Adrenal Crisis

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168 Adrenal Crisis

Brian K. Nelson

• Adrenal crisis is an uncommon cause of shock.

• An inappropriate adrenal response may contribute to shock in patients with sepsis, trauma, myocardial infarction, and other conditions associated with extreme physiologic stress.

• The diagnosis of acute adrenal crisis may be challenging because the symptoms are often nonspecific (e.g., weakness, fatigue, gastrointestinal symptoms, abdominal, flank, or back pain).

• Laboratory findings include hyponatremia, hyperkalemia, hypoglycemia, lymphocytosis, and eosinophilia.

• Adrenal crisis may result from either primary adrenal insufficiency or secondary adrenal suppression as a result of exogenous steroids or from failure of the hypothalamic-pituitary-adrenal axis. In the latter, mineralocorticoid replacement is not necessary, but thyroid supplementation may be lifesaving.

• Emergency department management includes aggressive fluid resuscitation, correction of electrolyte abnormalities, maintenance of euglycemia, and administration of glucocorticoids and mineralocorticoids.

• Treatment should begin with initial suspicion of adrenal crisis, not at the time of laboratory confirmation. Interventions are indicated when the cause of the shock is obscure, the patient fails to respond to volume and pressors within 1 hour, or the diagnosis of adrenal insufficiency is confirmed.

Epidemiology

Most cases of primary adrenal insufficiency are autoimmune mediated, but other common causes include infection and hemorrhage. Onset is generally indolent, although acute adrenal crisis accounts for approximately 25% of all cases. Primary adrenal insufficiency has an estimated incidence of 50 per 1 million persons. Secondary insufficiency as a result of chronic glucocorticoid administration is more common than primary insufficiency in the United States; 2% of the population is estimated to have relative insufficiency that becomes manifested only at times of physiologic stress.¹

Pathophysiology

Adrenal insufficiency is an uncommon disease with nonspecific manifestations, including fatigue, nausea, vomiting, hyperpigmentation, hypotension, and weight loss. Failure to recognize and treat the often subtle signs and symptoms of adrenal crisis can result in significant morbidity and mortality.

Acute adrenal crisis may complicate a variety of conditions that are related to an inadequate neuroendocrine response to stress. Crisis may result from primary adrenal failure or may occur secondary to failure of the hypothalamic-pituitary-adrenal axis. Failure may result from a primary process or may be secondary to suppression by exogenous steroid administration.

Anatomy

The adrenal glands are retroperitoneal structures that lie within the fascia of Gerota, superior and medial to the kidneys. Their blood supply arises from the aorta and the renal and inferior phrenic arteries. Blood flows from the arteries through a sinusoidal system and collects in single veins draining into either the inferior vena cava or the left renal vein for the right and left adrenals, respectively. The adrenal glands are encapsulated and divided into a cortex and a catecholamine-producing medullary zone. The cortex is further subdivided into the zona glomerulosa, which produces mineralocorticoids, and the zona fasciculata and zona reticularis, which secrete glucocorticoids and androgens.

Adrenal Products

Cholesterol is converted to pregnenolone, an adrenal precursor of more than 50 separate chemical pathways and by-products. Of these, the most clinically important glucocorticoid is cortisol, the most important androgen is dehydroepiandrosterone acetate, and the most important mineralocorticoid is aldosterone.

Feedback Loops

Adrenocorticotropic hormone (ACTH) is the major regulator of cortisol and adrenal androgen production. ACTH is regulated by corticotropin-releasing hormone and antidiuretic hormone. Cortisol levels feed back on corticotropin-releasing hormone production. The renin-angiotensin system regulates aldosterone production.

Cortisol Physiology

ACTH and cortisol levels vary by circadian rhythm. They both reach their nadir at about 4 AM and peak at approximately 8 AM. Serum levels also peak within minutes of stress-induced release of corticotropin-releasing hormone in the central nervous system. Most circulating cortisol is bound to protein (75% to corticosteroid-binding globulin and 15% to albumin); only 10% is “free cortisol” (unbound).

Targets of Action

Mineralocorticoids act at the renal tubules to maintain Na⁺, K⁺, and water balance. Glucocorticoid subunits enter various cell nuclei and modify the expression of a wide range of genes in different organ systems (Table 168.1). Cortisol is capable of targeting the mineralocorticoid receptors at pharmacologic doses, although at physiologic levels it is converted to inactive cortisone on entering the kidney.

