Adrenal Crisis

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Continuing Education Activity

Adrenal crisis is an acute life-threatening condition precipitated by an internal or external process in the setting of known or unknown adrenal insufficiency and corticosteroid deficiency. This activity explains the difference between adrenal insufficiency and adrenal crisis, reviews the evaluation and management of adrenal crisis, and highlights the role of the interprofessional team in treating patients with this condition.


  • Review the etiology of adrenal crisis.
  • Outline the role of steroids in the management of adrenal crisis.
  • Explain how to use the algorithm to evaluate patients suspected of having adrenal crisis.
  • Summarize the importance of collaboration and communication among interprofessional team members to enhance care coordination for patients with adrenal crisis.


Adrenal crisis, also termed acute adrenal insufficiency is an acute life-threatening condition with a mortality rate of 0.5/100 patient-years and remains a significant cause of death in patients with adrenal insufficiency.[1] Patients may deteriorate quickly, resulting in death at home or soon upon arrival in hospital. It is an endocrine emergency precipitated by an internal or external process in the setting of known or unknown lack of production of the adrenal hormone cortisol, which is the primary glucocorticoid. Early identification and prompt management can save the patient's life and impact survival.[2] The clinicians should differentiate between adrenal insufficiency and adrenal crisis since the adrenal crisis is fatal if left untreated. While this disease is well described, it is often difficult to recognize, and treatment initiation may be delayed leading to notable morbidity and mortality.[3] Educating patients and their families about sick day rules and the availability of intramuscular hydrocortisone at home are essential in preventing adrenal crisis.[4]


In 1855, Thomas Addison described the first case of adrenal insufficiency.[5] In 1856, Trousseau termed adrenal insufficiency as "bronze Addison disease," which became known widely as Addison disease. With the discovery of cortisone by Hench, Kendall, and Reichstein in the late 1940s, the life expectancy of patients with adrenal insufficiency dramatically improved, and initial data suggested that life expectancy was normalized. Tuberculosis was the most common cause (70%) during the 1930s. Currently, autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in developed countries, and tuberculosis is still the leading cause of adrenal insufficiency in developing countries.[6]

Precipitating Factors for Adrenal Crisis

Acute adrenal crisis can be the first presentation of unknown adrenal insufficiency and can occur in up to 50% of patients with known adrenal insufficiency.[7] The majority of adrenal crises may not have any known precipitating events. Gastrointestinal illness is the most commonly observed precipitating factor for adrenal crisis.[8] Other causes include:

  • Infections- bacterial (StreptococcusPseudomonasHemophilus influenzaTreponema pallidum/Syphilis - reported in case reports), mycobacteria, fungal (histoplasmosis, Pneumocystis cariniiCandida), parasitic (toxoplasmosis, African trypanosomiasis), or viral (human immunodeficiency virus, herpes simplex, cytomegalovirus, echovirus).[9]
  • Stressful situations-trauma, pregnancy, parturition, surgery, extreme hot and cold weather, and strenuous physical activity.
  • Emotional stress
  • Strenuous physical activity
  • Thyrotoxicosis (as it increases cortisol metabolism)
  • Medications: antiadrenal medications, mitotane, metyrapone, anticancer medications, immune checkpoint inhibitors, tyrosine kinase inhibitors (sunitinib, imatinib), ketoconazole, fluconazole, etomidate, rifampicin, cyproterone acetate, diuretics, and megestrol acetate. Immunotherapy with checkpoint therapy, such as atezolizumab for breast cancer, is associated with acquired endocrinopathies such as adrenal insufficiency due to causing hypophysitis, the autoimmune destruction of the pituitary. Checkpoint therapy for lung, breast, and melanoma cancers may precipitate an adrenal crisis. Some other complications include thyroiditis and type 1 diabetes. The average onset of endocrine-related complications from checkpoint therapy may occur from 6 to 12 weeks after starting therapy.[10]
  • Dehydration
  • Alcohol intoxication
  • Severe migraine
  • Seizures 
  • Acute myeloid leukemia[11] 
  • Unknown causes

Risk factors for Adrenal Crisis

  1. Known history of adrenal insufficiency or previous history of adrenal crisis
  2. Glucocorticoid therapy including topical and inhalation-suppress HPA axis (sudden withdrawal can trigger adrenal crisis)
  3. Levothyroxine, phenytoin, phenobarbital, rifampin (increases cortisol metabolism)[12][13]
  4. Ketoconazole, etomidate, fluconazole (reduces intrinsic production of cortisol)[14]
  5. Anticoagulation agents (increased risk of adrenal hemorrhage)
  6. Pregnancy (an increased requirement in the third trimester of pregnancy)
  7. Diabetes insipidus.
  8. Diabetes mellitus type 1 and type 2, hypogonadism.
  9. Adrenal mass, adrenal hemorrhage.[15]
  10. Polyglandular autoimmune syndrome 1 and 2.

