Pathophysiology

To understand the pathogenesis of adrenal diseases one must understand the physiology of the adrenal glands and the causes that result in the disruption of the physiologic process.

The adrenal glands are pyramid-shaped, each weighing about 5 to 10 g, and located just superior to their respective kidneys. The left adrenal gland is usually slightly more cephalad than the right. Each adrenal gland is composed of an inner medulla and outer cortex. These layers are embryologically, anatomically, and physiologically distinct. The adrenal cortex is responsible for the secretion of multiple steroid hormones. The adrenal medulla is responsible for the secretion of catecholamines.

The adrenal cortex is composed of three zones: the outer zona glomerulosa, inner zona fasciculata, and zona reticularis. The zona glomerulosa secretes the mineralocorticoid aldosterone in response to angiotensin, ACTH, and a high circulating potassium concentration. The zona fasciculata and zona reticularis secrete glucocorticoids and adrenal androgens.

The principal mineralocorticoid is aldosterone, which is regulated not only by ACTH but also by serum sodium and potassium levels and by the renin-angiotensin system.7,8 Mineralocorticoids exert their primary effect on distal renal tubule cells, resulting in renal sodium retention at the expense of potassium loss in the urine. A third major class of adrenal steroids is the sex hormones: dehydroepiandrosterone (DHEA), DHEA-sulfate, and androstenedione. Like the glucocorticoids, ACTH primarily regulates these steroid hormones. They function mainly as precursors for the primary circulating androgen, testosterone, and also may undergo separate conversion to estrogen hormones. In critically ill patients, glucocorticoids are the steroid hormones of greatest concern and therefore remain the focus of the remainder of this discussion.

Glucocorticoid Synthesis

Glucocorticoid synthesis is regulated by (1) a negative feedback mechanism involving cortisol and adrenal steroids, (2) a diurnal rhythm, and (3) stress. The hypothalamus and the pituitary gland closely regulate adrenal hormone production. Corticotropin-releasing hormone (CRH) is produced in the hypothalamus and acts on specialized cells in the pituitary, stimulating production of ACTH, which serves, in turn, to stimulate adrenal cortical cells to produce numerous steroid hormones, including cortisol. Adrenal hormones have a negative influence at the level of the hypothalamus and the pituitary, inhibiting CRH and ACTH release. The adrenal gland in turn ceases its secretory activity until the cortisol concentration returns to normal. When serum cortisol levels are below normal, secretion of CRH and ACTH increases, stimulating the adrenal glands to produce cortisol until its level normalizes. Therefore, abnormalities in circulating serum levels of adrenal steroid hormone can be caused by either adrenal or hypothalamic pituitary disease. Because ACTH possesses α-melanocyte-stimulating hormone activity, excessive production of ACTH is associated with hyperpigmentation.

Cortisol is normally secreted in a diurnal pattern. The circulating cortisol level is increased in the morning hours, at approximately 8 AM. Serum cortisol concentrations decrease throughout the remainder of the day.⁹ Similarly, the serum cortisol response to ACTH stimulation also varies in a circadian rhythm. Afternoon responsiveness is much greater because of the decreased circadian level of cortisol at that time. In addition, cortisol is secreted in a series of pulses rather than in a continuous fashion. These factors contribute to make interpretation of a random cortisol level and the ACTH-stimulated value difficult.

“Stress” (exemplified by sepsis, major surgery, or trauma) also affects glucocorticoid synthesis.10–12 The stress response is characterized by continuous ACTH secretion despite a high serum cortisol concentration. Stress overrides all other regulatory mechanisms of cortisol secretion by the adrenal cortex and increases cortisol secretion irrespective of the time of day or the current serum cortisol concentration. The mechanism by which the HPA axis is regulated during stress is not clearly understood. Periventricular neurons in the hypothalamus respond to stress by increasing the levels of CRH messenger ribonucleic acid (mRNA).^13,14 It has been shown that production of the cytokines interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) also plays an important role in the regulation of the HPA axis.^15–19 The cortisol secretion that occurs because of the activation of the HPA axis causes an inhibitory effect not only on the secretion of CRH and ACTH but also on the liberation of interleukins.²⁰ Thus, there is a functional loop between immune activation and regulation of the HPA axis during stress.

