Continuing Education Activity

Adrenal crisis is an acute life-threatening condition precipitated by internal or external processes 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 the adrenal crisis, and highlights the role of the interprofessional team in treating patients with this condition.

Objectives:

• Review the etiology of adrenal crisis.
• Outline the critical 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.

Introduction

Adrenal crisis (also known as Addisonian 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 the hospital. It is an endocrine emergency precipitated by an internal or external process in the setting of a 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 increased 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].

There is no consensus regarding the definition of an adrenal crisis. Multiple expert reviews have tried to formulate their definitions of adrenal crisis. Here we will be using the definition suggested by Rushworth, et al 2019:

• "An acute deterioration in health status associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure ≥20 mm Hg lower than usual), with features that resolve within 1 to 2 hours after parenteral glucocorticoid administration (i.e., a marked resolution of hypotension within 1 hour and improvement in clinical symptoms over a period of 2 hours)".[5]

Etiology

In 1855, Thomas Addison described the first case of adrenal insufficiency [6]. With the discovery of cortisone by Hench, Kendall, and Reichstein in the late 1940s, the life expectancy of patients with adrenal insufficiency dramatically improved [7][8]. Tuberculosis was the most common cause (70%) during the 1930s. Currently, autoimmune adrenalitis (Addison's disease) 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 [9].

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 [10][11][12]. About 10% of the patients were not found to have any identifiable cause in a previous study [13]. The main causes include:

• Infections- bacterial, viral (including COVID-19), mycobacteria, fungal, or parasitic [13][14]
  • Gastrointestinal illness and flu-like illnesses are the most commonly observed precipitating factors for adrenal crisis [15][5]
• Stressful situations-trauma, pregnancy, parturition, surgery, extreme hot and cold weather
• Significant emotional distress [13]
• Strenuous physical activity [16]
• Non-adherence to glucocorticoid replacement therapy [17]
• Abrupt cessation of chronic glucocorticoid therapy [17]
• Thyrotoxicosis (as it increases cortisol metabolism) or initiation of levothyroxine therapy in a previously untreated case of adrenal insufficiency
• Medications:
  • Antiadrenal medications, mitotane, metyrapone, ketoconazole
  • Anticancer medications: Immunotherapy with checkpoint inhibitors [18][19], tyrosine kinase inhibitors [20][21] 

Epidemiology

The exact frequency of adrenal crisis in the general population is difficult to estimate. Patients with adrenal insufficiency have been estimated to have an episode of adrenal crisis in 6-8% cases annually [15][22]. The incidence continues to be high in patients who have undergone rigorous education regarding adrenal insufficiency management and prevention [13]. This educated group of educated patients had a 6% mortality rate with adrenal crisis in this study [13]. The frequency of adrenal crisis in patients with Addison's disease continues to be 8% annually [23].

Risk Factors for Adrenal Crisis

1. Known history of adrenal insufficiency or previous history of adrenal crisis
2. Diagnosis of primary adrenal insufficiency is associated with a higher risk of adrenal crisis compared to secondary adrenal insufficiency [10][24][10]
3. Ongoing glucocorticoid therapy including topical and inhalation - suppresses HPA axis (sudden withdrawal can trigger adrenal crisis)
4. Levothyroxine, phenytoin, phenobarbital, rifampin, carbamazepine, St. John's Wart (increases cortisol metabolism) [25][26][27][26]
5. Ketoconazole, etomidate, fluconazole (reduces intrinsic production of cortisol) [28]
6. Anticoagulation agents (increased risk of adrenal hemorrhage)
7. Other medications: megestrol acetate, medroxyprogesterone [29][30][31][30]
8. Pregnancy (an increased requirement in the third trimester of pregnancy) [32]
9. Older age [5]
10. Existence of co-morbidities [10][24][10]
11. Diabetes mellitus type 1 [5] 
12. Adrenal metastasis [33], adrenal hemorrhage [34]
13. Polyglandular autoimmune syndrome 1 and 2 [35][36]

Pathophysiology

A clear understanding of the pathophysiology of the adrenal crisis remains to be fully elucidated. A partial understanding of the clinical manifestations can be obtained by understanding the functions of glucocorticoids. Glucocorticoids (GC) have permissive, suppressive, stimulatory, and preparative effects in response to stress. These functions have been described in greater detail in an earlier review [37].

Cardiovascular System

• GCs have a permissive effect on the adrenergic receptors in the heart and the vascular. Catecholamines are unable to exert a full effect on these receptors in the absence of GCs [38]. Hence in an adrenal crisis, the patients experience hypotension or in worse cases experience profound fluid- and vasopressor-unresponsive shock.

