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Adrenal insufficiency

In medicine, adrenal insufficiency (or "hypocortisolism") is the inability of the adrenal gland to produce adequate amounts of cortisol in response to stress. See also: Adrenal Fatigue or Hypoadrenia.

Causes can include:

  • Acute adrenal insufficiency
    • Addison's disease (autoimmune adrenalitis)
    • Waterhouse-Friderichsen syndrome
  • Chronic adrenal insufficiency
    • Addison's disease
    • congenital adrenal hyperplasia
    • antiphospholipid syndrome
    • haemochromatosis
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Adrenal insufficiency in the critically ill : a new look at an old problem - critical care review
From CHEST, 11/1/02 by Paul E. Marik

Stress from many sources, including pain, fever, and hypotension, activates the hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of corticotropin and cortisol. Increased glucocorticoid action is an essential component of the stress response, and even minor degrees of adrenal insufficiency can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed disorder in the critically ill. We review the risk factors, pathophysiology, diagnostic approach, and management of HPA dysfunction in the critically ill. (CHEST 2002; 122:1784-1796)

Key words: adrenal axis; adrenal corticotropin hormone; adrenal insufficiency; cortisol; critical care; glucocorticoid receptors; hypothalamic-pituitary; ICU; sepsis; systemic inflammatory response syndrome

Abbreviations: ACTH = adrenal corticotropin hormone; CRH = corticotropin-releasing hormone; GR = glucocorticoid receptor; HD-ACTH = high-dose adrenal corticotropin stimulation; HPA = hypothalamic-pituitary-adrenal; IL = interleukin; LD-ACTH = low-dose adrenal corticotropin stimulation; Amax = change in cortisol level following corticotropin stimulation; SIRS = systemic inflammatory response syndrome; TNF = tumor necrosis factor


Severe illness and stress activate the hypothalamic-pituitary-adrenal (HPA) axis and stimulate the release of corticotropin (also known as adrenal corticotropic hormone [ACTH]) from the pituitary, which in turn increases the release of cortisol from the adrenal cortex. (1,2) This activation is an essential component of the general adaptation to illness and stress, and contributes to the maintenance of cellular and organ homeostasis. Animals that have had adrenalectomies succumb rapidly to hemorrhagic and septic shock, and steroid replacement is protective against these challenges. (3,4) Even minor degrees of adrenal insufficiency increases the mortality of critically ill or injured patients. (5) Chronic primary adrenal insufficiency, as first described by Addison in the mid-1800s, is a rare disease. (6,7) However, acute adrenal insufficiency is a common and largely unrecognized disorder in critically ill patients. We review basic actions of glucocorticoids, etiologies for adrenal insufficiency in critically ill patients, factors affecting the release and action of cortisol, new criteria for evaluation of adrenal function during critical illness, and the treatment of adrenal insufficiency.


Glucocorticoids exert their effects by binding to and activating a 90-kd intracellular glucocorticoid receptor (GR) protein. (8) All cells appear to have appreciable levels of GR. The GR is localized in the cytoplasm of the cell and translocates into the nucleus on ligand binding. In the absence of hormone, cytoplasmic GR is associated with a large protein complex that includes heat shock protein-90 and heat shock protein-56. (9) This protein complex functions to maintain the GR in an inactive conformation that is competent for glucocorticoid binding. When activated by a ligand, GRs bind as dimers to glucocorticoid response elements in target genes that then activate or repress transcription of the associated genes. Hormone-activated receptors also bind as monomers to nuclear transcription factors such as nuclear factor-[kappa]B and activator protein-1.


Glucocorticoids regulate gene transcription in every cell in the body. For the purposes of this review, we highlight some of the important actions of glucocorticoids during the stress response.

Metabolic Properties

Glucocorticoids increase blood glucose levels, facilitating the delivery of glucose to cells during acute and chronic stress. Glucocorticoids increase blood glucose concentrations by increasing the rate of hepatic gluconeogenesis and inhibiting adipose tissue glucose uptake. (10) Hepatic gluconeogenesis is stimulated by increasing the activities of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase as a result of binding of glucocorticoids to the glucocorticoid response elements of the genes for these enzymes. Glucocorticoids also stimulate free fatty-acid release from adipose tissue and amino-acid release from body proteins. Major roles of these processes are to supply energy and substrate to the cell, required for the response to stress and repair from injury.

Cardiovascular System

Glucocorticoids are required for normal cardiovascular reactivity to angiotensin II, epinephrine, and norepinephrine, contributing to the maintenance of cardiac contractility, vascular tone, and BP. These effects are mediated partly by the increased transcription and expression of the receptors for these hormones. (11,12) Glucocorticoids are required for the synthesis of N+,K+-adenosine triphosphatase and catecholamines. Glucocorticoid effects on synthesis of catecholamines and catecholamine receptors are partially responsible for the positive inotropic effects of these hormones. (13) Glucocorticoids also decrease the production of nitric oxide, a major vasorelaxant and modulator of vascular permeability. (14-17)

Anti-inflammatory and Immunosuppressive Actions

Glucocorticoids possess anti-inflammatory and immunosuppressive effects that are mediated through specific receptor mechanisms. (18-21) Glucocorticoids influence most cells that participate in immune and inflammatory reactions, including lymphocytes, natural killer cells, monocytes, macrophages, eosinophils, neutrophils, mast cells, and basophils. Glucocorticoids decrease the accumulation and function of most of these cells at inflammatory sites. Most of the suppressive effects of glucocorticoids on immune and inflammatory reactions appear to be a consequence of the modulation of production or activity of cytokines (ie, interleukin [IL]-1, IL-2, IL-3, IL-6, interferon-[gamma] tumor necrosis factor [TNF]-[alpha]), chemokines, eicosanoids, complement activation, and other inflammatory mediators (ie, bradykinin, histamine, macrophage migration inhibitory factor). Glucocorticoids control mediator production predominantly through inhibition of transcription factors such as nuclear factor-KB. (20,21) This inhibition is mediated by induction of the IKB[alpha] inhibitory protein. (22) Glucocorticoids also produce anti-inflammatory effects by enhancing release of anti-inflammatory factors such as IL-1 receptor antagonist, soluble TNF receptor, and IL-10. (23,24) Glucocorticoids also block the transcription of messenger RNA for enzymes required for the synthesis of some mediators (ie, cyclooxygenase-2, inducible nitric oxide synthase). (25,26) Furthermore, by stimulating the synthesis of lipocortin-1, cortisol inhibits phospholipase [A.sub.2] (another enzyme important in the inflammatory response).


Cortisol secretion by the adrenal cortex is under control of the HPA axis. Signals from the body (ie, cytokine release, tissue injury, pain, hypotension, hypoglycemia, hypoxemia) are sensed by the CNS and transmitted to the hypothalamus. The hypothalamus integrates these signals and increases or decreases the release of corticotropin-releasing hormone (CRH). CRH circulates to the anterior pituitary gland where it stimulates the release of ACTH, which in turn circulates to the adrenal cortex where it stimulates the release of cortisol, androgens, and aldosterone. Importantly, androgens and aldosterone release are not under primary control of ACTH. Androgens are primarily regulated by gonadotropins from the pituitary gland, and aldosterone primarily responds to the renin-angiotensin system and potassium levels. Cortisol, released from the adrenal glands or from exogenous sources, feeds back on the HPA axis to inhibit secretion (ie, negative feedback). Via the above-mentioned mechanisms, the body can control the secretion of cortisol within relatively narrow limits and can respond with increased secretion of cortisol to a variety of stresses and other signals.