However, regardless of the etiology, the adrenal crisis is an acute complication of adrenal insufficiency. There are several causes of adrenal insufficiency, which can be broken down into primary, secondary, and tertiary. 

Primary causes can be simplified to include etiologies that affect the adrenal gland directly, most notably Addison disease, which can involve the autoimmune destruction of the adrenal gland. Other primary causes can include surgical removal, congenital adrenal disorders, bilateral adrenal hemorrhage, adrenomyeloneuropathy/adrenoleukodystrophy, and finally infections such as tuberculosis, systemic fungal infection, and acquired immunodeficiency syndrome (AIDS). In the setting of meningitis, Waterhouse-Friderichsen syndrome can precipitate adrenal crises. Adrenal insufficiency is also part of autoimmune polyglandular endocrinopathies types 1,2, and 4, so other endocrine diseases should be ruled out. 

Secondary causes of adrenal insufficiency are a disruption of cortisol regulation, usually from the compromise of the pituitary gland that produces adrenocorticotropic hormone (ACTH), which ultimately stimulates cortisol release from the adrenal gland. The most common cause is chronic exogenous glucocorticoid use. Other causes include pituitary tumors or metastasis, pituitary apoplexy, pituitary surgery, radiation, lymphocytic hypophysitis, head trauma, Sheehan syndrome in pregnancy, pituitary infiltrative disease, empty-sella syndrome, etc.

Tertiary causes refer to disruption of the hypothalamus, which in turn affects CRH and ACTH release. Notable causes are exogenous steroids and opiates.[16]


The exact frequency of adrenal crisis in the general population is difficult to estimate. In a study conducted by Hahner et al., the incidence rate of adrenal crisis is 6.3 per 100 patient-years.[8] The reported prevalence of adrenal insufficiency in Europe has been increasing over time. It was initially 39 cases/million in England in 1968; then the number increased to 60 cases/million in Denmark in 1974 then 93 cases/million in Coventry (UK) in 1992. The number of patients continued to increase to reach 110 cases/million in Nottingham (UK) in 1993, then 117 cases/million in Italy in 1996, and 144 cases/million in Norway in 2007. The highest prevalence was reported in Iceland in 2016, with 221 cases/million.[17] The remaining data from all over the world have been sparse. There have been reports of increased risk of adrenal crisis in the elderly (older than 60 years old) with no difference between males and females. Also, there were reports of an increased incidence in patients with thyroid or other endocrine disorders. Patients with autoimmune polyglandular endocrinopathy have a higher incidence of developing adrenal insufficiency (10.9 per 100 patient-years). In addition, in patients with type 1 diabetes, the incidence of adrenal insufficiency increases up to 12.5/100 patient years.[16] The prevalence of primary adrenal insufficiency is 40-100 cases per one million, and the incidence is 6 cases per million in the USA.[18]