The stress response is biphasic, consisting of an early phase in which both ACTH and cortisol are elevated and a late phase in which the serum cortisol level is elevated but the serum ACTH level is paradoxically low.⁸ This is explained by the fact that endothelin and atrial natriuretic peptide are both elevated in severe illnesses. Endothelin increases cortisol production by the adrenals, whereas the atrial natriuretic peptide inhibits ACTH production by acting at the hypothalamic-pituitary level. Vasopressin and angiotensin II can increase ACTH secretion during stress conditions, such as sepsis and septic shock

Acute respiratory failure causes a 50% to 100% rise in serum cortisol concentration. A twofold to sixfold rise occurs with septic shock and following surgical procedures and trauma. The rise in serum cortisol correlates positively with severity of illness⁶ and negatively with survival.⁷

The normal daily output of cortisol by the adrenal glands is 20 to 30 mg. The normal adrenal gland secretes about 10 to 12 times the normal daily output of cortisol when under maximal physiologic stress. Hence approximately 200 to 300 mg of hydrocortisone or its equivalent is considered a daily “stress dose” of glucocorticoid.

Glucocorticoid Actions

After uptake of free hormone from the circulation, the effects of cortisol and aldosterone are mediated by binding to intracellular receptors termed the glucocorticoid receptor and the mineralocorticoid receptor.

Autoimmune Disease

Autoimmune disease (Addison’s disease) is currently the most common cause of primary AI and accounts for approximately 80% of cases. For many years tuberculosis was the most common cause. AI may occur as isolated disease or as part of a polyglandular autoimmune syndrome associated with thyroiditis, diabetes mellitus (Schmidt’s syndrome), hypogonadism, vitiligo, and pernicious anemia.27–29 Autoimmune AI is more common in women than men and usually occurs in the third to fifth decades of life. The mean duration of symptoms before diagnosis is approximately 3 years. In this disorder high levels of circulating autoantibodies attack the cytoplasm of adrenal cortical cells and inhibit synthesis of glucocorticoids.^27,28

Infectious Disease

Acquired Immunodeficiency Syndrome

Patients with acquired immunodeficiency syndrome (AIDS) are at risk of developing AI by several different mechanisms. Fungal infections are more common in this patient population, and disseminated disease may involve the adrenal glands. Similarly, mycobacterial infection, cytomegalovirus infection, and Kaposi sarcoma may cause involvement of the adrenals in up to 50% of patients.³ In addition, sepsis and spontaneous adrenal hemorrhage are also seen in this group of patients. Because patients with human immunodeficiency virus (HIV) infection now survive longer, an increased incidence of AI is likely.

Neoplasia

Neoplastic metastasis to the adrenal glands has been found on autopsy in 27% to 40% of patients who die of malignancy.33–36 Yet metastatic carcinoma accounts for less than 1% of cases of primary AI.³³ This finding is explained by the tremendous functional reserve possessed by the adrenal glands. More than 90% of the adrenal gland must be destroyed before hypofunction occurs. Many patients with metastasis to the adrenals do not develop hormonal deficiency.³⁷ The most common neoplasms to involve the adrenals are lung cancer, breast cancer, melanoma, and lymphoma.³⁵ AI usually occurs in the setting of widespread metastatic disease and is rarely the initial manifestation of malignancy.

Medications

Certain medications can cause AI. Of particular interest to the intensivist are ketoconazole, phenytoin, phenobarbital, rifampin, and etomidate. Ketoconazole decreases glucocorticoid production and is also a glucocorticoid receptor antagonist. Etomidate decreases glucocorticoid production. Phenytoin, rifampin, and barbiturates increase the catabolism of glucocorticoids. These medications can precipitate acute AI by decreasing glucocorticoid production or function in a patient who has compromised adrenal reserve.

Adrenal Hemorrhage

Adrenal hemorrhage is an important but uncommon cause of AI in the ICU. The association of adrenal hemorrhage with fulminant sepsis was first described with Neisseria meningitidis (Waterhouse-Friderichsen syndrome). Infections with Streptococcus pneumoniae, Pseudomonas species, and Haemophilus influenzae type b can also cause this syndrome.

