Adrenal crisis, also termed acute adrenal insufficiency is an acute life-threatening condition with a mortality rate of 0.5/100 patients/year. It is considered one of the endocrine emergency precipitated by an internal or external process in the setting of known or unknown lack of production of the adrenal hormone cortisol, the major glucocorticoid. Early identification and prompt management can save the patient's life and impact survival. The clinicians should be able to 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.
In 1855, Thomas Addison described the first case of adrenal insufficiency. Tuberculosis was the most common cause (70%) during the 1930s. In 1856, Trousseau termed the adrenal insufficiency as “bronze Addison’s disease” which later has become known widely as Addison’s 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. There are multiple precipitating factors including:
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, tertiary as well as glucocorticoid-induced. While the most common cause of the adrenal crisis is a sudden withdrawal of long-term corticosteroid therapy (usually more than 5 mg prednisone and greater than 4 weeks), there are many other clinically important and often missed etiologies that can lead to significant mortality.
Primary causes can be simplified to include etiologies that affect the adrenal gland directly, most notably Addison's 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 infections as tuberculosis, systemic fungal infection, and AIDS. In the setting of meningitis, Waterhouse-Friderichsen Syndrome can precipitate adrenal crises. Adrenal insufficiency is also part of autoimmune polyglandular endocrinopathy type 1,2 and 4 so other endocrine diseases should be ruled out.
Secondary causes of adrenal insufficiency are due to a disruption of the regulation of cortisol usually from the compromise of the pituitary gland which produces ACTH, which stimulates cortisol release from the adrenal gland. The most common cause is chronic exogenous glucocorticoid use. Other causes include pituitary tumors/metastasis, pituitary apoplexy, pituitary surgery, radiation, lymphocytic hypophysitis, head trauma, Sheehan syndrome in pregnancy, pituitary infiltrative disease, Empty-Sella syndrome, etc.
The exact frequency of adrenal crisis in the general population is difficult to estimate. The estimated incidence in Europe range from 4.4 to 6.2 new cases/million/year in different studies. The reported prevalence in Europe has been increasing over time. It was initially 39 cases/million in England in 1968 then the number increased to 60 in Denmark in 1974 then 93 in Coventry (UK) in 1992. The number of cases continued to increase to reach 110 cases/million in Nottingham (UK) in 1993 then 117 in Italy in 1996 and lastly 144 in Norway in 2007. The highest prevalence has been reported in Iceland in 2016, with 221 cases/million. Remaining data from all over the world have been sparse. Most of the studies estimated the risk of an adrenal crisis occurring in a patient with adrenal insufficiency to be about 6-10 cases per 100 patient-years (PY). 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 to develop adrenal insufficiency (10.9/100 patient/year). In addition, patients with type 1 diabetes, the incidence of adrenal insufficiency increases up to 12.5/100 patients/year.
The pathophysiology of adrenal crisis formation is not fully understood. It is considered as a mismatch between the need and the use of cortisol. Elevated cortisol level during stress due to the stimulation of the hypothalamic-pituitary axis (HPA) leading to an increase in ACTH which therefore increases the cortisol level. However, some studies showed paradoxically low ACTH in the setting of stress.
The adrenal gland's main function is to produce both mineralocorticoids and glucocorticoids. There are other hormones secreted by the adrenal glands including catecholamines and precursors of sex hormones. The adrenocorticotropin hormone (ACTH) is produced by the pituitary gland and its main function is to stimulate the cortisol release from the adrenal glands. Based on the underlying reason for insufficiency (primary vs. secondary) there will be deficiencies in either both mineralocorticoids (aldosterone) and glucocorticoids (cortisol) or simply a deficiency in glucocorticoids alone. The main function of aldosterone is sodium retention and potassium secretion. The 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 only hypoglycemia due to impaired gluconeogenesis and hypotension due to decreased sensitivity to catecholamines. This is why hypotension is often refractory to vasopressors. Stressors that precipitate adrenal crisis also release inflammatory cytokines including Tumor necrosis factor (TNF)-alpha, interleukin 1 and 6 which activate HPA. 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 which increases the 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 be responsible for hypotension or hypoglycemia during crisis situations. 
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, infiltrative disease like sarcoidosis, hemochromatosis, adrenocortical carcinoma, metastasis from kidney carcinoma, lung carcinoma, breast carcinoma, and melanoma or even adrenal lymphomas.
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.
There are multiple laboratory abnormalities are expected in the setting of adrenal crisis. The Classic laboratory features may reveal:
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. 
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
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.
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%). 
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.
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:
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. (Level V)
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. (Level V)
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