The exact pathophysiology of an acute adrenal crisis formation is not fully understood. It is manifested when there is a mismatch between the need and the production of cortisol. Under stress, the stimulation of the hypothalamic-pituitary axis (HPA) leads to an increase in ACTH, which increases the cortisol level. However, some studies showed paradoxically low ACTH in the setting of stress.[19] The adrenal gland's primary function is to produce both mineralocorticoids and glucocorticoids. Other hormones are secreted by the adrenal glands, including catecholamines and precursors of sex hormones. The pituitary gland produces the adrenocorticotropin hormone (ACTH), and its primary function is to stimulate the cortisol release from the adrenal glands. Based on the underlying reason for insufficiency (primary versus secondary), there will be deficiencies in either mineralocorticoid (aldosterone) and glucocorticoids (cortisol) or simply a deficiency in glucocorticoids alone.[20] The primary function of aldosterone is sodium retention and potassium excretion. Cortisol promotes gluconeogenesis, increases sensitivity to catecholamines, and regulates the immune system. If a patient with primary insufficiency has an adrenal crisis, they may be found to be hyponatremic and hyperkalemic, in addition to having hypoglycemia and hypotension due to both aldosterone and cortisol deficiency, respectively. Patients with isolated cortisol deficiency may have hypoglycemia due to impaired gluconeogenesis and hypotension due to decreased sensitivity to catecholamines. Stressors that precipitate adrenal crisis also release inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and interleukin 1 and 6, which activate the HPA.[21]  Cortisol works to regulate these cytokines. One cytokine, TNF-alpha, can promote cortisol resistance. In the absence of cortisol in the case of adrenal insufficiency, the TNF-alpha release and sensitivity increase leading to further cortisol resistance that increases mortality in patients with adrenal crises despite appropriate treatment, especially when treatment or recognition is delayed. In healthy subjects, glucocorticoids enhance the synthesis of an enzyme that converts norepinephrine into epinephrine. In the case of adrenal insufficiency, the basal and stress-induced epinephrine release may be impaired and ultimately responsible for hypotension or hypoglycemia during crises.[22][23]


The histology of the adrenal gland will depend on the cause of the crisis and the precipitating factor. Usually, there is no histology available unless there is a need for adrenalectomy. The histological characteristics can be variable, including bilateral adrenal hemorrhage (hemorrhage, necrosis, fibrin deposition, neutrophilic infiltration of midline cortex with sparing of zona glomerulus), infiltrative disease like sarcoidosis (noncaseating granulomas composed of epithelioid cell with scattered Langhans giant cells and lymphocytes with the absence of necrosis or organisms), Tuberculosis of the adrenal gland (caseous necrosis and granulomatous inflammation with Langhans giant cells)[24], hemochromatosis, adrenocortical carcinoma, metastasis from kidney carcinoma, lung carcinoma, breast carcinoma, and melanoma or even rare adrenal lymphomas.[25]

History and Physical

In patients with known adrenal insufficiency, symptoms typical for the adrenal crisis should be sufficient to start treatment. History of prior steroid use of at least 5 mg of prednisone for seven days, associated infections, physiologic stressors, and other risk factors should be considered when analyzing and evaluating acute adrenal crisis. If the patient is medically unstable and the diagnosis is concerning for adrenal insufficiency or crisis, treatment with stress dose steroids should not be delayed.[26] A review of the patient's past medical history and past surgical history is mandatory. The clinicians should review the list of home medications.[27] Identifying the precipitating factors and confirming if there is any history of long-term steroid use is required as abrupt cessation or in the event of an acute process, adrenal crises can be precipitated in these patients.[28] Inquiring about other autoimmune diseases while obtaining history since a patient with autoimmune polyglandular endocrinopathy can present with multiple autoimmune diseases. Note that recurrent hypoglycemia can signify adrenal insufficiency in patients with type 1 diabetes on insulin. Patients with adrenal crisis usually present with an unexplained shock which is refractory to vasopressors and fluids.[29] Classical manifestations are weakness and fatigue (74 to 100%) and weight loss (78 to 100%) with decreased appetite. In children, weight loss with failure to thrive can be seen in 61 to 100% of cases, while other manifestations can be hypoglycemic crises with seizures. Additional manifestations such as anorexia, orthostatic hypotension, and tachycardia can be seen in 88 to 94% of patients, while skin and mucosal hyperpigmentation is found in 80 to 94%. The gastrointestinal manifestations can be either nausea, vomiting, and diarrhea, which occur in 75 to 86%, or recurrent abdominal pain, which occurs in 31% of the patients. Less common presentations are surgical emergency, amenorrhea, libido reduction, and depression which occur in less than 40% of the patients, and the least common presentation is salt-craving which is only seen in 9 to 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, or pituitary apoplexy, respectively.[30] Patients with pituitary apoplexy may present with a headache and bitemporal hemianopsia in addition to signs of adrenal crisis.[31]