Besides the infectious causes, other conditions may predispose to adrenal hemorrhage, including severe illness (particularly cardiac disease), coagulopathy, anticoagulant therapy, thromboembolism, burns, and trauma.³⁸ Under these circumstances the typical signs and symptoms of AI are often mistaken for those of other common conditions. Typical settings include the patient who is in the first or second postoperative week or a patient who has been started recently on anticoagulation therapy. Common findings include abdominal, back, flank, or chest pain; nausea; vomiting; fever; altered mental status; orthostatic hypotension; and a sudden drop in hematocrit. The hemodynamic crisis associated with adrenal hemorrhage occurs 1 to 3 days after the initial hemorrhage.

Etiology of Secondary Adrenal Insufficiency

Causes of secondary AI have been discussed previously and are shown in Box 59.2. Secondary AI occurs because of a decrease in ACTH caused by either hypothalamic-pituitary disease or suppression of the HPA axis as a result of glucocorticoid therapy. The most common cause today is discontinuation of corticosteroid therapy. Chronic glucocorticoid therapy leads to HPA axis suppression with resulting secondary AI if glucocorticoids are abruptly discontinued. With the exception of AI because of discontinuation of chronic glucocorticoid therapy, secondary adrenocortical insufficiency is much less common than primary AI. Isolated ACTH deficiency is rare, and ACTH is the last pituitary hormone to be impaired by enlarging sellar and suprasellar tumors.

Most patients admitted to the ICU with secondary AI have recently received steroid therapy or have taken steroids within the year prior to admission. No clear evidence indicates that detailing the duration or dose of steroid therapy predisposes patients to adrenal suppression. Doses of 25 mg of prednisone twice a day for 2 days, 12.5 mg per day for 6 months, or 5 mg per day for 5 years have all been shown to cause adrenal suppression. On the other hand, studies have shown that prednisone in doses less than 40 mg per day given every morning for 5 to 7 days did not cause adrenal suppression.³⁹

As a practical guideline, all patients who have taken 40 mg of prednisone per day or its equivalent for a period greater than 2 or 3 weeks should be considered to be adrenal insufficient until proved otherwise. If glucocorticoids have been given to a patient for more than 1 to 2 weeks, they should be tapered off to allow time for the adrenal glands to recover function. AI can occur in response to stress as long as 1 year after steroids are discontinued.⁴⁰ All of these patients should be evaluated for adrenal function and should be treated with stress doses of steroids during the interim period.

Laboratory Findings

Laboratory evaluation of patients with suspected AI is essential. In a patient with acute worsening of a chronic hypoadrenal state, the common laboratory findings shown in Box 59.4 are more likely to be present and are likely to be more pronounced. Electrolyte abnormalities depend on the type of deficiency: a combined glucocorticoid and mineralocorticoid deficiency (typically seen in primary AI) or an isolated glucocorticoid deficiency (characteristic of secondary AI).

Patients who have a combined deficiency may show hyponatremia, hyperkalemia, decreased serum bicarbonate, and increased blood urea nitrogen (BUN). This is primarily caused by the mineralocorticoid deficiency, which leads to renal sodium loss, potassium retention, and dehydration with acidosis and prerenal azotemia. Patients with secondary adrenocortical deficiency usually have milder electrolyte abnormalities. Their normal adrenal glands are able to produce sufficient amounts of mineralocorticoid even in the absence of ACTH stimulation. They usually have mild hyponatremia with normal potassium levels, and they show little evidence of dehydration. Patients with AI may also have hypoglycemia. This occurs as a result of increased utilization of glucose and decreased gluconeogenesis in the face of glucocorticoid deficiency.

Diagnostic Tests

When there is a high suspicion of AI, hormonal testing is necessary to confirm the diagnosis. The laboratory evaluations most commonly used to detect AI in critically ill patients are the random serum cortisol level and the rapid ACTH stimulation test.

Critical Illness–Related Corticosteroid Insufficiency

The term critical illness–related corticosteroid insufficiency (CIRCI) describes HPA axis dysfunction in critical illness, which is defined as a cellular corticosteroid activity that is inadequate for the severity of the patient’s illness. The use of the term relative adrenal insufficiency is no longer recommended by some authors.

