Douglas B. Coursin, MD. Kenneth E. Wood, DO

Author Affiliations: Departments of Anesthesiology and Medicine (Dr Coursin) and Department of Medicine (Dr Wood), University of Wisconsin-Madison Medical School.

Corresponding Author and Reprints: Douglas B. Coursin, MD, University of Wisconsin-Madison Medical School, 600 Highland Ave, B6/319 Clinical Science Center, Madison, WI 53792-3272; E-mail: dcoursin@facstaff.wisc.edu.

Contempo Updates Section Editor: Janet M. Torpy, MD, Fishbein Fellow.

In 1949, the clinical introduction of cortisone, a purified glucocorticoid preparation, revolutionized medical care of patients with a host of diseases and provided lifesustaining physiologic replacement in patients with acute or chronic adrenal insufficiency (AI).^1,2 Case reports appeared shortly after the introduction of chronic glucocorticoid therapy describing life-threatening adrenal crises in patients with medical or surgical stresses not receiving adequate corticosteroid supplementation.^3,4 Prior edicts suggesting large-dose, long-duration therapy were not tailored to either patient or procedure. Current recommendations about supplementation during major and minor illnesses or invasive procedures, rationale, and dosing schedules have changed.^5,6 During preparationβ of this manuscript, we searched MEDLINE and several other evidence-based medicine databases, including the Cochrane Database of Systematic Reviews.

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Adrenal Cortex Corticosteroid Production and Function

Glucocorticoids are lifesustaining cholesterol derivatives produced in the zona fasciculata of the adrenal cortex under the negative feedback control of both the hypothalamus and pituitary gland, (hypothalamic-pituitary-adrenal [HPA] axis). The hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to synthesize adrenocorticotropic hormone (ACTH) to signal production of cortisol, the main endogenous glucocorticoid.^2,7 Cellular receptors for cortisol are ubiquitous in cell cytoplasm, reflecting the crucial role the hormone plays in maintaining cell homeostasis and viability of the organism. Glucocorticoids are required to maintain normal carbohydrate, lipid, and protein metabolism.⁷ Cortisol facilitates catecholamine production and modulates β-adrenergic receptor synthesis, regulation, coupling, and responsiveness.⁸ Glucocorticoids enhance normal immune activity and wound healing, maintenance of cardiovascular integrity and cardiac contractility, and various other functions.⁷

Mineralocorticoid synthesis occurs in the adrenal zona glomerulosa when stimulated by the renin-angiotensin-aldosterone system or hyperkalemia. Aldosterone, the main endogenous mineralocorticoid, facilitates sodium and potassium homeostasis and maintenance of intravascular volume.^2,9

Recent estimates of glucocorticoid secretion are approximately 5 mg/m² per day to 10 mg/m² per day of cortisol (the equivalent of about 20-30 mg/d of hydrocortisone or 5 to 7 mg/d of oral prednisone), which is less than previously reported.^10,11 Glucocorticoid levels have diurnal variation with the peak level between 4 AM and 8 AM, depending on age. There is minimal production of cortisol during the evening, lasting until 2 AM to 4 AM.² Synthesis of cortisol can increase 5- to 10-fold under conditions of severe stress, to a maximal level of approximately 100 mg/m² per day.^2,5

Adrenal Insufficiency

Adrenal insufficiency may be an acute or chronic primary, secondary, or tertiary process (TABLE 1).^2,12,13 Primary AI is relatively rare but develops in patients who have greater than 90% destruction or replacement of the adrenal glands with inflammation, tumor, infection, or hemorrhage.^2,12 Patients with primary AI are both glucocorticoid and mineralocorticoid deficient; autoimmune disease is the most common etiology of primary AI.^2,12 Pituitary dysfunction or failure with insufficient ACTH production causes secondary AI and is uncommon. Tertiary AI develops from hypothalamic or HPA axis dysfunction or failure.