There are multiple laboratory abnormalities 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 
  • Thyroid-stimulating hormone (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, clinicians may be able to use laboratory findings to distinguish between primary and secondary causes.[1] 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.[32] 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.[33] An ACTH stimulation test would confirm the diagnosis but should not be done in the acute setting.[34] 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.[35] 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 greater than 20 mg/dL (550 nmol/L) can exclude the diagnosis, while a low cortisol level of less than 5 mg/dl in the early morning in the setting of acute illness supports the diagnosis.[36] Other investigations for the underlying precipitating factors like infections, infiltrative disease, and 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 there is suspected bilateral adrenal hemorrhage, adrenal cancer, or in specific cases. Bilateral hyperdense lesions are characteristic of adrenal hemorrhage.[37]

Treatment / Management

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 to 3 days either as boluses every 6 hours or as continuous infusion until full recovery.[32] 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.[38] A thorough search should also be done for the cause, and empiric antibiotics should be considered. 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 followed by 100 mg IV every 6 to 8 hours.[39]
  2. Since dehydration and hypovolemia are common precipitating factors, rehydration of the patient with normal saline 0.9% is essential. That will also correct the hypovolemia and prerenal failure. 1-liter of 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 to 6 liters are needed in the first 24 hours).[38]
  3. Correction of hypoglycemia with intravenous dextrose with frequent monitoring of the blood glucose is essential. 
  4. Avoid rapid correction of hyponatremia of more than 6 to 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.[40]
  5. The assessment of the urine output is required.
  6. Contact the endocrinologist as soon as possible for further advice.
  7. Only taper steroids after there is a clinical improvement. The tapering should be gradual.[41]

Differential Diagnosis

Because 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.[25] However, there should be further investigation to determine the precipitating cause of the adrenal crisis, whether that is sepsis, septic shock, circulatory shock, myxedema coma, 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 otherwise appropriate management, the diagnosis of adrenal crisis should be considered and adequately ruled out.[4]


Adrenal crisis is not a common disease, but it has a high mortality.[2] 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 crisis.[25] Prompt recognition and treatment of both the underlying condition and adrenal crisis may lead to clinical improvement, but in many cases, mortality remains high.[33] 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 were associated with increased mortality. Data from the European Adrenal Insufficiency Registry found the major causes of death in patients with adrenal insufficiency were cardiovascular disease (35%) and infection (15%).[42]


Even with proper recognition and treatment, the adrenal crisis may result in death.[2] Other complications may include seizures, arrhythmias, coma, etc., due to electrolyte abnormalities such as hyponatremia, hyperkalemia, and hypoglycemia.[25] Hypotension may lead to hypoperfusion as well as multi-organ failure. Additionally, many other complications may arise related to the precipitating disease or event.[38]


A critical care evaluation and consultation are needed in these patients as many of them will present with hypotension, altered mental status, and cardiovascular collapse. The severity of their presentation 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 help confirm the diagnosis and to tailor the proper administration of corticosteroids further, as well as to manage any underlying endocrine disorders in the longterm both as inpatient and outpatient.

Deterrence and Patient Education

More than 50% of patients with adrenal crisis do not have a prior diagnosis of adrenal insufficiency. Education regarding the diagnosis and the stress dose steroids is a crucial part of the management of adrenal crisis.[25] The patients should receive the following education:

  • Sick days rule includes doubling or tripling the daily oral dose during minor illnesses.
  • 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 a medical alert bracelet or necklace.[41]
  • The patient should have additional supplies at home in case it is needed.[39]
  • 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).[25]
  • Patients undergoing elective surgeries should have a stress dose of hydrocortisone 100 mg IV prior to induction of anesthesia. They may also require stress-dose steroids during or after the operation, depending on the nature, severity and length of surgery.[43]

Pearls and Other Issues

An adrenal crisis should be suspected in patients presenting with an acute shock 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.

Enhancing Healthcare Team Outcomes

Given that adrenal crises affect many organs and have a high mortality rate, the disorder should be managed by an interprofessional team inside the ICU. This team should include an intensivist, an 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.  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.[41] The patients and their 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 clinician and the pharmacist. Finally, all patients should be encouraged to wear a medical alert bracelet indicating the disorder.[44] [Level 5]


Despite steroid 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.[45] In addition, if the cause is due to secondary adrenal insufficiency, it 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] [Level 5]

Article Details

Article Author

Ghada Elshimy

Article Author

Venu Chippa

Article Editor:

Jordan M. Jeong


5/5/2022 4:38:09 PM

PubMed Link:

Adrenal Crisis



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