Cortisol circulates in the blood in a bound and unbound form. The bound form is primarily carried on cortisol binding globulin (90%). It is the unbound or free cortisol that is physiologically active and homeostatically regulated. Unfortunately, current clinical assays measure total (bound and unbound) rather than free cortisol. Although free cortisol levels have not been well studied, recent evidence suggests that in critically ill patients there is a decrease in cortisol binding with an increase in the free fraction. (27)


The HPA axis and the immune response are linked in a negative feedback loop in which activated immune cells produce cytokines that signal the brain. Activation of the HPA axis by specific cytokines increases the release of cortisol that in turn feeds back and suppresses the immune reaction (and further cytokine release). (28) IL-1[alpha], IL-1[beta], and IL-6 administered peripherally increase HPA activity, increasing levels of CRH, ACTH, and glucocorticoids. (29,30) Cytokines also affect the pituitary and adrenal cortex directly. IL-1[alpha], IL-1[beta], IL-6, and TNF-[alpha] stimulate ACTH secretion from cultured pituitary preparations and IL-1[alpha], IL-1[beta], and IL-6 stimulate glucocorticoid production in cultured adrenal preparations. (29,30)

Cytokines, however, also suppress the HPA axis and GR function. Chronic IL-6 elevation may blunt ACTH release. (31) In addition, TNF-[alpha] impairs CRH-stimulated ACTH release, (32,33) and a number of clinical studies have reported inappropriately low ACTH levels in patients with severe sepsis and the systemic inflammatory response syndrome (SIRS). (32,34,35) Indeed, Schroeder and coworkers (36) reported similar circulating levels of ACTH in healthy control subjects as in patients with severe sepsis. In addition, plasma from patients with septic shock impairs synthesis of corticosteroids by adrenocortical cells. (37-39) TNF-[alpha] and corticostatin have been demonstrated to inhibit adrenal gland function. (33,40,41) Corticostatin ("defensin") is a peptide produced by immune cells. (42) Concentrations of corticostatin increase > 20-fold in animals with infection but not other forms of stress. (43) TNF-[alpha] has been shown to reduce adrenal cortisol synthesis by inhibiting the stimulatory actions of ACTH and angiotensin II on adrenal cells. (40,44,45) Proinflammatory cytokines have been shown to influence the number, expression, and function of the GR. IL-1[alpha] has been demonstrated to decrease GR translocation and transcription. (46) The half-life of cortisol has been demonstrated to be prolonged in sepsis; this may reflect a decreased number of GRs or decreased affinity of the receptor for its ligand. (39,47,48) Reduced activity of gluconeogenic enzymes during endotoxemia despite elevated circulating glucocorticoid levels provides further evidence to support impaired intracellular actions of glucocorticoids during sepsis. (49) In total, these data support the concept that mediators released in patients with sepsis may either stimulate or inhibit the synthesis and release of cortisol via actions on the HPA axis and GR. The pathophysiologic alterations that explain these different responses are unknown, as are the evolutionary advantages of inhibition of the HPA axis and GR.


Stress from many sources, including cold, fever, infection, trauma, emotional distress, burns, inflammatory agents, pain, hypotension, exercise, hemorrhage, and other challenges to homeostasis, stimulates the HPA axis, increasing secretion of cortisol. There is much controversy regarding levels of circulating cortisol that are considered to be an adequate response to stress. (50) Many textbooks and published articles state that the normal circulating cortisol response to stress is a level > 18 to 20 [micro]g/dL. However, the choice of 18 to 20 [micro]g/dL is based primarily on the response to exogenous high-dose ACTH stimulation (HD-ACTH) [250 [micro]g] (51) and the response to insulin-induced hypoglycemia in nonstressed noncritically ill patients. Endogenous stress may be produced by administering insulin to decrease blood glucose levels. However, the cortisol response varies with the degree of hypoglycemia (ie, level of endogenous stress). Importantly, severe hypoglycemia (glucose < 30 mg/dL) usually increases cortisol levels > 25 [micro]g/dL, while moderate hypoglycemia (glucose, 40 to 60 mg/dL) produces cortisol levels > 20 [micro]g/dL. (52)

Critical illness activates the HPA axis through different mechanisms, and the kinetics of the response differ from those found with the abovementioned provocative tests. Pain, fever, hypovolemia, hypotension, and tissue damage all result in a sustained increase in corticotropin and cortisol secretion and a loss of the normal diurnal variation in these hormones. (53,54) During surgical procedures such as laparotomy, serum corticotropin and cortisol rise rapidly peaking in the immediate postoperative period and then decline to baseline levels over the next 72 h. (53) The magnitude of the postoperative increase in serum cortisol concentration is correlated with the extent of the surgery, with a peak between 30 [micro]g/dL and 45 [micro]g/dL in patients undergoing major surgery. (54-59) During severe illness, serum cortisol concentrations tend to be higher than those of patients undergoing major surgery. (53) In patients with multiple trauma, the serum cortisol level remains > 30 [micro]g/dL for at least a week, with peak values between 40 [micro]g/dL and 50 [micro]g/dL. (60) Cortisol levels are increased in critically ill ICU patients, with the highest values being reported in those patients with the highest illness-severity scores and those with the highest mortality. (1,61) Rothwell and Lawler (62) measured the ICU admission cortisol level in a group of 260 patients. In this study, the mean serum cortisol level was 27 [micro]g/dL in survivors compared to 47 [micro]g/dL in the nonsurvivors. The serum cortisol level was an independent predictor of outcome. (62) This data clearly demonstrates that the degree of activation of the HPA axis and serum cortisol level is related to the severity of the stressor. Animal and human studies demonstrate increasing serum levels of epinephrine and cortisol with increasing severity of stress, with hypotension and sepsis being two of the most intense stressors. (63,64) Based on these data, we believe that a random cortisol level (stress level) in severely stressed patients (ie, with hypotension, hypoxemia, burn, high fever, multiple trauma) should be > 25 [micro]g/dL. Higher levels may be appropriate in patients with septic shock due to "tissue cortisol resistance."