Therapeutic glucocorticoid administration is the most common cause of AI.² The CRH and ACTH stimulation of the adrenal gland is suppressed by an ample quantity of glucocorticoid administered for a sufficient period.^2,12 Tertiary iatrogenic AI then develops as the adrenal gland atrophies with time. A reduced response to exogenous ACTH has been reported to last for 5 days after discontinuation of oral prednisone (25 mg twice a day) for as brief a period as 5 days.¹³

Although many clinicians believe that the duration of corticosteroid therapy, the highest corticosteroid dose, and the total cumulative corticosteroid dose are important predictors of HPA axis suppression, there are inconsistent data to accurately predict the degree of adrenal suppression in patients receiving exogenous glucocorticoid therapy. Recent literature reveals that patients who receive 5 mg/d or less of prednisone continue to have an intact HPA axis.14 Recovery of the HPA axis after the discontinuation of exogenous glucocorticoids may take up to a year.⁵ Measurement of plasma cortisol levels when patients are not receiving exogenous glucocorticoids and judicious application of adrenal stimulation with the lowor highdose cosyntropin stimulation test are recommended on an individual basis to determine HPA axis reserve in persons with suspected tertiary AI.¹⁵ Patients with secondary or tertiary AI usually have intact mineralocorticoid function via the renin-angiotensin-aldosterone system, but require stress glucocorticoid supplementation when an acute illness develops or a stressful procedure is performed.^2,9,12

Rationale and Recommendations for Replacement or Supplemental Therapy

Replacement therapy for patients with primary AI should be individualized and usually requires 20 mg to 30 mg of hydrocortisone administered in 2 to 3 divided doses a day for homeostatic glucocorticoid replacement.^2,12 Many experts currently advise maintenance therapy, however, with equivalent doses of longer-acting corticosteroid preparations, such as dexamethasone, 0.5 mg/d or prednisone, 5 mg/d to avoid excessively high peak levels and periods of inadequate replacement associated with the shorter-acting hydrocortisone.¹² Dose adjustment is based on patient weight, age, and use of concurrent medications; patients treated with phenytoin, rifampin, barbiturates, mitotane, and aminoglutethimide require larger doses because of increased corticosteroid metabolism. The patient’s sense of well-being, normalcy of blood pressure, heart rate and temperature, and elimination of symptoms, such as anorexia, nausea, vomiting, and dizziness, should be assessed before initiation or adjustment of dosage. Excess glucocorticoid-induced adverse effects, such as hypertension, muscle and skin changes, hyperglycemia, and electrolyte abnormalities, should be identified.² Glucocorticoid production does not diminish significantly with age but various parameters, such as lean body weight, glucocorticoid metabolism, and corticosteroid and adrenergic receptor function may change during the aging process. Therefore, the dose of supplemental glucocorticoids should be individualized. By definition, all patients with primary AI (Table 1) are hypoaldosteronemic and require adequate salt intake and mineralocorticoid supplementation with fludrocortisone (9-α-fluorohydrocortisone), a potent synthetic mineralocorticoid. Fludrocortisone is given orally at a dose of 0.05 mg/d to 0.20 mg/d; the dose is adjusted based upon the serum sodium level and the presence of postural hypotension or marked orthostasis.^2,9

Because severe illnesses, surgery, anesthesia, and trauma activate the HPA axis resulting in increased CRH, ACTH, and cortisol production, patients with AI may require physiologic or stress supplemental therapy in addition to their normal corticosteroid doses when they have an acute illness or undergo a stressful procedure.^5-7,16,17 Given the large variation in cortisol production in healthy patients undergoing stress, it is difficult to exactly predict the needs of patients during such circumstances. The adrenal response to acute medical illness may be quite variable.¹⁸ Some studies report an increased mortality rate when very high cortisol levels are present in acutely ill patients.^5,19 Whether this reflects severity of underlying illness, excessive proinflammatory effect, or hyporesponsiveness to endogenous glucocorticoids and an inadequate anti-inflammatory response to critical illness remains under investigation.

Patients who cannot take oral medications or who experience a significant stress and potential instability should receive intravenous corticosteroid supplementation.⁵ The optimal dosing, frequency, and duration of such therapy continue to be debated, but recent expert recommendations call for lower doses and shorter duration administration of supplemental therapy (TABLE 2)^{5 6,1115,20-22} than many conventional textbooks suggest.^5,6 Supplementary glucocorticoid dosing is based on the likelihood of adrenal suppression, the degree of medical or surgical stress, and the cardiovascular and metabolic response to therapy.