Table 168.1 Actions of Glucocorticoids

FUNCTION/TARGET SYSTEM	ACTION
Metabolism	Stimulate gluconeogenesis Promote lipolysis Induce muscle protein catabolism Increase plasma glucose during stress

Endocrine

Inhibit insulin secretion, promote peripheral insulin resistance

Increase epinephrine synthesis

Inflammatory

Cause demargination of granulocytes, suppress adhesion

Reduce circulating eosinophils and lymphocytes

Decrease production of inflammatory cytokines

Cardiovascular

Increase contractility and the vascular response to vasoconstrictors

Renal

Increase the glomerular filtration rate; pharmacologic doses act at mineralocorticoid receptors

Clinical Application

Adrenal insufficiency is classified as primary, secondary, or relative. Causes of primary insufficiency are numerous (Table 168.2). Secondary insufficiency is most commonly due to exogenous steroid withdrawal. Relative adrenal insufficiency occurs in individuals who may have normal glucocorticoid levels but exhibit an inadequate response of the hypothalamic-pituitary-adrenal axis to major stress.

Table 168.2 Causes of Primary Adrenal Insufficiency

CAUSE	ASSOCIATED FACTORS
Autoimmune adrenal atrophy (80% of cases)
Associated endocrinopathies	Hypoparathyroidism, hepatitis, type 1 diabetes mellitus, hypogonadism, hypothyroidism
Infections	Disseminated tuberculosis, cytomegalovirus, histoplasmosis, human immunodeficiency virus, candidiasis
Genetic diseases	Congenital adrenal hyperplasia, adrenoleukodystrophy, familial glucocorticoid deficiency
Metastatic malignancy or lymphoma
Adrenal hemorrhage
Infiltrative disorders	Amyloidosis, hemochromatosis
Drugs	Ketoconazole, suramin

Relative adrenal insufficiency is one of the most important subtypes of adrenal insufficiency encountered in emergency medicine. It should be considered in any seriously ill patient who fails to respond to the usual interventions. This condition is most commonly observed in patients with severe sepsis, but it may develop in any patient with uncompensated shock that is resistant to adequate fluid resuscitation and vasopressors.

Presenting Signs and Symptoms

Patients with primary and secondary adrenal insufficiency typically have chronic complaints. Those with primary disease may exhibit weakness, fatigue, anorexia, nausea, vomiting, weight loss, hypotension, hyperpigmentation, hyponatremia, and hyperkalemia. The hyperpigmentation is initially generalized and later becomes evident in the mucous membranes, palmar creases, nail beds, and nipples. Gastrointestinal disturbances are present in about half of patients with postural symptoms. Salt craving is a less common complaint. Associated endocrinopathies may complicate the initial findings (see Table 168.2).

Patients with secondary adrenal insufficiency typically have normal mineralocorticoid levels and therefore less serious volume or electrolyte abnormalities. The chronic findings of secondary adrenal insufficiency are classically nonspecific in nature and consist of weakness, lethargy, anorexia, and myalgias. Hyperpigmentation is not a feature of secondary adrenal insufficiency.

Types of Adrenal Insufficiency

Acute Adrenal Insufficiency

Although most patients with subacute or chronic adrenal insufficiency are identified during outpatient evaluation, some patients in whom it has not yet been diagnosed will be encountered in the emergency department (ED) with acute insufficiency. Such patients may have either primary or secondary insufficiency and seek care because of physiologic stress that cannot be met with appropriate rises in adrenal hormones. The majority of these patients will exhibit shock, nausea, vomiting, confusion, fever, and abdominal pain.

Acute Adrenal Hemorrhage

Acute adrenal hemorrhage is a rare condition that should be suspected in seriously ill postoperative patients and in those with antiphospholipid syndrome, severe sepsis, or shock. Such patients have the general features of acute adrenal crisis and focal findings of abdominal, flank, or back tenderness. Abdominal examination may reveal a surgical abdomen.

Treatment should begin on suspicion of this diagnosis. Early intervention has been shown to reduce mortality in postoperative patients and those with antiphospholipid syndrome; the timing of therapy does not appear to affect the usually high mortality associated with this condition in patients with sepsis or severe shock. Only a minority of patients will be found to have hyponatremia or hyperkalemia. The diagnosis is confirmed through imaging studies ^2,³ (Fig. 168.1).

Fig. 168.1 Coronal section showing left adrenal hemorrhage.

The right adrenal demonstrates a usual inverted “y” appearance.