The use of a threshold random (stress) serum cortisol of 25 [micro]g/dL for the diagnosis of an adequate cortisol response to critical illness is supported by the literature. (65) Melby and Spink (47) reported a mean cortisol level of 63 [micro]g/dL in 20 patients with shock (range, 30 to 160 [micro]g/dL). Schein et al (66) reported a median cortisol concentration of 50.7 [micro]g/dL (range, 5.6 to 400 [micro]g/dL) in 37 patients with septic shock. Only 8% of these patients had a cortisol level < 25 [micro]g/dL. Drucker and Shandling (67) reported a mean cortisol value of 45 [micro]g/dL in 40 medical ICU patients. Chernow et al (68) reported a mean cortisol level of 32 [micro]g/dL 1 h after moderate stress (ie, cholecystectomy) and 52 [micro]g/dL 1 h after severe stress (ie, subtotal colectomy). Uncomplicated cholecystectomy increases cortisol concentrations to 27 to 34 [micro]g/dL at 30 rain after the start of surgery and 46 to 49 [micro]g/dL at 5 h after the start of surgery? Lamberts et al (53) reported mean [+ or -] SD cortisol levels of 45 [+ or -] 3 [micro]g/dL in patients with multiple trauma and 48 [+ or -] 2 [micro]g/dL in patients with sepsis. We measured cortisol levels in 12 critically ill patients with hypotension secondary to acute GI bleeding; cortisol levels averaged 50 [micro]g/dL, with a range of 32 to 100 [micro]g/dL (unpublished data).

Rivers et al (70) studied the HPA axis in a group of vasopressor-dependent surgical patients. In a subgroup of patients treated with corticosteroids, the basal serum cortisol was 49 [micro]g/dL in the steroid nonresponders and 20 [micro]g/dL in those patients who were weaned from vasopressors within 24 h of the initiation of steroid treatment. Only one patient in the steroid responsive group had a baseline serum cortisol > 25 [micro]g/dL, and only two nonresponders had a baseline level < 25 [micro]g/dL. This study suggests that cortisol levels < 25 [micro]g/dL are associated with steroid-responsive hypotension.

Clearly, there is no absolute serum cortisol level that distinguishes an adequate from an insufficient adrenal response. However, based on current evidence, we believe that a random (stress) ortisol level should be interpreted in conjunction with the severity of illness and 25 [micro]g/dL is a useful threshold value for an appropriate response to critical illness. Furthermore, the random cortisol level should be interpreted in conjunction with the clinical response to steroid replacement therapy (see below).


As there are no clinically useful tests to assess the cellular actions of cortisol (ie, end-organ effects), the diagnosis of adrenal insufficiency is based on the measurement of serum cortisol levels; this has resulted in much confusion and misunderstanding. (35,50,67,71-79) Traditionally the "integrity" of the HPA axis has been assessed by the short corticotropin stimulation test (also known as the cosyntropin stimulation test). This test is usually performed by administering 250 [micro]g of synthetic corticotropin IV and obtaining a serum cortisol before and 30 min and 60 rain following corticotropin. (50,51) A 30- to 60-min serum cortisol level < 18 [micro]g/dL or an increase in the cortisol concentration of < 9 [micro]g/dL has been regarded by many as diagnostic of adrenal insufficiency. (50) However, these criteria were developed to assess adrenal reserve in patients with destructive diseases of the adrenal gland, and are based on responses in normal nonstressed, healthy control subjects. (50,51) We believe that the standard corticotropin stimulation test lacks sensitivity for the diagnosis of adrenal insufficiency. (50)

As discussed above, a threshold cortisol level of 18 [micro]g/dL is inappropriately low in critically ill patients. "Normal" critically ill patients should elevate their cortisol level > 25 [micro]g/dL. Furthermore, 250 [micro]g of corticotropin is supraphysiologic (>100-fold higher than normal maximal-stress ACTH levels). (35,67,74-76) The very high levels of corticotropin obtained with 250 [micro]g can override adrenal resistance to ACTH and result in a normal cortisol response (similar to the effect of insulin in patients with type 2 diabetes mellitus). Importantly, patients with normal responses to the HD-ACTH test (250 [micro]g) may fail to respond normally to stress. (73,80) For example, Borst et al (81) described four patients with pituitary disease in whom standard HD-ACTH test results were normal. These patients failed to respond adequately to insulin-induced hypoglycemia. Discordant results between the HD-ACTH test and insulin-induced hypoglycemia have also been reported by others. (82)

Due to the decreased sensitivity of the HD-ACTH test for diagnosis of adrenal insufficiency, many investigators evaluated the use of stress levels of ACTH (ie, 1 to 2 [micro]g) for the diagnosis of adrenal insufficiency. A number of studies have demonstrated that a 1-[micro]g dose (low-dose corticotropin stimulation [LD-ACTH] test) of corticotropin is more sensitive and specific for diagnosing primary and secondary adrenal insufficiency than the 250-[micro]g dose of corticotropin. (34,83-87) We studied the adrenal response to LD-ACTH and HD-ACTH in 59 patients with septic shock; 11 patients (18%) failed to respond to LD-ACTH but responded to HD-ACTH. (80) These patients were believed to have adrenal resistance to ACTH. Using the cortisol response to hypotension as the "gold standard" for diagnosis of adrenal insufficiency (with a diagnostic threshold of 25 [micro]g/dL), the sensitivity of the LD-ACTH test for diagnosis of adrenal insufficiency was 69%. The sensitivity of the HD-ACTH test was 42%. In a separate study of adrenal insufficiency in critically ill patients with HIV infection, the sensitivity of the LD-ACTH and HD-ACTH tests for diagnosis of adrenal insufficiency were 62% and 29%, respectively. (88) Due to the fairly mediocre sensitivities of the LD-ACTH test, we would recommend using the cortisol response to stress (with a diagnostic threshold of 25 [micro]g/dL) as the diagnostic test of choice in stressed ICU patients. The adrenal reserve of unstressed patients is best determined by the LD-ACTH test.

The change in cortisol level following corticotropin stimulation ([DELTA]max) is used by some clinicians to diagnose adrenal insufficiency. (67,71,75) However, the [DELTA]max is a measure of adrenal reserve and not adrenal function. The increase in cortisol following administration of corticotropin should not be used as a criterion for the diagnosis of adrenal insufficiency. A maximally stressed patient may be secreting all the cortisol that his/her adrenal glands can synthesize. This patient may have an appropriately high serum cortisol but be unable to respond further following corticotropin injection (no reserve). For example, a critically ill patient with a basal stress cortisol level of 54 [micro]g/dL that increases to 57 [micro]g/dL with corticotropin does not have adrenal insufficiency. It is the absolute level that is of importance rather than the [DELTA]max.

Most importantly, the administration of exogenous ACTH bypasses the CNS-hypothalamic-pituitary axis and tests the integrity of the adrenal glands directly. It is essential that one evaluate the entire axis since defects in the hypothalmic-pituitary components frequently cause adrenal insufficiency. Endogenous stresses such as hypotension, hypoxemia, fever, and hypoglycemia are superior stimuli for testing the integrity of the HPA axis than is ACTH testing. These endogenous stressors test the function of the entire HPA axis, and are therefore regarded as the "gold standards" for adrenal testing. ACTH testing is not required to diagnose adrenal insufficiency in severely stressed patients because the CNS-HPA axis should already be maximally activated. In such patients, a random stress cortisol level provides information on the integrity of the entire HPA axis. In patients in whom the level of stress is less intense (not hypotensive, hypoxemic, or in pain), the LD-ACTH test should be used to assess adrenal reserve.