The conventional recommendations for corticosteroid supplementation in patients with known AI, suspected AI, or at risk for AI are empirical suggestions derived from early case reports of severe morbidity or death in stressed patients with AI. Recently, 2 reviews of prior literature about supplemental therapy have been conducted.^5,6 Several insights from their commentaries deserve emphasis. All patients with AI who undergo a procedure or have a medical illness require their normal daily corticosteroid therapy.^2,5,6 Patients who undergo a superficial procedure of less than 1 hour in duration under local anesthesia, such as routine dental work, skin biopsy, or minor orthopedic surgery, only require their normal daily dose of replacement therapy and not a supplemental dose.^5,6 Patients with tertiary AI who receive the equivalent of 5 mg/d or less of prednisone usually do not require additional supplementation because their adrenal glands remain adequately responsive to endogenous ACTH release.¹⁴ They should receive their daily maintenance dose of glucocorticoid (and mineralocorticoid if they require it), orally or intravenously as the clinical situation mandates.^5,6,14 This depends on whether the patient is unable to take medications by mouth or unable to absorb oral medications reliably. Some clinicians advocate administering hydrocortisone as a continuous infusion to limit the rapid clearance and peak levels associated with bolus therapy of this shorter-acting glucocorticoid or intermittent administration of equivalent long-acting corticosteroids.^2,5,6 Others suggest using appropriate doses of longer-acting glucocorticoid preparations, such as methylprednisolone or dexamethasone, in place of hydrocortisone to avoid problems with clearance and cortisol levels.^2,5,6 As synthetic glucocorticoid medications become increasingly longer acting and potent, their mineralocorticoid potency decreases.²³

One supplemental corticosteroid dose does not accommodate all patients or procedures.^2,5,6 The routine administration of stress doses equivalent to 200 mg to 300 mg of hydrocortisone when a patient undergoes any procedure or has any medical illness should be discouraged.^5,6 There is no benefit to excessive dosing (>200-300 mg/d) or extensive duration of dosing. Deleterious effects secondary to undue glucocorticoid supplementation include hyperglycemia, immunosuppression, and accelerated protein catabolism resulting in altered wound healing, hypertension, volume overload, and acute corticosteroid-induced psychosis.^2,5,6

Physicians also tend to administer supplementation to medically and surgically stressed patients for longer periods than necessary.^5,6 The diurnal production of cortisol is transiently eliminated after surgery and levels of cortisol increase with surgical stress.^5,24 Production of cortisol, however, returns to normal within 24 hours to 48 hours after surgery.5,24 Mineralocorticoid supplementation is usually not required in patients with secondary or tertiary AI or patients with primary AI who are supplemented with more than 50 mg/d of hydrocortisone.²

There is a wide range in the cortisol response in patients with medical illness or those undergoing surgical intervention.^{5,7,13,17,18,25} This may be secondary to age, underlying health, genetic variability, and other factors.² Table 2 provides recommended hydrocortisone doses for patients experiencing various levels of medical illness or undergoing increasingly invasive and stressful procedures.¹¹ An adequate response to corticosteroid supplementation is predicated on maintenance of intravascular volume and a normal serum sodium level.^5,6 Hypotension in a patient with AI may mimic hypovolemic or septic shock and should be considered in the differential diagnosis of either. The presence of hypotension in a patient with AI who has received exogenous corticosteroid supplementation is usually secondary to hypovolemia, cardiac depression, distributive processes, or an etiology other than AI.^2,5,6 Therefore, additional corticosteroid supplementation should be administered to such patients only after such concurrent processes are identified and treated.^5,6

Corticosteroid Replacement and Adjunctive Therapy in the Critically III

Empirical glucocorticoid therapy during life-threatening critical illnesses has received intense interest and investigation over the past 40 years.^2,5,6,25,26 Large prospective trials of short-term, suprapharmacologic doses of glucocorticoids (eg, methylprednisolone, ≥30 mg/kg/d) in patients with acute respiratory distress syndrome or septic shock have shown inconsistent or no benefit and may be harmful.^21,27-30 Currently, the concept of acute administration of smaller doses of glucocorticoids equivalent to physiologic or slightly supraphysiologic stress levels in selected patients with sepsis or patients dependent upon vasopressors is under evaluation.^{19,22,24,31-37} Recent data suggest an imbalance between systemic inflammation (host defense response) and compensatory anti-inflammatory responses, possibly related to glucocorticoid inadequacy and/or unresponsiveness in some critically ill patients.^32,38 Although glucocorticoid replacement will effectively treat patients with known or acquired absolute AI, supplementation in patients with relative insufficiency or impaired adrenergic receptors also may be beneficial. This positive effect is postulated to be a consequence of enhancement of anti-inflammatory activity, inhibition of deleterious proinflammatory responses, and diminution of nitric oxide-induced vasodilation and hypotension.³⁸ There are data also suggesting that down-regulation of adrenergic receptors secondary to severe inflammation or excessive exogenous catecholamine administration may be blunted with exogenous corticosteroid infusion.⁸ This results in improved adrenergic receptor function and a more stable blood pressure,^22,31 possibly facilitating reversal of sepsis-induced hypotension, decreasing vasopressor requirements, shortening the duration of mechanical ventilation, and improving outcome.^8,33,34,37 A multicenter prospective randomized controlled trial to evaluate the potential benefit of glucocorticoid therapy in severe sepsis is ongoing.33 Patients in this study also receive empirical mineralocorticoid therapy to facilitate the reversal of sepsis-induced hypotension.³³