Relative Adrenal Insufficiency in Critically Ill Patients *

It is estimated that approximately 2% of the U.S. population has an inadequate adrenal response to stress. The incidence of relative adrenal insufficiency in critically ill patients has been reported to be as low as 0% and as high as 77%.^12,¹⁵

Diagnosis and treatment of relative adrenal insufficiency are controversial. Disagreement exists about the incidence of disease, the normal range of serum cortisol levels in response to stress or corticotropin testing in the seriously ill, the dose of corticotropin to be administered for testing, and the indications for, optimal dosing of, and desired efficacy of steroids in the critically ill.⁴^–¹³ ¹⁵

The use of steroids for sepsis has been explored. Well-designed trials of supraphysiologic doses of steroids have demonstrated no beneficial effect. Two recent randomized clinical trials of corticosteroids in septic shock populations with new criteria for relative adrenal insufficiency and lower dosages of steroids have been completed with conflicting results. Entry criteria differed somewhat between the studies. At present, the following conclusions can be drawn:

1. There is evidence that the use of “low-dose” hydrocortisone may be beneficial for severe septic shock refractory to fluid resuscitation and vasopressors if given early in the course of the shock (within 8 hours).¹⁵

2. Delayed administration of steroids in resuscitated patients is not beneficial and may be harmful.⁶

Drug-Induced Adrenal Insufficiency

A number of medications may cause reversible adrenal insufficiency. Examples include ketoconazole, rifampin, phenytoin, and etomidate. Use of etomidate as an induction agent for rapid-sequence intubation (RSI) of critically ill patients is controversial. A single dose can cause relative adrenal insufficiency for up to 48 hours, but the clinical significance of this degree of suppression is unclear.^14,^16,¹⁷ In two retrospective and one prospective observational studies of single-dose etomidate RSI in the ED, no significant difference was found in in-hospital mortality.¹⁸^–²⁰ In a randomized study of trauma patients requiring RSI, those receiving etomidate had longer intensive care unit and hospital length of stay and more ventilator days and required more red blood cell transfusions and fresh frozen plasma.²¹ In an a priori substudy of the CORTICUS trial, use of etomidate in the 72 hours before study inclusion was associated with higher mortality.²² However, the survival curves did not separate until 10 to 18 days after the administration of etomidate, thus leading to questions about how the drug could have caused the deaths because relative adrenal suppression usually resolves within 72 hours of a single dose.

The benefits of etomidate for RSI should be weighed against the need for an adrenal stress response. Alternative induction agents can be considered for patients being treated chronically with steroid therapy, for trauma victims, and for those at risk for severe sepsis. Supplemental corticosteroids may be administered empirically for 24 hours if etomidate is used.

Differential Diagnosis

The differential diagnosis of adrenal crisis includes most other conditions known to cause shock (Box 168.1). These same conditions may induce relative adrenal insufficiency, and therefore their diagnosis does not exclude a concurrent adrenal crisis.

Red Flags

Conditions that promote shock may induce concurrent relative adrenal insufficiency; diagnosis of one condition does not exclude a second occult disease.

Induction doses of etomidate may cause relative adrenal insufficiency for up to 72 hours after rapid-sequence intubation in critically ill patients.

Diagnostic Testing

Empiric treatment of patients with suspected acute adrenal crisis should not be delayed for confirmatory laboratory testing. The initiation of glucocorticoid therapy should be accompanied by a concurrent, single measurement of serum cortisol. Levels below 15 mcg/dL in a patient with severe sepsis or shock suggest adrenal crisis. Laboratory standards for adrenal function were established in normal subjects and are thus not applicable to populations under physiologic stress.

Adrenal function testing begins with the administration of 250 mcg of synthetic ACTH. A rise in serum cortisol to greater than 8 mcg/dL within 30 minutes is considered a normal response. Such a finding excludes primary insufficiency but does not evaluate hypothalamic-pituitary-adrenal axis–related causes of secondary insufficiency. The hypothalamic-pituitary-adrenal axis is usually tested afterward with a metapyrone or insulin-hypoglycemia challenge. Critically ill patients in whom serum cortisol fails to rise by more than 9 mcg in serial measurements should be considered nonresponders who require glucocorticoid therapy.

The classic finding of concurrent hyponatremia and hyperkalemia may indicate subacute or chronic adrenal insufficiency in the appropriate clinical setting.

Imaging studies may identify adrenal tumors or hemorrhage that may be responsible for the insufficiency. Incidental adrenal pathology is observed in approximately 2% of abdominal scans. Tumors may be benign or malignant, primary or metastatic.^19,²⁰

Treatment

For the purposes of immediate resuscitation before testing, a functional parameter is used: a patient in shock who fails to respond to fluids and vasopressors within 1 hour should be treated empirically for adrenal insufficiency.