Immune System

• Infectious or non-infectious stressors are known to lead to the activation of the immune system. There is an increase in cytokine release. Interleukin (IL) 1, IL-2, IL-6, tumor necrosis factor (TNF)-α and TNF-γ then lead to the activation of the hypothalamic-pituitary axis (HPA) with an increase in GC levels [39][40]. GC will in turn dampen this immune response by inhibiting the production, release, and effects of the cytokines, playing an important role in the regulation of immune response [41][42]. In an adrenal crisis, any major stressor can lead to an unchecked cytokine response (inflammation) leading to fever, widespread vasodilatation, and capillary leak leading to hypovolemia and shock.

Intravascular Volume

• GCs suppress the expression of anti-diuretic hormone (ADH) in the hypothalamic neurons [43][44]. GCs also suppress the secretion of ADH. In adrenal crisis, there is an increase in the action of ADH leading to increased diuresis and volume depletion.

Glucose Homeostasis

• In response to stress, GCs lead to increased glucose levels by increasing glycogenolysis and gluconeogenesis [45]. GCs also increase insulin resistance, thereby decreasing the uptake of glucose by the peripheral cells [45]. In adrenal crisis, hypoglycemia develops to the lack of these responses in the GC-deficient state.

Regulation of Appetite:

• Corticotropin-releasing hormone (CRH) is known to be a potent appetite suppressant in response to stress [46]. GCs are a powerful inhibitor of CRH release, leading to increased appetite [43]. In adrenal crisis, the release of CRH remains uninhibited in the GC-deficient state leading to the development of anorexia.

Electrolyte Disturbances

• Mineralocorticoid deficiency is seen in primary adrenal insufficiency due to the direct destruction of the adrenal cortex. The cortex remains preserved in secondary and tertiary adrenal insufficiency. Aldosterone production and secretion are regulated by renin-angiotensin-aldosterone system [47]. An isolated deficiency in ACTH secretion seen in secondary or tertiary adrenal insufficiency does not significantly affect the aldosterone levels [48][47]. Aldosterone deficiency leads to volume loss, loss of sodium (leading to hyponatremia), and potassium retention (leading to hyperkalemia) [12]. 

History and Physical

The most common clinical manifestations of adrenal crisis include: weakness, severe fatigue, unintentional weight loss, nausea, vomiting, abdominal pain, decreased appetite, back or limb pain, dizziness, somnolence, confusion, and loss of consciousness [5][49]. In children, weight loss with failure to thrive can be seen frequently, while other manifestations can include hypoglycemic crises with seizures. Less common presentations include surgical emergency as acute abdomen, salt-craving, amenorrhea, loss of libido, and depression. 

On the assessment of vitals, these patients can have fever, tachycardia, and hypotension (including orthostatic) [49]. On physical examination, they can look ill-appearing. Patients with primary adrenal insufficiency can have hyperpigmentation of skin, buccal mucosa, and/or scars [50].

A review of the patient's past medical history and past surgical history is mandatory. The clinicians should review the list of home medications and supplements.[51] 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.[52] 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.[53] 

Evaluation

 There are multiple laboratory abnormalities seen 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 hypovolemia)
• Prerenal failure with elevated creatinine level
• Low aldosterone (due to mineralocorticoid deficiency in primary adrenal insufficiency)
• 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 (due to glucocorticoid deficiency)
• Thyroid-stimulating hormone (TSH) levels may be increased (due to coexisting hypothyroidism in autoimmune polyglandular endocrinopathy or due to the lack of the inhibitory effect of cortisol on TSH production)

Evaluation of Cortisol Levels

Treatment of adrenal crisis should never be delayed to obtain blood work for assessment of etiology. If no delay in treatment is expected, then blood work can be quickly obtained prior to the administration of hydrocortisone. Blood work to be obtained: ACTH, cortisol, aldosterone, renin, basic metabolic profile including glucose.

• High ACTH with low cortisol and aldosterone levels will be seen in primary adrenal insufficiency
• Low ACTH and low cortisol levels will be seen in secondary or tertiary adrenal insufficiency

In case there is doubt regarding the diagnosis of adrenal crisis with borderline cortisol levels, an ACTH stimulation test should not be done in the acute setting until the patient's condition has stabilized [54].