Despite no conclusive evidence of benefit, in the 1950s, 1960s, and into the 1970s cortisol at low doses over days was often used in patients with severe manifestations of sepsis to counter the AI that was assumed to be present. This was based on autopsy studies that revealed adrenal necrosis in patients dying with severe infection. The subsequent recognition of the systemic effects of inflammation in sepsis and the discovery that the majority of patients in septic shock had normal or increased cortisol levels led to a paradigm shift in treating septic shock with massive doses of steroids given for a short period of time. This practice was based on animal studies showing that large doses of steroids given prior to boluses of endotoxin or gram-negative bacteria prevented death.⁴² Clinical trials testing the utility of several large doses of steroids in patients with septic shock failed to show benefit.^47,48

One study in patients with septic shock demonstrated that regardless of baseline cortisol level, the inability to raise the cortisol level following ACTH stimulation by at least 10 µg/dL signified poor prognosis.⁴⁹ Of this poor prognostic group, the higher the baseline cortisol level with failure to produce a 10 µg/dL increase, the worse the prognosis.

Preexisting Adrenal Insufficiency

Patients who are known to have AI or who have received glucocorticoid therapy in the past year should receive stress doses of corticosteroids during critical illnesses and during surgical procedures. Hydrocortisone 100 mg IV bolus is administered followed by 100 mg as an intravenous infusion every 6 to 8 hours. Isotonic saline is administered intravenously in volumes sufficient to support blood pressure. Five percent dextrose in isotonic saline may be used in the hypoglycemic patient. Once the acute insult has resolved, the hydrocortisone should be tapered to a maintenance dose. The replacement dose is usually 5 mg of prednisone or 30 mg of hydrocortisone each day.

Patients with known AI scheduled for operation should continue the existing steroid dose prior to surgery. The morning of the operation hydrocortisone 100 mg is given intravenously. During the operation a 100-mg hydrocortisone infusion is given. Following surgery 100 mg of hydrocortisone is administered intravenously every 8 hours during the first postoperative day. The dose is then tapered back to the baseline steroid dose over the next 3 to 4 days.

Adequate instruction is important in this group of patients. Patients with AI should be advised to wear a medical alert bracelet. These patients should be provided with a parenteral form of glucocorticoid and taught to self-administer the drug in case of emergency. They should be taught about the clinical situations in which increased amounts of glucocorticoids are required.

Hemodynamically Stable Patient

A patient who is suspected of having AI and who is hemodynamically stable should be managed in the following manner. A serum cortisol level and a rapid ACTH stimulation test should be performed prior to initiation of stress doses of corticosteroids. Hypovolemia should be treated with isotonic saline. If the diagnosis of AI is confirmed, hydrocortisone 100 mg should be administered as an intravenous infusion every 6 to 8 hours.

Hemodynamically Unstable Patient

Acute AI is a life-threatening emergency and requires immediate and aggressive therapy to ensure prompt recovery. A patient who is suspected of having AI and who is hemodynamically unstable should be managed in the following manner. Immediate glucocorticoid therapy and intravenous administration of isotonic fluids are warranted. Blood should be obtained for baseline serum cortisol concentration, electrolytes, glucose, BUN, and creatinine.

The dose of hydrocortisone is 100 mg IV bolus followed by 100 mg IV every 6 hours. After the patient has stabilized, the hydrocortisone is tapered at 10 to 15 mg per day until a maintenance dose of 30 mg per day is achieved.

Vigorous intravascular volume expansion with saline-containing solutions is recommended. Volume resuscitation is usually initiated with 0.9% normal saline. Dextrose 5% in saline is added to prevent hypoglycemia. The patient’s fluid, electrolyte, and glucose status should be carefully monitored during resuscitation. In general, patients with acute AI have a deficit that is approximately 20% of their extracellular space. The rapidity of infusion depends on the patient’s hemodynamic status and the presence or absence of underlying cardiovascular disease. A pulmonary artery catheter may be helpful in monitoring hemodynamic status and guiding fluid therapy. Vasopressors may be necessary in the initial stages to maintain an adequate blood pressure to ensure tissue perfusion. In general, if the hypotension is caused by AI, improvement in blood pressure should be seen within 6 hours of corticosteroid therapy.

