Addisonian crisis, also known as adrenal crisis or acute adrenal insufficiency is an endocrinologic emergency with a high mortality rate secondary to physiologic derangements from an acute deficiency of the adrenal hormone cortisol, requiring immediate recognition and treatment to avoid death . It is characterized as an acute change in physiologic status, quickly progression from nonspecific symptoms of fatigue, weakness, nausea, vomiting, abdominal pain, back pain, diarrhea, dizziness, hypotension, syncope, eventually to obtundation, metabolic encephalopathy, and shock. The mainstay of treatment is early recognition of the underlying adrenal insufficiency and resolution of symptoms after the administering IV fluids and parenteral glucocorticoid administration. 
Addisonian crisis refers to an episode of acute adrenal insufficiency (which may be primary, secondary, or tertiary), which is a medical emergency. Chronic, stable primary adrenal insufficiency is called Addison's disease, which is a chronic condition controlled with long-term glucocorticoid therapy. 
An Addisonian crisis most often occurs in a patient with known adrenal insufficiency, either primary or secondary. 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. Most cases are patients with known adrenal insufficiency who experience an acute stress event, who do not adjust their usual dose of glucocorticoid therapy and their body's cortisol stores are quickly depleted leading to an Addisonian crisis as these patients cannot produce their own cortisol. Roughly half of the patients have undiagnosed Addison's disease and present to the emergency room in acute crisis and shock after an acute stress event.
The most common precipitating cause is acute infection, such as from a gastrointestinal upset.  Uncommonly, a patient will have no prior history or family history of autoimmune disease or adrenal insufficiency but will have acquired adrenal insufficiency due to chronic infection, such as from mycobacterium tuberculosis leading to chronic infectious adrenalitis and fibrosis, or have acute Meningococcal meningitis causing Waterhouse-Friderichsen Syndrome and massive bilateral adrenal hemorrhage. One of the more common presentations of the Addisonian crisis is a patient who is on chronic steroid therapy, who abruptly stop their usual doses of corticosteroid due to the long-term suppression of the hypothalamic-pituitary Axis.    
Primary Adrenal Insufficiency (Addison's disease) 
- Autoimmune Adrenalitis
- Immunotherapy with a checkpoint inhibitor
- Infiltrative diseases
- Most commonly due to an acute illness from a viral or bacterial infection
- Adrenal hemorrhage
- Waterhouse-Friderichsen Syndrome
- Myocardial infarction
- Physical overexertion and dehydration
- Other endocrinopathies (DKA, thyrotoxicosis, myxedema coma)
Secondary Adrenal Insufficiency
- Iatrogenic after the rapid withdrawal of corticosteroids without tapering
- oral and inhaled steroids
- Pituitary causes
- Pituitary adenoma
- Infiltrative disorders
- Lymphocytic hypophysitis
- Sheehan's syndrome
- Pituitary apoplexy
An Addisonian crisis frequently occurs in patients with known adrenal insufficiency. Studies in patients on chronic replacement therapy for adrenal insufficiency have revealed an incidence of 5 to 10 adrenal crises/100 patient-years and suggested a mortality rate from an adrenal crisis of 0.5/100 patient-years. Of 444 patients in one study, 42% reported at least one crisis; the frequency of crises was calculated to be 6.3/100 patient years. Patients with primary adrenal insufficiency were slightly more likely than those with secondary adrenal insufficiency to have a crisis. The most frequent triggers of adrenal crisis are infectious causes. Studies of critically ill patients with septic shock (excluding patients with known adrenal insufficiency or patients on glucocorticoid therapy) have shown an incidence of adrenal insufficiency of up to 57%.
Addisonian crisis refers to an acute status of severe cortisol and aldosterone deficiency. As a response to an environmental stressor, the hypothalamus releases corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release adrenocorticotropin hormone (ACTH), which travels through the bloodstream to the adrenal cortex and upregulates cortisol production. Cortisol is a glucocorticoid hormone synthesized from cholesterol by enzymes of the cytochrome P450 family in the zona fasciculate, the middle area of the adrenal cortex.
Cortisol is the primary hormone involved in the human stress response and has multiple effects throughout the body such as causing vasoconstriction and inhibition of pro-inflammatory cytokines. It helps regulate the supply of glucose in the body by triggering gluconeogenesis or stimulating glycogen synthesis in the liver as well as the production and release of amino acids from free fatty acids. It weakens the immune response by preventing T-cell proliferation and preventing T-cells from recognizing interleukin signals. Aldosterone deficiency is usually seen in more severe cases as the primary cause of electrolyte arrangements in cases of more severe adrenal gland dysfunction. . Deficient levels of aldosterone cause increased renal sodium loss and potassium reabsorption, resulting in decreased intravascular volume, vascular tone, cardiac output, and renal perfusion. This, in turn, lowers arterial blood pressure, which may lead to postural hypotension, compensatory tachycardia, and eventual vascular collapse. Reduced renal perfusion causes water retention, which dilutes the extracellular fluid and causes the cells to leak potassium, leading to hyperkalemia and metabolic acidosis. Circulatory collapse impairs urinary excretion of waste products, causing elevated levels of blood urea nitrogen and creatinine.
History and Physical
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. Patients may have hyperpyrexia, with temperatures reaching 105 F or higher. . 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. 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. 
An EKG may show peaked T waves from hyperkalemia or short QT interval from hypercalcemia. 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.
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:
- Acute myocardial infarction
- Diabetic Ketoacidosis
- Hyperosmolar Hyperglycemic state
- Myxedema coma
- Pituitary adenoma
- Poor oral intake
- Acute Abdomen (such as appendicitis, diverticulitis, obstruction)
- history of melanoma, breast cancers, on Immunotherapy with a checkpoint inhibitor
- Hyperemesis gravidarum
- Acute localized or systemic infection
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.
Deterrence and Patient Education
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.  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
Pearls and Other Issues
- 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.
Enhancing Healthcare Team Outcomes
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. 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%.
Finally, the interprofessional team should urge the patient to wear an ID bracelet detailing the Addisonian crisis. (Level 5)