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STEROIDS AND THE SURGICAL PATIENT
POSTOPERATIVE MEDICAL COMPLICATIONS
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STEROIDS AND THE SURGICAL PATIENT Serge A. Jabbour, MD
The primary role of the endocrine system is the maintenance of normal physiologic functioning of many organ systems of the body.31 The endocrine response to many forms of stress, including surgery, is complicated and comprehensive in scope. The adrenal cortex plays a crucial role in the endocrine response to major stress. Cortisol, the primary glucocorticoid secreted from the human adrenal gland, has long been recognized as a requirement for survival in critical illness.21,31 Case Study
A 42-year-old white woman was admitted for resection of a potentially malignant right ovarian cyst. A medical consultation was requested for preoperative clearance. The patient’s past medical history was significant for a car accident 3 months previously that resulted in a major cerebral contusion, which was treated with dexamethasone, 16 mg/d for 4 weeks. Otherwise, the patient had no other medical problems. She was not taking any medications. She did not smoke or drink. The review of systems was positive for an intermittent right lower quadrant pain from the ovarian cyst. The patient had no other complaints. The patient’s vital signs showed a blood pressure of 120/60 mm Hg and a heart rate of 76 beats/min. The physical examination was unremarkable except for a mild tenderness on palpation of the right lower quadrant. After receipt of normal results for the preoperative routine laboratory studies, electrocardiogram, and chest radiograph, the patient was cleared for surgery. Soon after the cyst was resected, in the recovery room, the patient became hypotensive with a blood pressure of 80/42 mm Hg. Saline, 2 L, was infused
From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
MEDICAL CLINICS OF NORTH AMERICA
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without improvement. Hydrocortisone, 100 mg, was given as an intravenous bolus, with subsequent normalization of the blood pressure. KEY POINTS
The case study raises a few questions: 1. What is the effect of surgery on the hypothalamic-pituitary-adrenal (HPA) axis? How can the HPA axis be affected by previous steroid intake? 2. What are the dose and duration of any steroid treatment capable of inducing suppression of the HPA axis, leading to secondary adrenal insufficiency? 3. How should patients who have undergone steroid treatment be managed when exposed to stress, including surgery? DISCUSSION Normal Physiology
The production of glucocorticoids by the adrenal cortex is regulated predominantly by adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary under the influence of hypothalamic corticotropin-releasing hormone (CRH). ACTH and CRH are under direct negative feedback from cortisol. Normal daily production of cortisol is approximately 15 to 20 mg/d.28Glucocorticoids play an important role in the metabolism of carbohydrates, lipids, and proteins and have profound regulatory effects on immune and circulatory function.40Glucocorticoids increase glucose production through gluconeogenesis and antagonism of insulin action. Lipolysis is stimulated as well as proteolysis, making amino acid substrates available for gluconeogenesis. Glucocorticoids have a positive inotropic influence on the heart and a permissive effect on the actions of epinephrine and norepinephrine.4o Aldosterone secretion by the adrenal gland is regulated mainly by the reninangiotensin system. Aldosterooe acts by promoting sodium reabsorption and stimulating the excretion of potassium and hydrogen ions in the kidney.20 Patients with primary adrenal insufficiency (Addison’s disease) have defects in cortisol and aldosterone secretion. In secondary adrenal insufficiency (e.g., from previous steroid intake), aldosterone secretion is intact. Effect of Surgery
Acute physical or psychologic stress activates the HPA axis, resulting in increased plasma ACTH and cortisol concentrations. Physical stresses include severe trauma, burns, major surgery, hypoglycemia, fever, hypotension, exercise, and cold exposure.1o, 16, 37, 38 Surgery is one of the most potent and best-studied activators of the HPA axis.I2The degree of activation depends on the type of surgery5and a n e s t h e ~ i aDuring . ~ ~ a major surgical procedure, CRH, ACTH, and cortisol levels rise significantlyu Plasma ACTH concentrations increase at the time of incision and during the surgery, but the greatest ACTH secretion occurs during reversal of anesthesia, during extubation, and during the immediate
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postoperative recovery period.29,37 From a normal secretion of 15 to 20 mg/d, cortisol production rates increase to 75 to 150 mg/d,'3 leading to mean cortisol values ranging from 30 to 50 mg/dL.5 The increase in cortisol production is believed to enhance survival through increased cardiac contractility, cardiac output, sensitivity to catecholamines, work capacity of skeletal muscles, and ability to mobilize energy sources through gluconeogenesis, proteolysis, and lipolysis.40 Patients who have suppression of the HPA axis from previous steroid therapy cannot increase ACTH and cortisol production during surgery, leading to hypotensive shock. To prevent such a disastrous situation, these patients need to be given stress doses of glucocorticoids around the surgical period. Hypothalamic-Pituitary-AdrenalAxis Suppression