Mineralocorticoid administration is usually not required initially during acute AI, because the large doses of hydrocortisone provide adequate mineralocorticoid activity. Once the acute event has resolved and the hydrocortisone is tapered to less than 100 mg per day, mineralocorticoids should be started. Fludrocortisone is recommended at a dose of 0.05 to 0.20 mg per day. Excess mineralocorticoids can cause congestive heart failure, hypokalemia, and metabolic alkalosis.

In patients with concurrent hypothyroidism, glucocorticoid replacement should begin prior to thyroid hormone replacement. Administration of thyroid hormone increases the metabolism of glucocorticoids. Thus treatment with thyroid hormone before glucocorticoid therapy might worsen the hypoadrenal state and precipitate AI.

Reversal of the underlying cause of adrenal dysfunction is an important aspect of treatment. The precipitation of acute adrenal failure is provoked by another acute process and thus the causes of both primary and secondary AI should be sought. Prophylactic use of antibiotics is not beneficial, but specific infections should be treated aggressively with appropriate antibiotic therapy.

Severe Sepsis and Septic Shock

Six randomized clinical trials suggest that replacement of moderate-dose hydrocortisone (200-300 mg/day) decreases the need for vasopressor support in patients with septic shock.2,53 Among them, the two larger trials were better powered to detect a survival difference but had differing results. These differences were attributed in part to varying demographics and other factors. In the Corticus study, hydrocortisone did not decrease mortality rate in both responders and nonresponders to ACTH, but the patients who received hydrocortisone had more rapid resolution of shock, which has been seen in other studies as well. These results were different from the Annane study, in which the nonresponders to ACTH had both reduction in mortality rate and reversal of shock. The differences were attributed in part to the fact that in the Annane study, the patients enrolled were sicker, patients had higher SAPS II scores, and time to enrollment differed (8 hours versus 72 hours in the Corticus study). The Corticus study was published some years after the Annane study; it is possible that variations in the supportive care of the critically ill with advances in the care of the septic patient in the last few years could have made it difficult to show a mortality rate difference in Corticus. More patients in the Corticus study had a surgical source of sepsis, and thus source control may have played a bigger role in improving outcomes. In addition, fludrocortisones was not administered in the Corticus study. The duration of steroid therapy was different in the two studies, and this could have caused the differing results. In addition, Corticus had a higher rate of superinfection. Compounding all these issues is the difficulty surrounding the accurate diagnosis of AI.^53,54 However, in a recent study, the addition of enteral fludrocortisone did not result in a significant improvement in hospital mortality rates.⁵⁵

In the trials mentioned here, there was resolution of shock in both responders and nonresponders to ACTH stimulation. The decision to treat patients with septic shock with hydrocortisone should, therefore, probably not be based on the results of a random total cortisol level or the response to cosyntropin. If a clinician decides to perform an ACTH test, until the test is performed, treatment with dexamethasone in patients with septic shock should not be done because of the possibility that a single dose of a long-acting corticosteroid may cause prolonged suppression of the hypothalamic-pituitary axis.²

Once initiated, hydrocortisone should ideally be continued for about 7 days. At the present time, the optimum duration of therapy is not clear, but data from studies would suggest that abrupt discontinuation of hydrocortisone could precipitate a rebound inflammatory response and recurrent shock. The ideal dose of steroid should help decrease the proinflammatory responses and at the same time minimize adverse effects, such as interference with wound healing, and decrease any negative impact on immune function. From studies, it appears that adverse effects of myopathy and superinfections are more common with doses greater than 200 to 300 mg/day of hydrocortisone. Hydrocortisone can be administered as a bolus dose or as a continuous infusion. Continuous infusions tend to cause less glycemic fluctuations.

To date, no studies document an improved outcome with corticosteroid use in the absence of septic shock (Fig. 59.1).

Additional Indications for Corticosteroids

Observational studies suggest that stress doses of corticosteroids may have a role in the management of critically ill patients with liver failure and cardiac surgery. Additional large randomized studies are needed in these areas.³

Etomidate

Etomidate is a drug increasingly used as an induction agent for endotracheal intubation. It has the advantage of not causing hemodynamic instability. This drug inhibits the 11β-hydroxylase enzyme that converts 11-deoxycortisol into cortisol in the adrenal gland, and can cause AI. This adverse event has been described with single bolus and continuous infusions.