The cortisol response to the short (60 min) corticotropin stimulation test may not adequately reflect the adrenal response to chronic stress (as seen during critical illness). When prolonged corticotropin elevation is produced in normal individuals by infusion of corticotropin, cortisol concentrations at 8 h averaged 54.6 [+ or -] 2.8 [micro]g/dL (range, 35 to 85 [micro]g/dL). (52) Thus, the level of and duration of corticotropin elevation affects the amount of cortisol secreted by the adrenal glands. Chronic stress results in responses that differ from acute stress. In addition, preexisting adrenal corticotropin tone (which affects adrenal mass) modulates the cortisol response to both stress and exogenous corticotropin stimulation.

One may also evaluate the pituitary-adrenal axis by administering CRH. (36) This test bypasses the hypothalamus but does require the integrity of the pituitary and adrenal glands. However, the sensitivity and specificity of the test for detecting adrenal insufficiency in critically ill patients has not been determined.

Taking all of these factors into account, we believe that a random cortisol level should be > 25 [micro]g/dL in severely stressed ICU patients with normal adrenal function. It is not necessary to obtain cortisol levels at a specific time of the day since critically ill patients lose the diurnal variation in their cortisol levels. (54) In hypotensive patients with a random cortisol level < 25 [micro]g/dL (ie, patients with adrenal insufficiency), the LD-ACTH and HD-ACTH tests can distinguish between primary adrenal failure, HPA-axis failure, and ACTH resistance. (80) Primary adrenal insufficiency is characterized by a low baseline (stress) cortisol level (< 25 [micro]g/dL), which remains below 25 [micro]g/dL with both low-dose and high-dose corticotropin. Patients with adrenal insufficiency due to HPA-axis failure have a baseline cortisol level < 25 [micro]g/dL, and increase their cortisol levels > 25 [micro]g/dL with both low-dose and high-dose corticotropin. ACTH resistance is characterized by a low baseline cortisol level that fails to increase > 25 [micro]g/dL with low-dose corticotropin, but increases > 25 [micro]g/dL with high-dose corticotropin.

In nonhypotensive critically ill patients, the normal cortisol response (30 to 60 min) after 1 to 2 [micro]g corticotropin administration (LD-ACTH) should be a level > 25 [micro]g/dL. However, a random cortisol level of < 20 [micro]g/dL in a nonhypotensive critically ill patient with unexplained fever, eosinophilia, or mental status changes may warrant a trial of replacement doses of corticosteroids.


The incidence of adrenal insufficiency in critically ill patients is variable and depends on the underlying disease and severity of the illness. The reported incidence varies widely (0 to 77%) depending on the population of patients studied and the diagnostic criteria used to diagnose adrenal insufficiency. (35,47,66,67,70,74-76,80,89-91) However, the overall incidence of adrenal insufficiency in critically ill patients approximates 30%, with an incidence as high as 50 to 60% in patients with septic shock. (65) For example, using the criteria cited above, we diagnosed adrenal insufficiency in 36 of 59 patients (61%) with septic shock. (80) Only five of these patients (9%) met the "classic" criteria (cortisol < 18 [micro]g/dL 60 min after 250 [micro]g corticotropin) for adrenal insufficiency. Importantly, 27 of the 36 patients showed hemodynamic improvement following steroid replacement therapy. Rydvall (92) et al reported a 47% incidence of adrenal insufficiency in a general ICU population (using the stress cortisol level). Briegel et al (90) reported 13 of 20 patients (65%) with septic shock having a stress cortisol < 25 [micro]g/dL. Sibbald et al76 reported 20 of 26 septic patients (77%) stress cortisol levels < 25 [micro]g/dL. Moran et al (93) reported a 49% incidence of adrenal insufficiency in patients with septic shock.


Patients with chronic adrenal insufficiency usually present with a history of weakness, weight loss, anorexia, and lethargy, with some patients complaining of nausea, vomiting, abdominal pain, and diarrhea. Clinical signs include orthostatic hypotension and hyperpigmentation (primary adrenal insufficiency). Laboratory testing may demonstrate hyponatremia, hyperkalemia, hypoglycemia, and a normocytic anemia. (94) This presentation contrasts with the features of acute adrenal insufficiency (Table 1). Hypotension refractory to fluids and requiring vasopressors is the most common feature of acute adrenal insufficiency. (80,94) Patients usually have a hyperdynamic circulation that may compound the hyperdynamic profile of septic patients. (80) However, the systemic vascular resistance, cardiac output, and pulmonary capillary wedge pressure can be low, normal, or high. (65) The variability in hemodynamics reflects the combination of adrenal insufficiency and the underlying disease. However, acute adrenal insufficiency should always be excluded in critically ill patients requiring vasopressor support. CNS dysfunction is common, frequently a result of the underlying disease. Laboratory assessment may demonstrate eosinophilia and hypoglycemia. Hyponatremia and hyperkalemia are uncommon.


Acute adrenal insufficiency occurs in patients who are unable to increase their production of cortisol during acute stress. This includes patients with hypothalamic and pituitary disorders (secondary adrenal insufficiency) and patients with destructive diseases of the adrenal glands (primary adrenal insufficiency) [Table 2]. Secondary adrenal insufficiency is common in patients who have been treated with exogenous corticosteroids. However, the most common cause of acute adrenal insufficiency is sepsis and the SIRS. (65,80)

Destructive Disease of the Adrenal Gland

The most common cause of chronic primary adrenal insufficiency (Addison's disease) in the past was tuberculosis. However, HIV infection and other infections in immunosuppressed patients (ie, tuberculosis, cytomegalovirus, fungal) are currently the most important causes of primary adrenal insufficiency. The adrenal gland is the endocrine organ most commonly involved in patients with AIDS. (95-99) Human cytomegalovirus has been demonstrated in the adrenal glands of 33 to 88% of patients who die of AIDS. Less commonly, tubercle bacilli, Cryptococcus neoformans, Toxoplasma gondii, Histoplasma capsulatum, lymphoma, hemorrhage, or Kaposi sarcoma may involve the adrenal gland. (98) In addition, a number of drugs used in patients with HIV infection, most notably ketoconazole, megesterol acetate, and rifampin, can impair adrenal function. (100-101) Although the adrenal gland is commonly affected by opportunistic infections and tumor infiltration in AIDS, adrenal insufficiency in the outpatient setting is uncommon. (98,102) However, these patients may be unable to increase the synthesis of cortisol during stress. Using the revised diagnostic criteria, we re ported adrenal insufficiency in 13 of 28 critically ill, HIV-positive patients (46%) who had not been treated with corticosteroids. (88)

Glucocorticoid-Induced Adrenal Insufficiency

Synthetic glucocorticoids are commonly used drugs. The use of these drugs is associated with suppression of the HPA axis. The degree of suppression depends on many factors, including the glucocorticoid potency, the dose, the dosing schedule, and the duration of use. The degree of suppression, however, is generally not predictable in any individual patient. (103) The use of inhaled corticosteroids in asthmatics has also been associated with varying degrees of adrenal suppression. (83,104) Systemic glucocorticoids probably do not cause significant HPA suppression when used for < 5 days. When these drugs are used for between 5 days and 30 days, the HPA axis will recover in most patients within 14 days of stopping treatment. (105) However, when used for > 30 days, it may take up to a year for the HPA axis to recover. The recovery of the HPA axis can most reliably be assessed by measurement of a random cortisol level in a stressed patient. The degree of adrenal recovery in the unstressed patient can be determined by the response to 1 [micro]g of corticotropin. (105) However, it is important to note that supraphysiologic doses of glucocorticoids suppress both CRH production in the hypothalamus and ACTH production in the pituitary gland. This suppression can outlast the duration of adrenal suppression. (106) Therefore, a normal cortisol response to corticotropin does not conclusively predict a normal response to stress (which involves the hypothalamicpituitary components of the axis). (107)

