Addisonian Crisis

Etiology

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 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. [3] 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.   [4] [5] [6] [7]

Primary Adrenal Insufficiency (Addison disease) [8]

• Autoimmune Adrenalitis
• Medication-Induced
  • Ketoconazole
  • Rifampin
  • Phenytoin
  • Mitotane
  • Immunotherapy with a checkpoint inhibitor
  • diuretics
• Infiltrative diseases
  • Sarcoidosis
  • Amyloidosis
  • hemochromatosis
• Infectious
  • Most commonly due to an acute illness from a viral or bacterial infection
  • Tuberculosis
  • HIV/AIDs
  • CMV
• Adrenal hemorrhage
  • Waterhouse-Friderichsen Syndrome
• Other:
  • Trauma
  • Pregnancy
  • Sepsis
  • Myocardial infarction
  • Physical overexertion and dehydration
  • Surgery
  • 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
  • Trauma 

Epidemiology

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[1][3][9]. 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[3][10]. Patients with primary adrenal insufficiency were slightly more likely than those with secondary adrenal insufficiency to have a crisis[11]. The most frequent triggers of adrenal crisis are infectious causes[3][9]. 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%[12][13].

Pathophysiology

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[14].

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[15]. Aldosterone deficiency is usually seen in more severe cases as the primary cause of electrolyte arrangements in cases of more severe adrenal gland dysfunction. [14]. 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, the healthcare team needs 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 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 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.  

Evaluation

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 be unable to increase their cortisol reserves; thus, normal or increased eosinophil counts in an unstable patient raise 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.

Treatment / Management

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.)(A1)

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 adrenocorticotropic hormone test.
6. Never delay treatment because of testing.
7. If in doubt and suspicion is high, administer IV hydrocortisone and hydrate the patient.

Differential Diagnosis

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 immediate 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
• Obstetrics
  • Pregnancy
  • Hyperemesis gravidarum
• Infectious
  • Acute localized or systemic infection
• Other:
  • Trauma 

Treatment Planning

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 follow-up with a primary care provider or endocrinologist. 

Prognosis

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. 

Complications

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