoids when the picture is not clear. A high cortisol level of >20 mg/dL (550 nmol/L) can exclude the diagnosis, while a low cortisol level of <5 mg/dl in the early morning and in the setting of acute illness support the diagnosis. Other investigation for the underlying precipitating factors like infections, infiltrative disease, metastasis should also be addressed. In addition, given the hyponatremia, other autoimmune diseases should be tested including thyroid function tests. Adrenal imaging studies are usually not required unless suspected bilateral adrenal hemorrhage or cancer or in specific cases. Bilateral hyperdense lesions are characteristic for adrenal hemorrhage.  [1][31][32][7][33][34][15]

The definitive treatment of adrenal crisis is the administration of glucocorticoids, specifically hydrocortisone. The dose is 100 mg intravenously or intramuscularly (IV/IM) as an initial bolus followed by 100 to 300 mg daily after that for another 2-3 days either as boluses every 6 hours or as continuous infusion until full recovery. At this dosage, hydrocortisone will also provide sufficient mineralocorticoid coverage as well. While hydrocortisone is the preferred treatment, administration of prednisolone or methylprednisolone, and dexamethasone has been described. In addition to medical therapy, these individuals also require aggressive fluid and vasopressor management. A thorough search should also be made for the cause, and empiric antibiotics are recommended. Close monitoring in the intensive care unit (ICU) is required. Note that if the patient is pregnant, the preferred agent is hydrocortisone and the patient should be discharged on hydrocortisone instead of cortisone acetate. 

Guidelines for managing adrenal crisis during an emergency

1. If the patient has clinical and laboratory features of adrenal crisis, administer 100 mg hydrocortisone IV every 6-8 hours. 
2. Since dehydration and hypovolemia are common precipitating factors, rehydration of the patient with normal saline 0.9% is essential ( it will also correct the hypovolemia and the prerenal failure). 1-liter normal saline should be given in the first hour then the need for further intravenous fluid resuscitation should be addressed according to the hemodynamic status of the patient(usually 4–6 liters are needed in the first 24 hours)
3. Correction of hypoglycemia with intravenous dextrose with frequent monitoring of the blood glucose is essential. 
4. Avoid rapid correction of hyponatremia ( more than 6-8 meq in the first 24 hours) to avoid osmotic demyelination syndrome (Take into consideration that Cortisol replacement can induce water diuresis and suppress antidiuretic hormone )
5. The assessment of the urine output is required.
6. Contact endocrinologist as soon as possible on further advice.
7. Only taper steroids after there are a clinical improvement and the tapering should be gradual. [35][36][7][37][5][38][39]

Because the adrenal crisis is rarely an independent process, the differential diagnosis may be very broad depending on the presentation and underlying etiology. While altered mental status, abdominal pain, nausea vomiting, fever, among others are all common presenting symptoms. Hypotension is usually the most significant. In a patient with these symptoms and known adrenal insufficiency, the adrenal crisis should be the top differential. However, there should be further investigation to determine the precipitating cause of the adrenal crisis whether that is sepsis, infection, trauma, physical or emotional stress, myocardial infarction, and so forth. In a patient with no known adrenal pathology who presents with hypotension that is refractory to fluid administration, vasopressor support, and appropriate management otherwise, the diagnosis of adrenal crisis should be considered and adequately ruled out.[5][39]

Adrenal crisis is not a common disease however it has a high mortality. The estimated mortality rate is 0.5/100 patients/year. However, the actual rate of death is difficult to be estimated. There is some data stating that mortality can be as high as 25% of the patients presenting with adrenal crises. Prompt recognition and treatment of both the underlying condition and adrenal crisis may lead to clinical improvement, but in many cases, mortality remains high. However, a Japanese study looking at an adrenal crisis in patients with known insufficiency found a mortality rate of closer to 3% while a German study was just over 6%. In the Japanese study older age, concomitant endocrine disorders and impaired level of consciousness was associated with increased mortality.  Data from the European Adrenal Insufficiency Registry found the major causes of death in patients with AI were cardiovascular disease (35%) and infection (15%). [5][15][3][40][41]