Sepsis and SIRS-Induced Acute Reversible Adrenal Insufficiency

There is increasing evidence of HPA insufficiency in critically ill septic patients, (35,67,74-76) which appears to result from circulating suppressive factors released during systemic inflammation. (108) Animal studies confirm the high incidence of adrenal insufficiency during sepsis. (109) It is important to recognize these patients since this disorder has a high mortality rate if untreated. (36) As discussed above, systemic. inflammatory states such as sepsis are associated with both primary and secondary adrenal insufficiency that is reversible with treatment of the inflammation. The most convincing evidence of reversible adrenal failure during sepsis comes from the study of Briegel and colleagnes. (90) These authors performed a HD-ACTH test in 20 patients during septic shock and after recovery. Thirteen of the 20 patients had adrenal insufficiency as defined by a stress cortisol level of < 25 [micro]g/dL. Remarkably, in these 13 patients the basal and simulated cortisol levels were higher after recovery than during the episode of septic shock (Fig 1). Others have similarly observed reversible dysfunction of the HPA axis during sepsis. (110)


The diagnostic criteria, as outlined above, should be used to assess the entire HPA axis during sepsis. Using these criteria, we studied 59 patients in septic shock; 15 of these patients (25%) had primary adrenal insufficiency, 10 patients (17%) had HPA-axis failure, and 11 patients (19%) ACTH resistance. (80) Surviving septic patients had return of adrenal function and did not require long-term treatment with corticosteroids.

Adrenocorticotropin and Cortisol Resistance

Patients with systemic infections (ie, sepsis, HIV) may acquire adrenal insufficiency associated with resistance to ACTH. In two recent studies in critically, ill patients, we found that 30% of patients with septic shock and 25% of critically ill, HIV-infected patients acquired adrenal insufficiency associated with ACTH resistance. (80,88) Stress doses of exogenous corticotropin did not increase their serum cortisol levels, but pharmacologic doses of corticotropin were able to increase the levels into the normal range.

Ali and colleagues (111) reported a 40% decline in the number of GRs in the liver of septic rats. The decline in hormone-binding activity was associated with a fall in GR messenger RNA. Decreased affinity of the GR from mononuclear leukocytes of patients with sepsis has also been reported. (112) In addition, Norbiato et al113 reported resistance to glucocorticoids in patients with AIDS. Cortisol-resistant patients had clinical evidence of adrenal insufficiency associated with decreased affinity of GRs for glucocorticoids and decreased GR function. We and others have also found that cortisol clearance from the circulation is impaired in many critically ill patients. (39,47) Decreased clearance reflects decreased tissue uptake and metabolism of cortisol.

Adrenal Exhaustion Syndrome

Patients with chronic critical illness may acquire adrenal insufficiency while in the ICU. Although not evaluated in prospective trials, we have observed patients who had normal adrenal function when admitted to the ICU but later acquired adrenal insufficiency (ie, ARDS patient receiving long-term mechanical ventilation). The only apparent cause was a prolonged systemic inflammatory response. The adrenal insufficiency may have resulted from chronic secretion of systemic cytokines and other HPA axis-suppressive substances. (108) These patients illustrate the importance of serial follow-up of adrenal function in long-term critically ill patients.


We believe that there is a bimodal distribution of mortality in relationship to the random cortisol level during sepsis. Patients with low cortisol levels (ie, < 25 [micro]g/dL) who are hot treated with corticosteroids and patients with very high levels (ie, > 45 [micro]g/dL) have the highest mortality. This hypothesis may explain the apparent contradictory reports in the literature. Annane et al (71) reported a mean random cortisol level of 34 [micro]g/dL in 189 patients with septic shock, with the nonsurvivors having higher levels than survivors (39 [micro]g/dL vs 28 [micro]g/dL, respectively). However, in the study of Schroeder et al (36), the mean random cortisol level was only 19 [micro]g/dL, with nonsurvivors having a lower cortisol level than survivors (10 [micro]g/mL vs 17 [micro]g/dL). Most of the patients included in the study of Schroeder et al (36) would have met our criteria for adrenal insufficiency. However, none of the patients were treated with corticosteroids.

Impaired responses to corticotropin and CRH are also associated with increased mortality. (36,93) However, it remains unclear as to whether the impaired response is a direct contributor to the increased mortality or is secondary to hypothalamic-pituitary dysfunction or suppression (ie, from circulating mediators or elevated cortisol levels).

Treatment of Acute Adrenal Insufficiency

Deficiency of cortisol is associated with increased morbidity and mortality during critical illness. McKee and Finlay (79) randomized 18 critically ill patients with adrenal insufficiency to glucocorticoid treatment or placebo. One of 8 steroid-treated patients (13%) died compared with 9 of 10 placebo-treated patients (90%). Evidence for high mortality from adrenal insufficiency in critically ill patients also comes from the report of Ledingham and Watt, (5) who noted increased mortality from use of etomidate (a sedative agent that causes adrenal insufficiency) in patients with multiple trauma (44% etomidate vs 27% other sedatives). The report by Ledingham and Watt emphasizes that even slight impairment of the adrenal response during severe illness can be lethal. Rivers et al (70) reported faster weaning from vasopressors and improved survival in hydrocortisone-treated patients (79% vs 55%).

Further evidence to support the benefit of glucocorticoid treatment of acute adrenal insufficiency in patients with septic shock comes from the studies of Bollaert and colleagues (114) and Briegel and coworkers. (115) Bollaert et al (114) randomized 41 patients with septic shock to hydrocortisone (100 mg IV q8h) or placebo. Although random cortisol levels were obtained, treatment with hydrocortisone was not stratified based on the levels. However, the glucocorticoid-treated patients had a significantly greater reversal of shock at 7 days and 28 days, and reduced 28-day mortality (30% vs 70%, respectively; p = 0.09) compared to the placebo group. Similarly, Briegel and colleagues (115) randomized 40 critically ill patients in septic shock to IV hydrocortisone or placebo. Hydrocortisone treatment was associated with improved shock reversal and decreased days of vasopressor support. There was also earlier resolution of organ dysfunction, shorter ventilator time, and shorter ICU stay. Annane et al (116) randomized 200 patients with septic shock to steroid replacement or placebo. There was a significant 30% decrease in death in the steroid-treated patients. Oppert et al (117) treated 20 patients with septic shock with hydrocortisone (10 mg/h for 7 days). Patients with "inadequate" steroid production were weaned from vasopressors significantly faster than patients with "adequate" steroid production. These studies of physiologic-stress doses of glucocorticoids administered for many days contrast with earlier studies of high-dose glucocorticoids (ie, 30 mg/kg of methylprednisolone) administered for one to two doses. The short-term, pharmacologic-dose studies of glucocorticoids failed to report benefit in patients with septic shock. (118,119)

Interestingly, Schelling et al (120) evaluated the effect of hydrocortisone treatment during septic shock on the incidence of posttraumatic stress disorder. The administration of hydrocortisone at stress levels during septic shock reduced the incidence of posttraumatic stress disorder and improved emotional well-being in survivors.