Additional randomized clinical trials are needed in this area to determine the clinical significance of this agent in causing AI septic shock and the effect on mortality rate, given that the incidence of AI in septic patients can be as high as 60%.⁴³

1. Cooper, MS, Stewart, PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003; 348:727–734.

2. Marik, PE, Pastores, SM, Annane, D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008; 36:1937–1949.

3. Marik, PE. Critical illness-related corticosteroid insufficiency. Chest. 2009; 135(1):181–193.

4. Bornstein, SR. Predisposing factors for adrenal insufficiency. N Engl J Med. 2009; 360:2328–2339.

5. Annane, D, Maxime, V, Ibrahim, F, et al. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med. 2006; 174:1319–1326.

6. Span, LFR, Hermus, ARMM, Bartelink, AKM, et al. Adrenocortical function: An indicator of severity of disease and survival in chronically ill patients. Intensive Care Med. 1992; 18:93.

7. Jurney, TH, Cockrell, JL, Lindberg, JS, et al. Spectrum of serum cortisol response to ACTH in patients: Correlation with degree of illness and mortality. Chest. 1987; 92:292.

8. Vermes, I, Beishuizen, A, Hampsink, RM, et al. Dissociation of plasma ACTH and cortisol levels in critically ill patients: Possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab. 1995; 80:1238.

9. Horrocks, PM, Jones, AF, Ratcliffe, WA, et al. Pattern of ACTH and cortisol pulsatility over 24 hours in normal males and females. Clin Endocrinol. 1990; 32:127.

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

11. Nto, T, Fukata, J, Tam, S, et al. Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab. 1991; 73:111.

12. Ellis, MJ, Schmidli, RS, Livesey, JH, et al. Plasma corticotropin releasing factor and vasopressin responses to hypoglycemia in normal man. Clin Endocrinol. 1990; 32:93.

13. Wittert, GA, Stewart, DE, Graves, MP, et al. Plasma corticotropin releasing factor and vasopressin responses to exercise in normal man. Clin Endocrinol. 1991; 35:311.

14. Bartanusz, V, Jezova, D, Bertini, LC, et al. Stress induced increase in vasopressin and corticotropin releasing factor expression in hypophysiotropic paraventricular neurons. Endocrinology. 1993; 132:895.

15. Gllard, WO, Turnhill, D, Sappino, P, Muller, AF. Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology. 1990; 127:101.

16. Darling, G, Goldstein, DS, Stull, R, et al. Tumor necrosis factor: Immune endocrine interaction. Surgery. 1989; 106:1155.

17. Jaattela, M, Ilvesmaki, V, Voutilnen, R, et al. Tumor necrosis factor 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.

18. Sharp, BM, Matta, SG, Peterson, PK, et al. Tumor necrosis factor alpha is a potent ACTH secretagogue: Comparison to interleukin 1 beta. Endocrinology. 1989; 124:3131.

19. Bateman, A, Singh, A, Kral, T, Solomon, S. The immune hypothalamo-pituitary axis. Endocrinol Rev. 1989; 10:92.

20. Besedovsky, H, Delrey, A, Sorkin, E, Dinarello, CA. Immunoregulatory feedback between interleukin 1 and glucocorticoid hormone. Science. 1986; 233:652.

21. Stewart, PM. The adrenal cortex and endocrine hypertension. In: Kronenberg HM, Melmed S, Polonsky KS, et al, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia: WB Saunders; 2011:479–534.

22. Svedmyr, N. Action of corticosteroids on beta-adrenergic receptors. Am Rev Respir Dis. 1990; 141:S31.

23. Bouachour, G, Tirot, P, Varache, N, et al. Hemodynamic changes in acute AI. Intensive Care Med. 1994; 20:138.

24. Luckert, BP, Rsz, LG. Glucocorticoid induced osteoporosis: Pathogenesis and management. Ann Intern Med. 1990; 112:352.

25. Munck, A, Náray-Fejes-Toth, A. Glucocorticoid physiology. In: DeGroot L, Jameson JL, eds. Endocrinology. 5th ed. Philadelphia: WB Saunders; 2005:2287–2309.

26. Schwartz, J, Keil, LC, Masseli, J, Reid, I. Role of vasopressin in regulating blood pressure in AI. Endocrinology. 1983; 112:234.

