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Addisonian Crisis

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Last Update: March 7, 2019.

Introduction

Addisonian crisis, or adrenal crisis, is a potentially life-threatening condition that results from an acute insufficiency of adrenal hormones (glucocorticoid or mineralocorticoid) and requires immediate treatment[1]. It is important to differentiate an Addisonian crisis from Addison Disease which has a more gradual course. An illness or acute stress can precipitate adrenal crisis in the setting of Addison's disease[2]. Addison's Disease is a condition in which the adrenal glands do not produce enough steroid hormones and occurs over several months.

Etiology

An Addisonian crisis results from an acute lack of glucocorticoids or mineralocorticoids. This condition most often occurs in a patient with known adrenal insufficiency, either primary or secondary. Primary adrenal insufficiency (Addison Disease) results in decreased cortisol as well as aldosterone. Some causes of primary adrenal insufficiency include autoimmune causes, adrenal hemorrhage, medications, infection, congenital adrenal hyperplasia. Secondary adrenal insufficiency is caused by decreased ACTH by the pituitary gland. Causes of secondary adrenal insufficiency include cessation of steroid therapy, pituitary disease, head trauma, postpartum pituitary necrosis, and infiltrative disorders of the pituitary or hypothalamus. An Addisonian crisis may develop when adrenal insufficiency goes untreated or the patient experiences stress such as from infection, surgery, trauma, myocardial infarction, dehydration, exposure to cold, burns, or overexertion[3]. An Addisonian crisis can occur in patients with previously normal adrenal functions in situations that result in adrenal or pituitary injury or when suddenly stopping long-term steroid treatment without tapering.

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][2][4]. 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[2][5]. Patients with primary adrenal insufficiency were slightly more likely than those with secondary adrenal insufficiency to have a crisis[6]. The most frequent triggers of adrenal crisis are infectious causes[2][4]. 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%[7][8].

Pathophysiology

Adrenal corticosteroids aid the body's ability to retain sodium, excrete potassium and handle stress[9]. Deficient levels 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. Circulatory collapse impairs urinary excretion of waste products, causing elevated levels of blood urea nitrogen and creatinine.

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[9]. Cortisol is the primary hormone involved in the human stress response and has multiple effects throughout the body. It helps regulate the supply of glucose in the body by triggering gluconeogenesis or stimulating glycogen synthesis in the liver. It affects pH by regulating sodium and potassium levels. It weakens the immune response by preventing T-cell proliferation and preventing T-cells from recognizing interleukin signals[10]. Additionally, excess cortisol may cause atrophy of the hippocampus, leading to memory loss.

History and Physical

It is important to determine if the patient has a history of adrenal insufficiency. If the patient is on chronic steroids, it is important to know whether the patient has been compliant or not. Other useful elements of the history include any recent illnesses, surgeries, traumatic injuries or other stressors.

The salient feature of patients in acute adrenal crisis is circulatory collapse[6]. They might have symptoms like nausea, vomiting, fever and lower chest/ abdominal pain along with the low blood pressure[1][2][6]. They may appear cyanotic due to shock. Sometimes the patients are confused, delirious, or lethargic. Abdominal symptoms may take on features of an acute abdomen[11]. Patients may have hyperpyrexia, with temperatures reaching 105 F or higher, and may be comatose. In acute adrenal hemorrhage, the patient can deteriorate with sudden collapse, abdominal or flank pain, and nausea with or without hyperpyrexia[12]

Evaluation

It is important to keep an Addisonian crisis on the differential in cases of shock, especailly since adrenal crisis can be the patient's first presentation of adrenal insufficiency.

Initial laboratory testing should include serum chemistry (particularly sodium, potassium, glucose, and calcium), blood count, cortisol level, adrenocorticotropic hormone (ACTH), aldosterone, renin, and thyroid function[11]. The serum chemistry is used to guide initial therapy. Patients often have hypoglycemia, hyponatremia, hyperkalemia, and hypercalcemia. Although a reliable diagnosis of underlying adrenal insufficiency is not possible during the adrenal crisis, measurement of blood ACTH and cortisol during the crisis (before treatment with corticosteroids is given) is often enough to make a preliminary diagnosis. Once the crisis is controlled, an ACTH stimulation test can be performed to help make a specific diagnosis[11]. More complex lab tests are sometimes used if the diagnosis remains unclear.