The stress of major surgery may precipitate acute adrenal insufficiency in patients with inadequate adrenal reserve (ie, adrenal crisis). This is especially true in patients with secondary adrenal insufficiency maintained on exogenous glucocorticoids. Prospective randomized trials have failed to adequately evaluate the dose of glucocorticoid required in various perioperative settings. Thus, recommendations for glucocorticoid coverage are based on a risk/ benefit evaluation, published studies in the literature, and clinical experience. Importantly, patients undergoing major and/or prolonged operations (high level of stress) should receive stress doses of glucocorticoids before, during, and after surgery. Patients with a high likelihood of impaired gastric emptying or impaired gut absorption should receive glucocorticoid repletion via the IV route until gut function has returned to relatively normal levels. Patients should also receive sufficient steroid to control their underlying disease. Minimal doses of glucocorticoids based on type of surgery are as follows: (1) Patients undergoing minor surgery (ie, hernia repair, laparoscopic cholycystectomy, knee surgery) should receive a minimal dose of 25-mg hydrocortisone equivaleht daily. This dose may be administered orally if gut function is intact, or IV. (2) Patients undergoing moderate surgical stress (ie, open cholycystectomy, partial colon resection, uncomplicated back surgery, hip replacement) should receive 50 to 75 mg/d hydroeortisone equivalent IV for 1 to 2 days. The dose may then be tapered to baseline levels based on clinical response. (3) Patients undergoing major surgical stress (ie, pancreatoduodenectomy, esophagectomy, total colectomy, repair for perforated bowel, cardiopulmonary bypass, ileofemoral bypass) should receive 100 to 150 mg/d hydrocortisone equivalent IV for 2 to 3 days. The dose can then be tapered to baseline doses based on clinical response. Importantly, the dose should be increased to maximal stress doses (300 mg/d hydrocortisone equivalent IV) in patients who remain hypotensive or deteriorate during recovery from surgery. (121)


In patients with severe stress (ie, hypotension, hypoxemia, pain), a random (stress) serum cortisol level should be obtained. Hypotensive patients and patients at high risk of adrenal insufficiency should be started empirically on hydroeortisone (100 mg IV q8h) pending results of testing. If the serum cortisol level returns to < 25 [micro]g/dL, the hydroeortisone should be continued. In addition, if the patient has improved clinically with hydrocortisone and the cortisol level is > 25 [micro]g/dL, we favor continuing the hydrocortisone for a few days (unless there is a specific contraindication). The dose of hydrocortisone should be tapered down toward maintenance doses as the patient's clinical status improves. This treatment regimen applies to patients with primary adrenal failure, HPA-axis failure, and ACTH resistance.

In unstressed patients and in patients with a low level of physiologic stress in whom adrenal insufficiency is suspected, we favor adrenal testing with LD-ACTH (1 [micro]g). We empirically treat the patient with hydrocortisone pending results (100 mg IV q8h). If the corticotropin stimulation test cannot be performed immediately, administer dexamethasone (2 mg) and perform the test within the next 12 h. Dexamethasone does not significantly cross-react with cortisol in the assay for cortisol and can be administered to patients pending adrenal testing.


HPA dysfunction is common in severely ill patients. Even slight impairment of the adrenal response to severe illness can increase morbidity and mortality, and we believe that low serum cortisol levels may be the cause, rather than the consequence, of poor outcome in these patients. Therefore, a high index of suspicion for adrenal insufficiency is required in all critically ill patients, particularly those with refractory hypotension. All patients with suspected HPA dysfunction should be treated with stress doses of corticosteroids pending the results of diagnostic testing.

* From the Department of Critical Care Medicine (Dr. Marik), University of Pittsburgh, Pittsburgh, PA; and Methodist Research Institute (Dr. Zaloga), Respiratory and Critical Care Consultants, and Department of Medicine of Indiana University School of Medicine, Indianapolis, IN.


(1) Jurney TH, Cockrell JL Jr, Lindberg JS, et al. Spectrum of serum cortisol response to ACTH in ICU patients: correlation with degree of illness and mortality. Chest 1987; 92:292-295

(2) Reincke M, Allolio B, Wurth G, et al. The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. J Clin Endocrinol Metab 1993; 77:151-156

(3) Hinshaw LB, Belier BK, Chang AC, et al. Corticosteroid/ antibiotic treatment of adrenalectomized dogs challenged with lethal E. coli. Circ Shock 1985; 16:265-277

(4) Darlington DN, Chew G, Ha T, et al. Corticosterone, but not glucose, treatment enables fasted adrenalectomized rats to survive moderate hemorrhage. Endocrinology 1990; 127: 766-772

(5) Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients [letter]. Lancet 1983; 1:1270

(6) Addison T. Anaemia-disease of the supra-renal capsules. Lond Med Gaz 1849; 43:517-518

(7) May ME, Vaughan ED, Carey RM. Adrenocortical insufficiency: clinical aspects. In: Vaughan ED, Carey RM, eds. Adrenal disorders. New York, NY: Thieme Medical, 1989; 171-189

(8) Hollenberg SM, Weinberger C, Ong ES, et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 1985; 318:635-641

(9) Yang J, DeFranco DB. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking. Mol Endocrinol 1996; 10:3-13

(10) Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol 1992; 54:885-909

(11) Sakaue M, Hoffman BB. Glucocorticoids induce transcription and expression of the [alpha]1B adrenergic receptor gene in DTT1 MF-2 smooth muscle cells. J Clin Invest 1991; 88:385-389

(12) Collins S, Caron MC, Lefkowitz RJ. [beta]-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids. J Biol Chem 1988; 263:9067-9070

(13) Orlowski J, Lingrel JB. Thyroid and glucocorticoid hormones regulate the expression of multiple Na,K-ATPase genes in cultured neonatal rat cardiac myocytes. J Biol Chem 1990; 265:3462-3470

(14) Satoh S, Oishi K, Iwagaki A, et al. Dexamethasone impairs pulmonary defense against Pseudomonas aeruginosa through suppressing iNOS gene expression and peroxynitrite production in mice. Clin Exp Immunol Life 2001; 126:266-273

(15) Matsumura M, Kakishita H, Suzuki M, et al. Dexamethasone suppresses iNOS gene expression by inhibiting NF-[kappa]B in vascular smooth muscle cells. Life Sci 2001; 69:1067-1077

(16) Redington AE, Meng QH, Springall DR, et al. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax 2001; 56:351-357

(17) Fujii E, Yoshioka T, Ishida H, et al. Evaluation of iNOS-dependent and independent mechanisms of the microvascular permeability change induced by lipopolysaccharide. Br J Pharmacol 2000; 130:90-94