27. Bright, GM, Singh, I. Adrenal autoantibodies bind to adrenal subcellular fractions enriched in cytochrome c reductase and 5′-nucleotidase. J Clin Endocrinol Metab. 1990; 70:95.

28. De Bellis, A, Bizzarro, A, Rossi, R, et al. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab. 1993; 76:1002.

29. Loriaux, DL. The polyendocrine deficiency syndromes. N Engl J Med. 1985; 312:1568.

30. Irwine, WJ, Barnes, EW. AI. Clin Endocrinol Metab. 1972; 1:549.

31. Guttma, PH. Addison’s disease. Arch Pathol. 1930; 10:742.

32. Sarosi, GA, Voth, DW, Dahl, BA, et al. Disseminated histoplasmosis: Results of long term follow up. A CDC cooperative mycoses study. Ann Intern Med. 1971; 75:511.

33. Knowlton, AI. Adrenal insufficiency in the intensive care setting. J Intensive Care Med. 1989; 4:35.

34. Dluhy, RG. The growing spectrum of HIV-related endocrine abnormalities. J Clin Endocrinol. 1990; 70:563.

35. Redman, BG, Pazdur, R, Zingas, AP, Loredo, R. Prospective evaluation of AI in patients with adrenal metastasis. Cancer. 1987; 60:103.

36. Irwine, W. Autoimmunity in endocrine disease. Proc R Soc Med. 1974; 67:548.

37. Kung, AWC, Pun, KK, Lam, K, et al. Addisonian crisis as presenting feature in malignancies. Cancer. 1990; 65:177.

38. Rao, RH, Vagnucci, AH, Amico, JA. Bilateral massive adrenal hemorrhage: Early recognition and treatment. Ann Intern Med. 1989; 110:227.

39. Christy, NP, Wallace, EZ, Jler, JW. Comparative effects of prednisone and cortisone in suppressing the response of the adrenal cortex to exogenous adrenocorticotropin. J Clin Endocrinol Metab. 1956; 16:1059.

40. Graber, AL, Ney, RL, Nicholson, WE, et al. Natural history of pituitary-adrenal recovery following long term suppression with corticosteroids. J Clin Endocrinol. 1956; 25:11.

41. Hamrahain, AH, Oseni, TS, Awafah, BM, et al. Measurement of serum free cortisol in critically ill patients. N Engl J Med. 2004; 350:1629–1639.

42. Cohen, J, Ward, G, Prins, J, et al. Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population. Intensive Care Med. 2006; 32:1901–1911.

43. Jackson, WL. Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock? A critical appraisal. Chest. 2005; 127:1031–1038.

44. Dickstein, G, Shechner, C, Nicholson, WE, et al. Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab. 1991; 72:773.

45. Crowley, S, Hindmarsh, C, Honour, JW, Brook, CGD. Reproducibility of the cortisol response to stimulation with dose of ACTH: The effect of basal cortisol levels and comparison of low dose with high dose secretory dynamics. Endocrinology. 1993; 136:167.

46. Motsay, GJ, Alho, A, Jaeger, T, et al. Effects of corticosteroids on the circulation in shock: Experimental and clinical results. Fed Proc. 1970; 29:1861–1873.

47. Sprung, CL, Caralis, PV, Marcial, EH, et al. The effects of high-dose corticosteroids in patients with septic shock. N Engl J Med. 1984; 311:1137–1143.

48. Bone, RC, Fisher, CJ, Clemmer, TP, et al. and the Methylprednisolone Severe Sepsis Study Group: 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.

49. Annane, D, Sébille, 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.

50. Nerup, J. Addison’s disease—A review of some clinical, pathological and immunological features. Dan Med Bull. 1974; 21:201.

51. Doppman, JL, Gill, JR, Nienhuis, AW, et al. CT findings in Addison’s disease. J Comput Assist Tomogr. 1982; 6:757.

52. Lamberts, SWJ, Bruining, HA, Dejong, FH. Drug therapy: Corticosteroid therapy in severe illness. N Engl J Med. 1997; 337:1285–1292.

53. 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.

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

55. Annane, D, Cariou, A, Maxime, V, et al. COIITSS Study Investigators: Corticosteroid treatment and intensive insulin therapy for septic shock in adults: A randomized controlled trial. JAMA. 2010; 303(4):341–348.