Other acute uses of corticosteroids in the critically ill include short-term administration in patients with acute spinal cord injury, Pneumocystis carinii pneumonia, and typhoid-induced shock or coma.^39-43 Selected patients with meningitis, particularly children with Haemophilus influenzae, appear to benefit from a 2-day course of glucocorticoids initiated just prior to antibiotic therapy.⁴⁴ Currently, the National Institutes of Health-supported Acute Respiratory Distress Syndrome Network has an ongoing multicenter trial designed to determine the utility of glucocorticoid therapy in patients with fibroproliferative acute respiratory distress syndrome.^45,46

Conclusion

Primary AI is relatively rare, but acquired AI is common, most often secondary to exogenous corticosteroid therapy with resultant adrenal depression and subsequent lack of cortisol production in response to a physiologic stress.^2,5 The incidence of AI in the surgical population is increased 2.5-fold in patients older than 55 years.¹⁶ Patients with known AI must receive at least their baseline therapy prior to any procedure or during an illness; this may require parenteral administration.^2,19,24 Patients who have suspected or known AI require additional supplemental therapy with glucocorticoids when they undergo stressful procedures or experience a significant medical illness.^2,5,6 Supplemental parenteral dosing should be individualized to the degree of challenge (Table 2). Intravenous hydrocortisone or dexamethasone are the 2 corticosteroid preparations most commonly administered to patients with AI experiencing a surgical or medical stress.

The dosing of supplemental corticosteroid therapy remains open to debate; the recommendations outlined in Table 2 are experiential rather than from large clinical databases.^5,6 Previous recommendations for large replacement doses and extended duration of dosing are currently unwarranted.^5,6 Excessive doses and duration of supplemental glucocorticoid therapy are not required and may be harmful due to the known adverse effects of these medications. Whether larger randomized trials of supplemental glucocorticoid administration during surgical procedures will take place is questionable; however, trials investigating the role of corticosteroids as therapy for a variety of acute, severe illnesses are under way.

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References

Hench PS, Slocumb CH, Polley HF, Kendall EC. Effect of cortisone and pituitary adrenocorticotrophic hormone (ACTH) on rheumatic diseases. JAMA. 1950; 144:1327-1335. 

Orth DN, Kovacs WJ. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook ofEndocrinology. 9th ed. Philadelphia, Pa: WB Saunders Co; 1998:517-665. 

Fraser CG, Preuss FS, Bigford WD. Adrenal atrophy and irreversible shock associated with cortisone therapy. JAMA. 1952;149:1542-1543. 

Lewis L, Robinson RF, Yee J, et al. Fatal adrenal cortical insufficiency precipitated by surgeryduring prolonged continuous cortisone infusion. Ann Intern Med. 1953;39:116-125. 

Lamberts SWJ, Bruining HA, DeJong FH. Corticosteroid therapy in severe illness. N EnglJMed. 1997; 337:1285-1292. 

Salem M, Tainsh RE, Bromberg J, et al. Perioper ative glucocorticoid coverage: a reassessment42 years after emergence of a problem. Ann Surg. 1994;219: 416-425. 

Zaloga GP, Marik P. Hypothalamic-pituitaryadrenal insufficiency. Crit Care Clin. 2001;17:25-41. 

Saito T, Takanashi M, Gallagher E, et al. Corticosteroid effect on early beta-adrenergic downregulation during circulatory shock: hemodynamic study and beta-adrenergic study. Intensive Care Med. 1995;21:204-210. 

Diederich S, BaehrV, Oelkers W. Therapie der Nebennierenrindeninsuffizienz. Dtsch Med Wochenschr. 1994;119:595-597. 