(18) Munck A, Naray-Fejes-Toth A. Glucocorticoids and stress: permissive and suppressive actions. Ann NY Acad Sci 1994; 746:115-130

(19) Fahey JV, Guyre PM. Mechanisms of anti-inflammatory actions of glucocorticoids. Adv Inflamm Res 1981; 2:21-51

(20) Barnes PJ, Adcock I. Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 1993; 14: 436-441

(21) Barnes PJ, Karin M. Nuclear factor-[kappa]B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336:1066-1071

(22) Auphan N, Didonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-[kappa]B activity through induction of IKB synthesis. Science 1995; 270:286-290

(23) Barber AEI, Coyle SM, Fischer E, et al. Influence of hypercortosolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings. Surgery 1995; 118:406-410

(24) van der Poll T, Barber AE, Coyle SM, et al. Hypercortisolemia increases plasma interleukin-10 concentrations during human endotoxemia: a clinical research center study. J Clin Endocrinol Metab 1996; 81:3604-3606

(25) Knudsen PJ, Dinarello CA, Strom TB. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 1987; 139: 4129-4134

(26) Szabo C, Thiemermann C, Wu CC, et al. Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Natl Acad Sci U S A 1994; 91:271-275

(27) Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and free cortisol index during septic shock and multitrauma. Intensive Care Med 2001; 27:1584-1591

(28) Zaloga GP, Bhatt B, Marik PE. Critical illness and systemic inflammation. In: Becker K, Nylen E, eds. Practice and principles of endocrinology and metabolism. Philadelphia, PA: Lippincott, Williams, and Wilkins, 2001; 2068-2076

(29) Besedovsky HO, del Ray A. Immuno-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 1996; 17:64-102

(30) Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999; 79:1-71

(31) Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993; 77:1690-1694

(32) Bateman A, Singh A, Kral T, et al. The immune-hypothalamic-pituitary-adrenal axis. Endocr Rev 1989; 10:92-112

(33) Gaillard RC, Turnill D, Sappino P, et al. Tumor necrosis factor ct inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology 1990; 127:101-106

(34) Richards ML, Caplan RH, Wickus GG, et al. The rapid low-dose (1 microgram) cosyntropin test in the immediate postoperative period: results in elderly subjects after major abdominal surgery. Surgery 1999; 125:431-440

(35) Soni A, Pepper GM, Wyrwinski PM, et al. Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995; 98:266-271

(36) Schroeder S, Wichers M, Klingmuller D, et al. The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med 2001; 29:310-316

(37) Catalano RD, Parameswaran V, Ramachandran J, et al. Mechanisms of adrenocortical depression during Escherichia coli shock. Arch Surg 1984; 119:145-150

(38) Keri G, Parameswaran V, Trunkey DD, et al. Effects of septic shock plasma on adrenocortical cell function. Life Sci 1981; 28:1917-1923

(39) Melby JC, Egdahl RH, Spink WW. Secretion and metabolism of cortisol after injection of endotoxin. J Lab Clin Med 1960; 56:50-62

(40) Jaattela M, Ilvesmaki V, Voutilainen R, et al. Tumor necrosis fkctor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology 1991; 128:623-629

(41) Zhu Q, Solomon s. Isolation and mode of action of rabbit corticostatic (antiadrenocorticotropin) peptides. Endocrinology 1992; 130:1413-1423

(42) Masera RG, Bateman A, Muscettola M, et al. Corticostatins/ defensins inhibit in vitro NK activity and cytokine production by human peripheral blood mononuclear cells. Regul Pept 1996; 62:13-21

(43) Tominaga T, Fukata J, Hayashi Y, et al. Distribution and characterization of immunoreactive corticostatin in the hypothalamic-pituitary-adrenal axis. Endocrinology 1992; 130:1593-1598

(44) Natarajan R, Ploszay S, Horton R, et al. Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin II induced aldosterone synthesis. Endocrinology 1989; 125: 3084-3089

(45) Jaattela M, Carpen O, Stenman UH, et al. Regulation of ACTH-induced steroidogenesis in human fetal adrenals by rTNF-[alpha]. Mol Cell Endocrinol 1990; 68:R31-R36

(46) Pariante CM, Pearce BD, Pisell TL, et al. The proinflammatory cytokine, interleukin-1[alpha], reduces glucocorticoid receptor translocation and function. Endocrinology 1999; 140:4359-4366

(47) Melby JC, Spink WW. Comparative studies of adrenal cortisol function and cortisol metabolism in healthy adults and in patients with septic shock due to infection. J Clin Invest 1958; 37:1791-1798

(48) McCallum RE, Stith RD. Endotoxin-induced inhibition of steroid binding by mouse liver cytosol. Circ Shock 1982; 9:357-367

(49) Schuler JJ, Erve PR, Schumer W. Glucocorticoid effect on hepatic carbohydrates metabolism in the endotoxin-shocked monkey. Ann Surg 1976; 183:345-354

(50) Streeten DHP. What test for hypothalamic-pituitary adrenocortical insufficiency? Lancet 1999; 354:179-180

(51) Clark PM, Neylon I, Raggatt PR, et al. Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol 1998; 49:287-292

(52) Streeten DHP, Anderson GH, Dalakos TG, et al. Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man. Endocr Rev 1984; 5: 371-394

(53) Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997; 337: 1285-1292

(54) Naito Y, Fukata J, Tamai S, et al. Biphasic changes in hypothalamic-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab 1991; 73:111-117

(55) Naito Y, Tamai S, Shingu K, et al. Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery. Anesthesiology 1992; 77:426-431

(56) Karayiannakis AJ, Makri GG, Mantzioka A, et al. Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br J Surg 1997; 84:467-471

(57) Schricker T, Carli F, Schreiber M, et al. Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after, lower abdominal surgery. Anesth Analg 2000; 90:450-455

(58) Motamed S, Klubien K, Edwardes M, et al. Metabolic changes during recovery in normothermic vs hypothermic patients undergoing surgery and receiving general anesthesia and epidural local anesthetic agents. Anesthesiology 1998; 88:1211-1218

(59) Plunkett JJ, Reeves JD, Ngo L, et al. Urine and plasma catecholamine and cortisol concentrations after myocardial revascularization: modulation by continuous sedation. Multicenter Study of Perioperative Ischemia (McSPI) Research Group, and the Ischemia Research and Education Foundation (IREF). Anesthesiology 1997; 86:785-796

(60) Vermes I, Beishuizen A, Hampsink RM, et al. Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 1995; 80:1238-1242

(61) Wade CE, Lindberg JS, Cockrell JL, et al. Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients. J Clin Endocrinol Metab 1988; 67:223-227

(62) Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med 1995; 23:78-83

(63) Chernow B, Rainey TR, Lake CR. Endogenous and exogenous catecholamines in critical care medicine. Crit Care Med 1982; 10:409-416

(64) Hart BB, Stanford GG, Ziegler MG, et al. Catecholamines: study of interspecies variation. Crit Care Med 1989; 17: 1203-1218

(65) Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency. Crit Care Clin 2001; 17:25-42