After long-term treatment with glucocorticoids, there is a suppression of the HPA axis. After cessation of ACTH secretion, the adrenocortical fascicular and reticular zones undergo functional and anatomic atrophy within few weeks, leading to secondary adrenal insufficiency.28 Most studies have shown that steroid doses equivalent to 5 mg/d or less of prednisone given for any length of time (even years) once daily in the morning generally are not associated with HPA axis suppression when prednisone is withdrawn.3,14,15,34 Any dose of glucocorticoid given for less than 3 weeks does not lead to clinically significant suppression of the HPA axis." Prednisone or dexamethasone given to patients as a single bedtime dose (even at physiologic doses) are associated more commonly with HPA axis suppression because the 24 negative feedback from steroids on ACTH and CRH becomes more potent!, Long-term alternate-day glucocorticoid therapy produces less suppression of the HPA function.z,7, l9 The situations in which the patient should be assumed to have suppression of the HPA function include: Any patient who has received more than 20 mg of prednisone daily (or equivalent dose of other glucocorticoids) for more than 3 weeks, within the previous year.6 Any patient who has clinical Cushing's syndrome (from any steroid dose). Such patients do not need testing to evaluate the HPA axis but should be treated similar to any patient with secondary adrenal insufficiency undergoing surgery. The intermediate category of patients includes patients taking more than 5 mg/d but less than 20 mg/d of prednisone for more than 3 weeks within the previous year. These patients may have suppression of HPA function, depending on the dose, duration of steroid therapy, and the individual patient. If there is an acute stress, such as surgery, one can test for the responsiveness of the adrenals if time permits or give stress doses of glucocorticoids prophylactically." After cessation of steroid therapy, recovery of the HPA axis can take 12 months or longer17,28; hypothalamic-pituitary function returns to normal before adrenocortical function.**During the recovery period, patients may be asymptomatic unless exposed to stress, such as surgery, which can precipitate an acute adrenal insufficiency crisis. The main symptoms are fatigue, anorexia, nausea, vomiting, abdominal pain, fever, hypoglycemia, hypotension, and circulatory ~ollapse.'~, z8 Hyponatremia can be seen in secondary adrenal insufficiency (from decreased water clearance and increased antidiuretic hormone release), but po-
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tassium and bicarbonate concentrations remain normal because aldosterone secretion is intact.28 In the case presented, 16 mg/d of dexamethasone (equivalent to 160 mg of prednisone) given for 1 month is enough to suppress the HPA function for a long time. The lack of cortisol production in response to surgery led to the postoperative hypotension. The glucocorticoid equivalencies between different corticosteroid preparations are shown in Table l . I 7 Testing of the Hypothalamic-Pituitary-AdrenalAxis
As mentioned previously, if patients are in the intermediate category (prednisone >5 mg/d but <20 mg/d), testing of adrenal responsiveness can be performed before the surgery, if time permits, to assess the need for stress-dose steroids. Many tests are available, each with some limitations. The best test of the response to stress, when done carefully, is measurement of plasma cortisol levels during insulin-induced hyp~glycemia.~~ This is probably the most sensitive test of adrenal suppression and is most frequently abnormal for long periods after corticosteroid use.15,l9 This test is difficult to perform, however, and carries some risk if not done properly. It is not used commonly in clinical practice. The response to administration of synthetic ACTH (cosyntropin) is the preferred method to assess adrenocortical function. Different protocols are available, using cosyntropin at a dose of 250 pg or 1 pg. The classic test described in most textbooks uses 250 pg. It can be performed at any time of the day. Cosyntropin (Cortrosyn),which comes in vials of 250 pg, is given intravenously or intramuscularly; plasma cortisol is measured before and 60 minutes after the injection. Adrenal function is considered to be normal if the basal or the postcosyntropin plasma cortisol concentration is at least 20 ~ g / d L Criteria .~~ that require a minimal increment in plasma cortisol are invalidz8because patients who have a high basal plasma cortisol, caused by either normal circadian rhythmicity or acute stress, may be stimulated nearly maximally and unable to increase cortisol secretion further. If the patient is stressed by the procedure, the basal cortisol level may exceed the postcosyntropin stimulation level?* It is useful to obtain baseline and postcosyntropin samples for accurate assessment of adrenal function. Some limitations of the 250-pg test have been reported. Cases of partial adrenal insufficiency may be missed because a cosyntropin dose of 250 p,g provides a supraphysiologic stimulus that can stimulate a partially diseased
Table 1. GLUCOCORTICOID EQUIVALENCIES Glucocorticoids
Hydrocortisone (Cortef, Solu-Cortef) Cortisone (Cortone) Prednisone (Deltasone) Methylprednisolone (Medrol, Soh-Medrol) Dexamethasone (Decadron)
Equivalent Dose (mg)
Biologic Half-Life (h)
20
&12
25 5 4
8-12 18-36 18-36
0.5
36-54