Treatment / Management

The definitive treatment of adrenal crisis is the administration of glucocorticoids, specifically hydrocortisone. In patients with known adrenal insufficiency, symptoms typical for the adrenal crisis should be sufficient to start treatment.  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.[55]

Guidelines for Managing Adrenal Crisis During an Emergency

• Continuous infusion has been shown to be a better delivery method for hydrocortisone in adrenal crisis compared to intermittent boluses [57]. Continuous infusion of hydrocortisone was able to maintain cortisol levels in the required range better than intermittent boluses.
• Involve an endocrinologist as soon as possible in the patient's care.
• Gradually taper steroids after there is a clinical improvement [58]
• If the dose of glucocorticoids being administered exceeds 50 mg, mineralocorticoid replacement is not necessary [59].
• In case hydrocortisone is unavailable, another parenteral glucocorticoid can be used [5][27][5]:
  • Prednisolone (Preferred alternative) 25 mg given as a bolus. The patient should then receive another two 25-mg doses in the first 24 hours. This should be followed by prednisone 50 mg every 24 hours.
  • Methylprednisolone 40 mg every 24 hours
  • Dexamethasone (least preferred alternative) 4 mg every 24 hours
• Prompt administration of antibiotics is necessary in patients in whom an infectious process was the precipitating event for adrenal crisis.

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, and 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 considered the most important differential [60]. 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 has hypotension that is refractory to fluid administration and vasopressor support, the diagnosis of adrenal crisis should be strongly considered [4].

Prognosis

Adrenal crisis is an uncommon diagnosis. Despite being easily treatable with the prompt administration of glucocorticoids, the high mortality rate remains unacceptably high. Most health professionals will rarely encounter such a patient and may not be familiar with the presentation or management. A retrospective study from the Uunited Kingdom demonstrated that adrenal crisis contributed to 10% of the deaths in patients with primary and secondary adrenal insufficiency [61]. 

Complications

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 [60]. Hypotension may lead to hypoperfusion as well as multi-organ failure. Additionally, many other complications may arise related to the precipitating disease or event [50].

Consultations

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 emergent 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 long-term both as an 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.[60] The patients should receive the following education:

Strategies for Prevention

• Discussion of sick days rule includes doubling or tripling the daily oral dose during acute illness (to mimic the physiologic response of increased cortisol levels under stressful situations) [17]:
  • If fever >38 C: doubling the dose of oral corticosteroids is recommended.
  • If fever >39 C: tripling the dose of oral corticosteroids is recommended.
• In case of significant emotional stress (e.g. death of a loved one, major upcoming examination): an additional dose of 10 mg hydrocortisone is recommended [17].
• Stress dose is needed during stressful situations, including trauma, surgery, major procedures, and severe illness (see Table below).
• The patient should be aware of signs and symptoms of adrenal insufficiency: nausea, vomiting, abdominal pain, unintentional weight loss, dizziness, confusion, low blood glucose, fever, loss of sense of well-being, etc.
• The importance of wearing a medical alert bracelet or necklace [58][27]
• The patient should have additional emergency supplies at home in case it is needed [62]
  • An emergency kit should be available in case it is needed when oral doses cannot be taken: significant nausea and vomiting, diarrhea, or loss of consciousness:
    • 100 mg hydrocortisone sodium succinate for injection or dexamethasone 4 mg, along with vials of sterile 0.9 percent normal saline and syringes
• The patient should carry a steroid card outlining what to do in an emergency in case they go to a hospital where the providers might be aware of the management of adrenal crisis.
  • This card to mention the dosing for glucocorticoid administration: 100 mg hydrocortisone IV/IM followed by 200 mg over the next 24 hours given IM/IV (50 mg every 6 hours)
• Regular follow-ups with an endocrinologist with the discussion of stress dosing in each visit
  • Frequency of follow-up:
    • Adults: yearly
    • Children: every 3-6 months

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 comorbities and 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.

Enhancing Healthcare Team Outcomes

Since 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 and an endocrinologist. Other important members of the team include an ICU nurse and a pharmacist. ICU nurses must monitor vitals, urine output, and hemodynamics continuously. The education of the patients about the disease and its potential complications along with discussion about sick day rules is of significant importance in the prevention of adrenal crisis [58]. The patients and their families 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 [65]. [Level 5]

Outcomes

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 [66]. Adrenal crisis continues to have an unacceptably high mortality rate. The cause of the mortality remains unclear in some cases, but it is most likely due to respiratory infections, adverse cardiovascular events, and stroke [1]. [Level 5]

Despite rigorous patient education, the incidence of adrenal crisis-related mortality remained as high as 6% in a study of 423 participants [13].

Patient satisfaction with the management of adrenal crisis in the emergency setting as been reported to be has low as 66% in a previous study [67].