(66) Schein RMH, Sprung CL, Martial E. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990; 18:259-263

(67) Drucker D, Shandling M. Variable adrenocortical function in acute medical illness. Crit Care Med 1985; 13:477-479

(68) Chernow B, Alexander HR, Smallridge RC, et al. Hormonal responses to graded surgical stress. Arch Intern Med 1987; 147:1273-1278

(69) Donald RA, Perry EG, Wittert GA, et al. The plasma ACTH, AVP, CRH, and catecholamine responses to conventional and laparoscopic cholecystectomy. Clin Endocrinol 1993; 38:609-615

(70) Rivers EP, Gaspari M, Abi Saad G, et al. Adrenal insufficiency in high-risk surgical ICU patients. Chest 2001; 119:889-896

(71) Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000; 283: 1038-1045

(72) Annane D, Bellissant E. Prognostic value of cortisol response in septic shock. JAMA 2000; 284:308-309

(73) Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996; 81:285-290

(74) Beishuizen A, Vermes I, Hylkema BS, et al. Relative eosinophilia and Junctional adrenal insufficiency in critically ill patients [letter]. Lancet 1999; 353:1675-1676

(75) Drucker D, McLaughlin J. Adrenocortical dysfunction in acute medical illness. Crit Care Med 1986; 14:789-791

(76) Sibbald WJ, Short A, Cohen MP, et al. Variations in adrenocortical responsiveness during severe bacterial infections: unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg 1977; 186:29-33

(77) Hampson N, Norkool D. Carbon monoxide poisoning in children riding in the back of pickup trucks. JAMA 1992; 267:538-540

(78) Dennhardt R, Gramm HJ, Meinhold K, et al. Patterns of endocrine secretion during sepsis. Prog Clin Biol Res 1989; 308:751-756

(79) McKee JI, Finlay WE. Cortisol replacement in severely stressed patients [letter]. Lancet 1983; 1:484

(80) Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med (in press)

(81) Borst GC, Michenfelder HJ, O'Brian JT. Discordant cortisol response to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 1982; 306:1462-1464

(82) Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 minute ACTH test in assessing he hypothalamic-pituitary-adrenocortical function. Clin Endoerinol 1987; 26: 53-59

(83) Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995; 80:1243-1246

(84) Mayenknecht J, Diederich S, Bahr V, et al. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83: 1558-1562

(85) Rasmuson S, Olsson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 1996; 44:151-156

(86) Tordjman K, Jaffe A, Grazas N, et al. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995; 80:1301-1305

(87) Abdu TA, Elhadd TA, Neary R, et al. Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 1999; 84:838-843

(88) Marik PE, Kiminyo K, Zaloga GP. Adrenal insufficiency in critically ill HIV infected patients. Crit Care Med 2002; 30:1267-1273

(89) Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 1985; 60:947-952

(90) Briegel J, Scheelling G, Haller M, et al. A comparison of the adrenocortical response during septic shock and after complete recovery. Intensive Care Med 1996; 22:894-899

(91) Barquist E, Kirton O. Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 1997; 42:27-31

(92) Rydvall A, Brandstrom AK, Banga R, et al. Plasma cortisol is often decreased in patients in an intensive care unit. Intensive Care Med 2000; 26:545-551

(93) Moran JL, Chapman MJ, O'Fathartaigh MS, et al. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock. Intensive Care Med 1994; 20:489-495

(94) Oelkers W. Adrenal insufficiency. N Engl J Med 1996; 335:1206-1212

(95) Pulakhandam U, Dincsoy HP. Cytomegaloviral adrenalitis and adrenal insufficiency in AIDS. Am J Clin Pathol 1990; 93:651-656

(96) Glasgow B J, Steinsapir KD, Anders K, et al. Adrenal pathology in the acquired immune deficiency syndrome. Am J Clin Pathol 1985; 84:594-597

(97) Welch K, Finkbeiner W, Alpers CE, et al. Autopsy findings in the acquired immune deficiency syndrome. JAMA 1984; 252:1152-1159

(98) Grinspoon SK, Bilezikian JP. HIV disease and the endocrine system. N Engl J Med 1992; 327:1360-1365

(99) Aron DC. Endocrine complications of the acquired immunodeficiency syndrome. Arch Intern Med 1989; 149: 330-333

(100) Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987; 317:812-818

(101) Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med 1994; 154:949-973

(102) Hofbauer LC, Heufelder AE. Endocrine implications of human immunodeficiency virus infection. Medicine 1996; 75:262-278

(103) Schlaghecke R, Kornely E, Santen RT, et al. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 1992; 326:226-230

(104) Kannisto S, Korpi M, Remes K, et al. Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids. J Clin Endocrinol Metab 2000; 85:652-657

(105) Henzen C, Suter A, Lerch E, et al. Suppression and recovery of adrenal response after short-term high-dose glucocorticoid treatment. Lancet 2000; 355:542-545

(106) Jasani MK, Boyle JA, Greig WR, et al. Corticosteroid-induced suppression of the hypothalamo-pituitary-adrenal axis: observations on patients given oral corticosteroids for rheumatoid arthritis. Q J Med 1967; 36:261-276

(107) Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671-676

(108) Zaloga GP. Sepsis-induced adrenal deficiency syndrome. Crit Care Med 2001; 29:688-690

(109) Koo DJ, Jackman D, Chaundry IH, et al. Adrenal insufficiency (luring the late stage of polymicrobial sepsis. Crit Care Med 2001; 29:618-622

(110) Annane D, Bellissant E, Bollaert PE. The hypothalamic-pituitary axis in septic shock. Br J Intensive Care 1996; 6:260-268

(111) Ali M, Allen HR, Vedeckis WV, et al. Depletion of rat liver glucocorticoid receptor hormone-binding and its mRNA in sepsis. Life Sci 1991; 48:603-611

(112) Molijn GJ, Koper Jw, van Uffelen CJ, et al. Temperature-induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leukocytes in patients with sepsis and septic shock. Clin Endocrinol 1995; 43:197-203

(113) Norbiato G, Bevilacqua M, Vago T, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74:608-613

(114) Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998; 26:645-650

(115) Briegel J, Forst H, Hailer M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999; 27:723-732

(116) Annane D. Effects of the combination of hydrocortisone-fludro-cortisone on mortality in septic shock [abstract]. Crit Care Med 2000; 28(suppl):A46

(117) Oppert M, Reinicke A, Graf KJ, et al. Plasma cortisol levels before and during "low-dose" hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock. Intensive Care Med 2000; 26:1747-1755

(118) The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317:659-665

(119) Bone RC, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317:653-658

(120) Schelling G, Stoll C, Kapfhammer HP, et al. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder and health-related quality of life in survivors. Crit Care Med 1999; 27:2678-2683

(121) Salem M, Trainsh RE, Bromberg J, et al. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. Ann Surg 1994; 219:416-425

Manuscript received February 8, 2002; revision accepted April 12, 2002.

Correspondence to: Paul Marik, MD, FCCP, Department of Critical Care, University of Pittsburgh Medical School, 640A Scaife Hall, 3550 Terrace St, Pittsburgh, PA, 1,5261; e-mail:

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2003 Gale Group

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