The subject of perioperative glucocorticoid replacement certainly needs no extensive preamble or introduction. Hospitalists are routinely required to exercise the art and science of estimating the steroid requirement for patients on steroids undergoing surgical procedures. What follows is a brief review of the literature for fellow internists.
History: Full Circle
It has been almost 60 years since corticosteroids were first recognized for their anti-inflammatory and immunosuppressive properties, initially in rheumatologic diseases. The beneficial effects of steroids in rheumatoid arthritis were described in 1949 by Philip S. Hench and colleagues, a discovery for which he received (together with Edward C. Kendall and Tadeus Reichstein) the Nobel Prize in medicine in 1950.1,2
Barely three years later, Fraser and coworkers reported the death of a 34-year-old man after routine orthopedic surgery due to shock, adrenal insufficiency, and circulatory collapse.3 The patient had been on corticosteroids for rheumatoid arthritis, but the treatment had been stopped prior to surgery. The potentially fatal consequences of steroid withdrawal prior to surgery were thrown into even greater prominence by a similar report, presented by Lewis and colleagues within a year of the first incident.4 This occurrence involved an even younger patient: a 24-year-old woman, who had been on steroids for rheumatoid arthritis and who died after her therapy was stopped a day prior to surgery.
The first recommendations for perioperative steroid replacement soon appeared.4 When loosely interpreted, routine steroid doses were often quadrupled prior to surgery—a practice that sometimes led to mammoth amounts of steroids administered during the surgical period.5 Not surprisingly, adverse clinical results were soon noted: decreased tissue repair and healing, infections, and hyperglycemia, to name a few.5 While mortality related to acute steroid withdrawal and circulatory collapse might have decreased, morbidity related to poor surgical wound healing and subsequent complications increased.
Finally, in 1994, the problem of perioperative glucocorticoid replacement was reassessed, and fresh guidelines were provided by Salem and colleagues.5 These guidelines recognized the need for steroid coverage but in more moderate doses than had previously been used, and this is where we stand today—replacement, but in moderation.
Why Perioperative Steroid Coverage?
Acute stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased plasma adrenocorticotropic hormone (ACTH) and cortisol levels.6 This increase is believed to be an adaptive mechanism meant to enhance the body’s ability to combat stress by increasing its sensitivity to catecholamines; its cardiac contractility and output; and its mobilization of energy sources with gluconeogenesis, proteolysis, and lipolysis.6 It follows that lack of increase in cortisol production during stress would cause the host to succumb to it. On the other hand, too much cortisol would be detrimental, causing increased tissue breakdown, poor wound healing, and immunosuppression.
Surgery is one of the most potent stressors that can cause activation of the HPA axis.6,7 The degree of activation depends on the type and duration of surgery and anesthesia, with many other variables adding to the picture, including analgesics, antihypertensive medications, infections, and age.5-9 The maximum stimulation of the HPA axis in uncomplicated surgery has been assessed to occur during reversal of anesthesia and in the immediate postoperative period.6,9,10 Normal daily cortisol production is about 15 to 20 mg/day.6 These levels can go up to as much as 75–100 mg/day with surgical stress.6,11,12
Given this background, it is clear that any patient who has inadequate cortisol production in response to surgical stress will fare poorly in such a situation. This patient will need to be recognized, and his acute steroid requirement will have to be estimated and supplemented; in addition, over- or under-dosing must be avoided in order to achieve a good post-surgical outcome.
Mechanisms of Adrenal Insufficiency in the Perioperative Period
Adrenal insufficiency can be primary, in which the adrenal gland itself does not function properly. It can also be secondary or central, in which the hypothalamic/pituitary axis is functioning at sub-par levels. It is, in fact, secondary adrenal insufficiency that is most commonly encountered in clinical practice; this condition is caused by HPA axis suppression due to negative feedback from exogenous administration of corticosteroids.
Who Needs Perioperative Steroid Replacement?
Following are situations in which perioperative steroid replacement should be considered:
- Any patient who has received more than 20 mg of prednisone daily (or an equivalent dose of other glucocorticoids) for more than five days in the previous year is at risk for HPA axis suppression;13,14
- Any patient who has clinical Cushing’s syndrome from any steroid dose should be considered to have a suppressed HPA axis;6 and
- Any steroid dose given at bedtime—even physiologic doses—is more likely to suppress the HPA axis than a similar dose given in the morning because, at nighttime, the negative feedback from steroids to ACTH and corticotropin-releasing hormone (CRH) is more prominent.6
Patients receiving doses equivalent to 5 mg of prednisone in the morning for any length of time are not associated with HPA axis suppression.13 If these patients are on steroid replacement for primary adrenal insufficiency, however, it is vital to realize that they do not have the capacity to compensate for increased stress, surgical or otherwise, and may need additional replacement depending upon the nature and duration of their stressors.14
Doses greater than physiologic range but less than 20 mg/day of prednisone can cause suppression of the HPA axis, but the demarcation of the time frame is not absolutely clear. It is said that doses closer to the physiologic range cause suppression after about one month, whereas doses closer to 20 mg/day can do so in five days or more.13, 14
For patients who cannot be clearly identified by these criteria, provocative testing is recommended, as discussed below.