An EKG may show peaked T waves from hyperkalemia or short QT interval from hypercalcemia[13]. A chest radiograph, urine studies and blood cultures should be ordered to evaluate 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. 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[14]. The dextrose-containing solution should be used in the setting of hypoglycemia. Volume status and urine output should be used to guide the resuscitation. Dexamethasone (4 mg IV bolus) or hydrocortisone (100 mg IV bolus) can be used In patients with known adrenal insufficiency presenting in crisis[9][11]. 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[9]. If the patient does not have known adrenal insufficiency, an ACTH stimulation test should be performed. It can then be followed by testing to determine the cause of the adrenal insufficiency. After initial stabilization of the patient using the above measures, the underlying cause of the crisis should be identified and treated[11].

Differential Diagnosis

  1. Septic shock
  2. Distributive shock due to inflammation (acute pancreatitis, burns, etc)
  3. Cardiogenic shock
  4. Hypovolemic shock (hemorrhagic versus nonhemorrhagic)
  5. Obstructive shock (pulmonary embolus, cardiac tamponade, etc)

Enhancing Healthcare Team Outcomes

The diagnosis and management of addisonian crises requires a multidisciplinary team; any delay in diagnosis can lead to a very high mortality. The endocrinologist, internist intensivist, and nephrologist should play an active role in the management. After initial stabilization of the patient using the above measures, the underlying cause of the crisis should be identified and treated[11]. 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 recurrence. Untreated cases have a mortality in excess of 90%.[15]

Questions

To access free multiple choice questions on this topic, click here.

References

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White K, Arlt W. Adrenal crisis in treated Addison's disease: a predictable but under-managed event. Eur. J. Endocrinol. 2010 Jan;162(1):115-20. [PubMed: 19776201]
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Hahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, Ventz M, Quinkler M, Allolio B. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur. J. Endocrinol. 2010 Mar;162(3):597-602. [PubMed: 19955259]
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Koo DJ, Jackman D, Chaudry IH, Wang P. Adrenal insufficiency during the late stage of polymicrobial sepsis. Crit. Care Med. 2001 Mar;29(3):618-22. [PubMed: 11373430]
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Vella A, Nippoldt TB, Morris JC. Adrenal hemorrhage: a 25-year experience at the Mayo Clinic. Mayo Clin. Proc. 2001 Feb;76(2):161-8. [PubMed: 11213304]
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Allolio B. Extensive expertise in endocrinology. Adrenal crisis. Eur. J. Endocrinol. 2015 Mar;172(3):R115-24. [PubMed: 25288693]
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Puar TH, Stikkelbroeck NM, Smans LC, Zelissen PM, Hermus AR. Adrenal Crisis: Still a Deadly Event in the 21st Century. Am. J. Med. 2016 Mar;129(3):339.e1-9. [PubMed: 26363354]
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Soni A, Pepper GM, Wyrwinski PM, Ramirez NE, Simon R, Pina T, Gruenspan H, Vaca CE. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am. J. Med. 1995 Mar;98(3):266-71. [PubMed: 7872343]
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Smans LC, Van der Valk ES, Hermus AR, Zelissen PM. Incidence of adrenal crisis in patients with adrenal insufficiency. Clin. Endocrinol. (Oxf). 2016 Jan;84(1):17-22. [PubMed: 26208266]
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Maqbool M, Shah ZA, Wani FA, Wahid A, Parveen S, Nazir A. Prevalence of occult adrenal insufficiency and the prognostic value of a short corticotropin stimulation test in patients with septic shock. Indian J Crit Care Med. 2009 Apr-Jun;13(2):85-91. [PMC free article: PMC2772244] [PubMed: 19881189]
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Gupta P, Bhatia V. Corticosteroid physiology and principles of therapy. Indian J Pediatr. 2008 Oct;75(10):1039-44. [PubMed: 19023528]
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Sherlock M, Gittoes NJ, Arlt W. Adrenal crisis causing critical illness related reversible myocardial dysfunction. Clin. Endocrinol. (Oxf). 2008 Apr;68(4):667-9. [PubMed: 17941905]
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Barber AE, Coyle SM, Marano MA, Fischer E, Calvano SE, Fong Y, Moldawer LL, Lowry SF. Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J. Immunol. 1993 Mar 01;150(5):1999-2006. [PubMed: 8436830]
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Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2016 Feb;101(2):364-89. [PMC free article: PMC4880116] [PubMed: 26760044]
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Bouillon R. Acute adrenal insufficiency. Endocrinol. Metab. Clin. North Am. 2006 Dec;35(4):767-75, ix. [PubMed: 17127145]
15.
Mulder AH, Nauta S, Pieters GF, Hermus AR. [Addisonian crisis in patients with known adrenal insufficiency: the importance of early intervention]. Ned Tijdschr Geneeskd. 2008 Jul 05;152(27):1497-500. [PubMed: 18681356]
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Bookshelf ID: NBK441933PMID: 28722962

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