Special Feature

Adrenal Insufficiency in Critically Ill Patients

By Karen Johnson PhD, RN

In 1936 Selye noted that rats exposed to stressors had enlarged adrenal glands. In the late 1940s, Kendall and Reichstein isolated cortisone as the active principle of the adrenal glands. In more recent years our understanding of the hypothalamic-pituitary-axis has grown immensely. The purpose of this special feature is to examine the adrenal corticosteroid function and adrenal insufficiency in critical illness.

The Hypothalamic-Pituitary-Adrenal Axis

The integrity of the hypothalamic-pituitary-adrenal (HPA) axis is a major determinant of the host’s response to stress.1,2 When confronted with stressors (trauma, infection, surgery, hypotension, etc), the HPA axis is activated (see Figure 1). The hypothalamus releases corticotropin releasing hormone (CRH), which in turn does 3 things: 1) It stimulates sympathetic nervous system to release (a) norepinephrine from its postganglionic neurons, and (b) epinephrine from the adrenal medulla; 2) It stimulates the posterior pituitary to release antidiuretic hormone; and 3) It stimulates the anterior pituitary to release adrenal corticotropin hormone (ACTH), which in turn stimulates the adrenal cortex to release the mineralocorticoid hormone aldosterone and the glucocorticoid hormone cortisol. Activation of the HPA axis, through its hormones, enhances cardiovascular function, substrate metabolism, and inhibits immune mediated inflammation.

Adrenal Cortex Corticosteroid Production and Function

With severe illness, trauma, infection, burns, or surgery, cortisol production increases 6-fold and this increase is roughly proportional to the severity of the illness.3-5 Cortisol is derived from cholesterol in the adrenal cortex under negative feedback control of the HPA axis. Approximately 90-95% of the cortisol in the plasma binds to plasma proteins (cortisol-binding globulin). This high degree of binding to proteins slows the elimination of cortisol from the plasma, giving cortisol a relatively long half-life of 60-90 minutes. Cortisol is degraded mainly in the liver and conjugated to an inactive form. Some of the conjugates are excreted in the bile and feces. The majority of the conjugates enter the circulation as highly soluble substances that are filtered by the kidneys and excreted in the urine. Therefore, liver disease can markedly impair the inactivation of cortisol and renal disease can reduce the excretion of inactive conjugates.

Cortisol is vitally important for carbohydrate, protein, and fat metabolism and for its anti-inflammatory effects (see Table 1). Cortisol’s net effects are to metabolically relieve the damaging nature of the stressor. Cortisol secretion has been estimated to be approximately 10 mg/m2 per day (equivalent of 20-30 mg/d of hydrocortisone or 5-7 mg/d of oral prednisone).3

Table 1

Effects of Cortisol

Carbohydrate Metabolism  

Stimulation of gluconeogenesis
Decreased glucose use by cells
Protein Metabolism

Reduction in cellular protein
Increase in plasma and liver proteins
Mobilization of amino acids from extra-hepatic tissues
Increase in protein synthesis in the liver

Fat Metabolism  

Mobilization of fatty acids from adipose tissue
Cells shift from using glucose for energy to use of fatty acids
Anti-inflammatory Effects Blocks early phases of inflammatory response
Causes rapid resolution of inflammation
Other   Facilitates catecholamine production
Modulates b-adrenergic receptor
synthesis, regulation, coupling,

Adrenal Insuffiency

Decreased production and/or secretion of cortisol can occur with adrenal insufficiency as a result of primary or secondary causes. Chronic primary adrenal insufficiency (Addison’s Disease) is most commonly caused by autoimmune adrenalitis (slow destruction of the adrenal cortex by cytotoxic lymphocytes) and is sometimes accompanied by autoimmune thyroid disease and other autoimmune endocrine disorders (autoimmune polyglandular syndromes).6

Secondary causes of adrenal insufficiency include necrosis of the adrenal gland, head trauma, pituitary lesions, and long-term glucocorticoid therapy. Head injury, pituitary infarction, and central nervous system depressants can impair CRH release from the hypothalamus.7 Cytokines, anesthetics, and anti-infective agents can impair adrenal cortisol synthesis, exogenous administration of corticosteroids, hemorrhage, infection, and HIV infiltration.8 Adrenal hemorrhage can occur in critically ill patients with septicemia and underlying coagulopathy.8 Inflammatory cytokines during sepsis also appear to promote corticosteroid resistance so that normal adrenal responses maybe insufficient.8-10 Long-term administration of corticosteroid therapy induces adrenal atrophy and suppresses CRH production. These effects can persist for months after cessation of corticosteroid therapy.11 The individual effect is highly variable and depends on the dose and duration of treatment but should be anticipated in any patient who has been receiving more than 30 mg of hydrocortisone (7.5 mg prednisone; 0.75 mg dexamethasone) per day for more than 3 weeks.8

Annane and colleagues suggested the presence of a relative adrenal insufficiency in critically ill patients.12 "Functional adrenal insufficiency" is a term used to describe subnormal adrenal corticosteroid production during acute illness.13 It has been estimated that the incidence of this functional adrenal insufficiency approaches 30% of all ICU patients.14 The incidence of adrenal insufficiency in patients with septic shock has been reported to be 54%.15 Inability to mount an adequate adrenal corticosteroid response increases mortality during critical illness.11,16 Therefore, early identification of functional adrenal insufficiency and treatment with exogenous corticosteroids may be beneficial.8

Diagnosis of Adrenal Insufficiency

Many of the symptoms of adrenal insufficiency are nonspecific and occur insidiously, but can include:6,8 weakness, fatigue, depression, anorexia, weight loss, nausea, vomiting, diarrhea, and a craving for salt. Findings on physical examination can include hyperpigmentation, vitiligo, decreased body hair, fever, hypotension, and tachycardia. Laboratory findings may include hyponatremia, hypoglycemia, hyperkalemia, and eosinophilia.