Hydrocortisone

Patients with adrenal crisis should receive intravenous (IV) hydrocortisone replacement. The initial adult dose of hydrocortisone is 100 mg every 6 hours. In children the dose can be given as 50 to 75 mg/m²/day divided into four IV doses. The dose can be tapered as the patient’s condition stabilizes. Severely ill patients, particularly those exhibiting septic shock, may require longer durations of treatment.

Dexamethasone

Stable patients may be given IV dexamethasone, 4 mg every 6 hours. Dexamethasone allows a corticotropin stimulation test to be conducted because it does not immediately suppress hypothalamic activity. Dexamethasone has little mineralocorticoid activity, however, and should therefore be avoided in patients with adrenal crisis.

Fludocortisone

Mineralocorticoid therapy is available only in oral form in the United States. Parenteral hydrocortisone, 100 mg given every 6 hours, has sufficient mineralocorticoid activity to adequately treat critically ill patients who cannot tolerate oral medications. As their condition stabilizes and patients are able to take medications by mouth, hydrocortisone is tapered and oral fludrocortisone, 0.05 to 0.1 mg, is added each morning. Patients with secondary adrenal insufficiency do not require mineralocorticoids.

Other Treatment Considerations

Patients with primary failure of the hypothalamic-pituitary-adrenal axis may have concurrent clinical hypothyroidism and require thyroxine supplementation. All patients with adrenal insufficiency should undergo prompt correction of volume status, electrolyte imbalance, and hypoglycemia.

Patients with incidental laboratory findings may be referred for outpatient management if they have no clinical evidence of acute adrenal insufficiency or excess, aldosterone excess, or pheochromocytoma. Adrenal masses larger than 6 cm will probably be removed, as well as those that demonstrate endocrine activity.

Priority Actions

Do Not

Withhold glucocorticoids while awaiting laboratory results.

Attempt endocrine stimulation testing in acutely ill patients.

Disposition

Patients with shock or obtundation should be admitted to a critical care unit. Those who quickly respond to treatment may be considered for admission to an unmonitored floor. Patients with mild symptoms, known disease, and reliable follow-up can be treated in the emergency department and be discharged to the care of their personal physician (see Tables 168.1 and 168.2).

Documentation

History of steroid administration and withdrawal

Risk factors for adrenal crisis: malignancy, tuberculosis, cytomegalovirus infection, human immunodeficiency virus infection, infiltrative disorders

Record of initial serum glucose, sodium, potassium, and volume status

Patient Teaching Tips

Absolute lifelong compliance with outpatient medication regimens is mandatory.

Double the steroid doses during times of physiologic stress and minor illness.

Seek medical attention if nausea and vomiting occur; they may be symptoms of adrenal crisis and might prevent tolerance of needed oral medications.

Suggested Readings

Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–871.

Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 2009;35:1868–1876.

Hildreth AN, Mejia VA, Maxwell RA, et al. Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study. J Trauma. 2008;65:573–579.

Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124.

Tekwani KL, Watts HF, Rzechula KH, et al. A prospective observational study of the effect of etomidate on septic patient mortality and length of stay. Acad Emerg Med. 2009;16:11–14.

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6 Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124.

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9 Pizarro CF, Troster EJ, Damiani D, et al. Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med. 2005;33:855–859.

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13 Yildiz O, Doganay M, Aygen B, et al. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care. 2002;6:251–259.

14 Absalom A, Pledger D, Kong A, et al. Adrenocortical function in critically ill patients 24 h after a single dose of etomidate. Anaesthesia. 1999;54:861–867.

15 Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–871.

16 De Coster R, Helmers JH, Noorduin H. Effect of etomidate on cortisol biosynthesis: site of action after induction of anaesthesia. Acta Endocrinol (Copenh). 1985;110:526–531.

17 Schenarts CL, Burton JH, Riker RR, et al. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med. 2001;8:1–7.

18 Baird CRW, Hay AW, McKeown DW, et al. Rapid sequence induction in the emergency department: induction drug and outcome of patients admitted to the intensive care unit. Emerg Med J. 2009;26:576–579.

19 Tekwani KL, Watts HF, Chan CW, et al. The effect of single bolus etomidate on septic patient mortality: a retrospective review. West J Emerg Med. 2008;9:195–200.

20 Tekwani KL, Watts HF, Rzechula KH, et al. A prospective observational study of the effect of etomidate on septic patient mortality and length of stay. Acad Emerg Med. 2009;16:11–14.

21 Hildreth AN, Mejia VA, Maxwell RA, et al. Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study. J Trauma. 2008;65:573–579.

22 Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 2009;35:1868–1876.

^* See references 4 to 14.

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