Esteban NV, Loughlin T, YergeyA, etal. Dailycortisol production in man determined by stable isotope dilution/mass spectrometry. J Clin EndocrinolMetab. 1991;72:39-45. 

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

OelkersW.Adrenal insufficiency. NEnglJMed. 1996;335:1206-1212. 

Streck WF, Lockwood DW. Pituitary adrenal recovery following short-term suppression with corticosteroids. Am J Med. 1979;66:910-914. 

LaRochelle GE, LaRochelle AG, Ratner RE, et al. Recovery of the hypothalamic-pituitary-adrenal axis in patients with rheumatic diseases receiving lowdose prednisone. Am J Med. 1993;326:258-264. 

Oelkers W. The role of highand low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency. EurJ Endocrinol. 1998;139:567-570. 

Rivers EP, Gaspari M, Saad GA, etal. Adrenal insufficiency in high-risk surgical ICU patients. Chest. 2001;119:889-896. 

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

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

Annane D, Sebille V, Torche 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. 

Zaloga GP, Marik PE. Adrenal insufficiency. In: O'Donnell JM, Nacol FE, eds. SurgicalIntensive Care Medicine. Boston, Mass: Kluwers Academic Publishers; 2001:547-558. 

Cronin L, Cook DJ, CartletJ, etal. Corticosteroid for sepsis: a critical appraisal and meta-analysis of the literature. CritCareMed. 1995;23:1430-1439. 

Nieboer P, Van derWerfTS, BeentjesJAM, etal. Catecholamine-dependency in a polytrauma patient: relative adrenal insufficiency? Intensive Care Med. 2000;26:125-127. 

Williams GH, Dluhy RG. Disease of the adrenal cortex. In: Fauci AS, Braunwald E, Isselebacher KJ, et al, eds. Harrison's Principles of Internal Medicine. New York, NY: McGraw-Hill; 1998:2055. 

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

SchroederS,WichersM,KlingmullerD,etal.The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropinreleasing hormone. Crit Care Med. 2001;29:310316. 

Shenke Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001; 163:1520-1523. 

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;317:659665. 

Bone RC, Fisher CJ Jr, 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. 

Bernard GR, Luce J, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317:15651570. 

Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med. 1995;23:1294-1303. 

Bollaert PE. Stress doses of glucocorticoids in catecholamine dependency: a new therapy for a new syndrome. Intensive Care Med. 2000;26:3-5. 

Meduri GU, Chrousos GP. Duration ofglucocorticoid treatmentand outcomein sepsis: is therightdrug used the wrong way? Chest. 1997;114:355-360. 

Annane D. Effects of combination of hydrocortisone (HC) and fludrocortisone (FC) on mortality in septic shock [abstract]. Crit Care Med. 2000;28: A63. 

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. 

Meduri GU, Kanangat S. Glucocorticoid treat- 

ment of sepsis and acute respiratory distress syndrome: time for a critical reappraisal. Crit Care Med. 1998;26:630-633. 

CarletJ. From megato more reasonable dosesof corticosteroids: a decade to recreate hope. Crit Care Med. 1999;27:672-674. 

Briegel J, Forst H, Haller 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. 

Meduri GU. Levels of evidence for the pharmacologic effectiveness of prolonged methylprednisolone treatment in unresolving ARDS. Chest. 1999;116 (suppl):116S-118S. 

Bracken MB, Shepard MJ, CollinsWF, etal. A randomized, controlled trial of methylprednisolone or naloxone in the treatmentofacute spinal-cord injury: results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990;322:1405-1411. 

Bracken MB, Shepard MJ, Holford TR, et al. Administrationofmethylprednisolonefor24or48hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial. JAMA. 1997;277:1597-1604. 

MacFadden DK, Edelson JD, Hyland RH, etal. Corticosteroids as adjunctive therapy in treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet. 1987;1:14771479. 

Gagnon S, Boota AM, Fischl MA, et al. Corticosteroids as adjunctive therapy forsevere Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med. 1990;323:14441450. 

Hoffman SL, Punjabi NH, KumalaS, etal. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984;310:82-88. 

McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in bacterial meningitis: a meta-analysis of randomized clinical trials since 1988. JAMA. 1997;278:925-931. 

Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280:159-165. 

ARDS Network Web site. Late Steroid Rescue Study. Available at: http://hedwig.mgh.harvard.edu/ ardsnet/lasrs6200web.pdf. Accessibility verified November 28, 2001.