When one considers these manifestations in the face of critical illness, it is obvious that adrenal insufficiency is difficult to detect in this patient population. Many patients are in altered levels of consciousness and are unaware of the physical symptoms. Fever and hypotension are common clinical findings in patients with hypovolemia and or sepsis. Electrolyte abnormalities in the critically ill are not only common, but also masked by continuous and frequent electrolyte administration. Hypoglycemia and eosinophilia are uncommon in critically ill patients and should alert clinicians to the possibility of adrenal insufficiency.17 A high index of suspicion of adrenal insufficiency should be considered with the presence of unexplained catecholamine-resistant hypotension6 despite adequate fluid resuscitation and ongoing evidence of inflammation (without an obvious source) that does not respond to empirical treatment.8,13,18

Evaluation of adrenal function can be made using serum cortisol levels and the corticotropin stimulation tests (see Table 2).

Table 2

Interpretation of Tests of Adrenal Function


Normal Range Interpretation  References
Cortisol (8-9 am)  6-24 ug/dL 

If < 3 ug/dL, confirm adrenal insufficency 

Spot (random) Minimal levels:
10-34 ug/dL
If 15 ug/dL adrenal insufficiency likely; > 34 ug/dL functional adrenal
insufficiency unlikely
Corticotropin 20 ug/dL Insufficient increase in plasma cortisol: insufficiency. Increase < 9 ug/dL from baseline cortisol levels = adrenal insufficiency unlikely; Increase ± 9 ug/dL from baseline cortisol level = functional adrenal insufficiency likely 6, 8

Cooper and Stewart8 have recently proposed an algorithm to investigate adrenal insufficiency in critically ill patients on the basis of these tests. If adrenal insufficiency is suspected, a random cortisol sample is drawn. If the results are < 15 m/mL, then adrenal insufficiency is likely and corticosteroid replacement should be considered. If the random cortisol is 15-34 m/dL, a corticotropin stimulation test is performed. Cosyntropin (synthetic peptide consisting of the first 24 amino acids of corticotropin) 250 m IV or IM is administered with plasma cortisol levels measured before, 30 and 60 minutes after administration. A small increase (< 9 m/dL) from the baseline cortisol level to the highest cortisol level (30, 60 minutes) has been associated with increased mortality20,21 and the diagnosis of adrenal insufficiency is likely. Absolute increment of cortisol concentration less than 9 m/dL may be associated with impaired vasopressor responsiveness to norepinephrine.22 Corticosteroid replacement should be considered. If the levels are ± 9 m/dL, functional adrenal insufficiency is unlikely. Critically ill patients with established adrenal insufficiency should be treated with hydrocortisone 60 mg intramuscularly or intravenously every 6 hours.8

Impaired Adrenal-Cortical Reserve in Septic Shock

During sepsis, activation of the HPA axis is associated with increased corticotropin release from the anterior pituitary,23 enhanced adrenal secretion of cortisol,24 and high plasma cortisol levels.18,24 Glucocorticoids modulate the stress response to sepsis through permissive (enhanced cardiovascular response) and suppressive (inhibit cytokine synthesis) effects.25 Proinflammatory mediators activate the HPA axis to release cortisol as a mechanism to counterattack the inflammatory process. It is this mechanism that for years provided the physiologic basis for the use of cortisol in sepsis trials. However, administration of short-term high-dose steroids in early septic shock was found to be harmful, primarily as a result of increased incidence of secondary infections.26,27 A meta-analysis examining the relative risk differences in steroid administration between 1963-1990 suggested a trend toward an increased risk of death among steroid-treated patients.28

In contrast to short-term, high-dose steroid administration of the past, 4 recent randomized clinical trials indicated that administration of low-dose hydrocortisone (240-300 mg/d) administered over longer periods (± 5 days) improves shock reversal.15,29-31 These results support the concept of an impaired "adrenal cortical reserve" in septic shock31 and have initiated a re-evaluation of the role of steroids in septic shock.


The integrity of the HPA axis is a major determinant of the host’s response to stress. Cortisol production and secretion from the adrenal cortex is significantly increased during critical illness. Cortisol is vitally important for substrate metabolism, modulation of the inflammatory response, and enhancement of the effects of catecholamines on vascular smooth muscle tone. Critically ill patients have multiple risk factors for developing adrenal insufficiency. Adrenal insufficiency is difficult to detect in this patient population. However, a high index of suspicion should be considered in patients with unexplained catecholamine resistant hypotension and ongoing evidence of inflammation. Cortisol and corticotropin stimulation tests can confirm the diagnosis of adrenal insufficiency. Exogenous cortisol replacement should be initiated accordingly. The use of short-term high-dose steroids in septic shock has not demonstrated an improvement in mortality. However, recent randomized clinical trials using low-dose steroids administered over longer periods of time may improve shock reversal. As our knowledge of sepsis pathophysiology increases, we are becoming more aware of the delicate balance between protection from overshooting the inflammatory response and the risk of aggravated immunosuppression.32


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