Laboratory Testing for HPA Axis Function
The ACTH stimulation test is recommended to test for HPA axis adequacy in perioperative patients.5,13,14 It has been shown to correlate well with the insulin tolerance test. Exogenous corticosteroids have to be held for 24 hours prior to testing because they affect the measured cortisol level, with the exception of dexamethasone, which does not affect the results.13
The test involves the administration of 250 mcg of cosyntropin—synthetic ACTH—intramuscularly or intravenously, followed by measurement of peak cortisol levels after 30 minutes.5 Traditionally, a plasma cortisol level greater than 18–20 mcg/dl defines adequate adrenal function, as quoted from Salem and colleagues.5
Basal values and the calculation of delta max—the difference between basal and peak values—have not been shown to correlate with clinical outcome in routine surgical patients.13 Although these values have been demonstrated to be useful in the setting of septic shock, the subject is still under debate, and readers interested in this aspect of adrenal insufficiency may refer to articles by Annane, Hollenberg, Gonzalez and colleagues.15,16,17
Use of a 250-mcg dose of cosyntropin has often been criticized for being supraphysiologic, and use of a 1-mcg dose has been suggested instead. This test has not yet been characterized well enough, however.13,18 In addition, a standardized, commercial preparation of the 1-mcg dose is not available.13 Thus, the low-dose test is, as yet, not routinely advocated.
To Replace or Not to Replace?
It is interesting to note that biochemical evidence of HPA axis dysfunction does not necessarily translate into clinical problems with surgical stress.19 Additionally, patients on chronic steroid supplementation higher than 5 mg/day of prednisone—or equivalent—may not necessarily suffer inappropriate biochemical responses to stress.20 With these observations comes the following question: Even if HPA axis dysfunction exists, when does it matter clinically, or does it matter? The difficulty of this situation has been discussed in detail by Levy and Shaw.21,22
Shaw brings the topic to another level when he states that, given the evidence we have today, it is still prudent to consider perioperative steroid coverage.22 The benefit—avoiding life-threatening adrenal insufficiency—outweighs the risk of enhanced catabolism and immunosuppression, especially if the steroid coverage is physiologic and of a very short duration.
Perioperative Glucocorticoid Coverage
Current recommendations for steroid coverage take into account the normal physiologic response to routine surgery. The idea is to mimic the transient increase in cortisol levels during the surgical and postoperative period but not to exceed the levels or the duration of the physiologic response. Doses above the physiologic ranges offer no particular benefit in routine surgical stress.5
Most of the current recommendations stem from those proposed by Salem and colleagues in 1994.5
For almost 50 years after it was first recognized, the need for steroid replacement in surgical situations had been addressed with high doses that created new problems in the forms of poor tissue healing and immunosuppression, causing a major dilemma in the surgical world. Now, with a more conservative and physiologic approach, the adverse consequences of glucocorticoid supplementation can be minimized and perhaps even prevented. TH
- Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24:181-197.
- Hench PS, Slocumb CH, Polley HF, et al. Effect of cortisone and pituitary adrenocorticotropic hormone (ACTH) on rheumatic diseases. JAMA. 1950 Dec 16;144(16):1327-1335.
- 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 surgery during prolonged continuous cortisone treatment. Ann Intern Med. 1953; 39:116-126.
- Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994 Apr;219(4):416-425.
- Jabbour SA. Steroids and the surgical patient. Med Clin North Am. 2001 Sep;85(5):1311-1317.
- Hume DM, Bell CC, Bartter F. Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery. 1962 Jul;52:174-187.
- Chernow B, Alexander HR, Smallridge RC, et al. Hormonal responses to graded surgical stress. Arch Intern Med. 1987 Jul;147(4):1273-1278.
- Raff H, Norton AJ, Flemma RJ, et al. Inhibition of the adrenocorticotropin response to surgery in humans: interaction between dexamethasone and fentanyl. J Clin Endocrinol Metab. 1987 Aug;65(2):295-298.
- Udelsman R, Norton JA, Jelenich SE, et al. Responses of the hypothalamic-pituitary-adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metab. 1987 May;64(5):986-994.
- Kehlet H. A rational approach to dosage and preparation of parenteral glucocorticoid substitution therapy during surgical procedures. A short review. Acta Anaesthesiol Scand. 1975;19(4):260-264.
- Kehlet H. Clinical course and hypothalamic-pituitary-adrenocortical function in glucocorticoid-treated surgical patients. Copenhagen: FADL; 1976.
- Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am. 2003;32:367-383.
- Connery LE, Coursin DB. Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North America. 2004 Mar;22(1):93-123.
- 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 Feb 23;283(8):1038-1045.
- Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004 Sep;32(9):1928-1948.
- Gonzalez H, Nardi O, Annane D. Relative adrenal failure in the ICU: an identifiable problem requiring treatment. Crit Care Clin. 2006 Jan;22(1):105-118.
- Streeten DHP. Shortcomings in the low-dose (1 microg) ACTH test for the diagnosis of ACTH deficiency states. J Clin Endocrinol Metab. 1999 Mar;84(3):835-837.
- Bromberg JS, Alfrey EJ, Barker CF, et al. Adrenal suppression and steroid supplementation in renal transplant recipients. Transplantation. 1991 Feb;51(2):385-390.
- Friedman RJ, Schiff CF, Bromberg JS. Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surg Am. 1995 Dec;77(12):1801-1806.
- Levy A. Perioperative steroid cover. Lancet. 1996 Mar;347(9005):846-847.
- Shaw M. When is perioperative ‘steroid coverage’ necessary? Available at: www.clevelandclinicmeded.com/ccjm/january2002/shaw.htm. Last accessed February 9, 2007.