Even with proper recognition and treatment, the adrenal crisis may result in death. Other complications may include seizures, arrhythmias, coma, etc. due to electrolyte abnormalities such as hyponatremia, hyperkalemia, and hypoglycemia. Hypotension may lead to hypoperfusion and organ failure as well. However, many other complications may arise secondary to the precipitating disease or event.[5][42][3]

A critical care evaluation and consultation is needed in these patients as many of them will present with hypotension, altered mental status, and cardiovascular collapse. The severity of their presentations will often necessitate a higher level of care and monitoring which may include vasopressors, fluids, antibiotics and further management depending on the precipitating etiology of the adrenal crisis. Once the diagnosis of adrenal crisis is suspected, an endocrinology consultation should be obtained to confirm the diagnosis or to tailor the proper administration of corticosteroids further as well as to manage any underlying endocrine disorders.

More than 50% of patients with adrenal crisis don't have a prior diagnosis of adrenal insufficiency. Education regarding the diagnosis and the stress dose steroids is a crucial part of the management of an adrenal crisis. The patients should receive the following education:

• Sick days rule: which includes doubling or tripling the daily oral dose during minor illness.
• Stress dose is needed during stressful situations including trauma, surgery, major procedures, and severe illness.
• The patient should be aware of signs and symptoms of adrenal insufficiency including nausea, vomiting, abdominal pain, hypoglycemia, hypotension, weight loss, etc.
• The importance of wearing medical alert bracelets or necklaces.
• The patient should have additional supplies at home in case it is needed.
• An emergency kit should be available in case it is needed(100 mg hydrocortisone sodium succinate for injection or dexamethasone 4 mg, along with vials of sterile 0.9 percent normal saline and syringes )
• In a special situation like pregnancy, during labor, the patients should receive 25 mg hydrocortisone IV every 6 hours. At the time of the delivery, 100 mg Hydrocortisone should be given. After the delivery, tapering the dose in 3 days is recommended).[5][14][43]

An adrenal crisis should be suspected in patients presenting with an acute shock that that is refractory to adequate fluid resuscitation and vasopressors.

Adrenal crisis may be found more often in the elderly and those with other endocrine disorders. Patients with altered mental status and concomitant endocrine disorders may be at risk for higher mortality.

Hyponatremia, hyperkalemia, and/or hypoglycemia may be clues toward a possible diagnosis of adrenal crisis especially in the setting of hypotension.

Hydrocortisone 100 mg IV/IM is the mainstay of treatment and should be given immediately when suspecting an adrenal crisis.

Pregnant patients, patients with meningitis and patients with a headache and vision changes represent a small subset of patients that may present with an occult adrenal crisis.

Given that adrenal crises affect many organs and have a high mortality rate, the disorder is managed by an interprofessional team inside the ICU. This team should include an intensivist, endocrinologist and a radiologist. Other important members of the team include an ICU nurse and a pharmacist. ICU nurses must monitor vitals, urine output, and hemodynamics continuously- and deviation from the standard should be communicated to the interprofessional team. The education of the patients about the disease and its potential complications is of significant importance in the prevention of adrenal crisis. The patient and family should be educated by the nurse and reinforced by the clinician that abrupt cessation of exogenous corticosteroids is the most common cause of the adrenal crisis and this should be avoided. These patients depend heavily on exogenous corticosteroids to maintain their baseline health and they must be extensively educated to monitor for any aberrations and adjust their doses appropriately. Education regarding corticosteroid adverse effects should be performed by both the physician and the pharmacist. Finally, all patients should be encouraged to wear a medical alert bracelet indicating the disorder. [44][45](Level V)

Outcomes

Despite steroids replacement therapy in patients with adrenal crisis, once an adrenal crisis occurs, data show that the majority of patients have a poor quality of life as many patients remain disabled and are no longer able to work given depression and chronic fatigue. In addition, if the cause is due to secondary adrenal insufficiency, this is also associated with an increase in mortality. The cause of the mortality remains unclear, but it is most likely due to respiratory infections, adverse cardiovascular events, and stroke. [1][46](Level V)