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adrenal?Sz6It has been shown that ACTH levels during the 250-pg test are much higher than those attained in response to the most severe stressful situations9; that would explain the reports of false normal results of the 250-pg test, in which steroid-suppressed patients responded normally to the cosyntropin (250 pg) while clinically in adrenal insufficiency.1,4, 30, 36 ACTH levels obtained with the l-pg test are equivalent to ACTH levels after stressful situations, such as surgery or hyp~glycemia.~ Many studies showed a much better correlation between the insulin-induced hypoglycemia and the 1pg test than with the 250-pg test.', 32, 36 A subgroup of patients on long-term steroids may have a diminished response to 1 pg of cosyntropin, although they still respond to 250 pg9 It is recommended by many experts that the 1-pg test replace the conventional 250-pg test as the screening test for assessment of patients with probable HPA axis suppression from steroid therapy.', 9, 36 The test is performed by injecting 1 pg of cosyntropin intravenously, not intramuscularly (because 1 pg may not be enough to reach the systemic circulation if given in the muscle). Because cosyntropin comes in vials of 250 pg, one can prepare the 1-pg solution by injecting the 250-1-1.8vial into a 250-mL bottle of saline and drawing 1 mL for injection. Plasma cortisol levels are measured before and 30 minutes after the injection. A normal response is a plasma cortisol concentration at least 18 pg/dL at 30 minutes.z7 In all tests performed, cross-reaction between all glucocorticoids except dexamethasone and the cortisol assay can occur, leading to falsely high cortisol values. Steroids taken at the time of the testing should be stopped (except dexamethasone) for at least 24 hours.18 In the case presented, testing was not necessary because adrenal insufficiency was almost certain with the high doses of dexamethasone given to the patient a few months previously. Stress-dose steroids should have been given to the patient to prevent an adrenal crisis precipitated by the surgery. Management
Patients with known or suspected secondary adrenal insufficiency should receive stress doses of steroid when undergoing surgery. For minor surgical stress ( e g , hand surgery, hemorrhoidectomy, inguinal herniorrhaphy), 100 mg of hydrocortisone is given intravenously with the induction of anesthesia, followed by usual maintenance dose (approximately 20 mg/d of hydrocortione).^^,^^ For major surgical stress (e.g., chest or abdominal surgery), it is recommended to give hydrocortisone, 100 mg intravenously, starting with induction of anesthesia and to continue the same dose every 8 hours for at least the first 24 h o ~ r ~ When . ~ ~ the , ~ major ~ , ~stress ~ of the postoperative period is resolved, and the patient is stable and free of complications (fever, vomiting), hydrocortisone can be tapered during a few days to the usual maintenance dose. Table 2 provides an example of steroid tapering. SUMMARY
In patients undergoing surgery, a thorough history is important to obtain, including use of any steroid therapy within the previous year. If there is a history of steroid use, and if time permits, testing of the HPA axis should be performed. If adrenal unresponsiveness is documented or if clinical suspicion of
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Table 2. POSTOPERATIVE STEROID TAPERING
Day 1 Hydrocortisone, 100 mg N q 8 h, starting with induction of anesthesia Day 2 if patient stable and major postoperative stress resolved, lower dose of hydrocortisone to 50 mg q 8 h Day 3 Hydrocortisone, 25 mg q 8 h Dav 4 Hydrocortisone, 25 mg bid Day 5 Maintenance dose (12-15 mg hydrocortisone/mz/d): 15-20 mg A.M. and 5-10 mg P.M.
N
= intravenously,
q = every, bid = twice a day.
adrenal insufficiency is high (without testing), a stress dose of steroids should be administered during the perioperative period to prevent an adrenal crisis. References 1. Abdu TAM, Elhadd TA, Neary R, et a1 Comparison of the low dose short synacthen test (1 mcg), the conventional dose short synacthen test (250 mcg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 84S38-843, 1999 2. Ackerman GL, Nolan CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 278:405-409, 1968 3. Axelrod L: Glucocorticoid therapy. Medicine 55:39-65, 1976 4. Borst GC, Michenfelder HJ, OBrian JT: Discordant cortisol response to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 3061462-1464, 1982 5. Chernow 8, Alexander HR, Smallridge RC, et al: Hormonal responses to graded surgical stress. Arch Intern Med 1471273-1278, 1987 6. Christy NP:Corticosteroid withdrawal. In Bardin CW (ed): Current Therapy in Endocrinology and Metabolism, ed 3. Toronto, BC Decker, 1988, p 113 7. Dale DC, Fauci AS, Wolff SM: Alternate-day prednisone. N Engl J Med 291:11541158, 1974 8. Danowski TS, Bonessi JV, Sabeh G, et al: Probabilities of pituitary-adrenal responsiveness after steroid therapy. Ann Intern Med 61:ll-26, 1964 9. Dickstein G, Arad E, Shechner C: Low-dose ACTH stimulation test. Endocrinologist 7285-293, 1997 10. Fish HR, Chernow 8, OBrian JT Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia. Metabolism 35:763-780, 1986 11. Furst .DE, Saag KG, Orth D N Glucocorticoid withdrawal regimens. UpToDate 8:l-8, 1999 12. Hume DM, Bell CC, Bartter F: Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery 52:174-187,1962 13. Kehlet H: A rational approach to dosage and preparation of parenteral glucocorticoid substitution therapy during surgical procedure. Acta Anaesth Scand 19:260-264, 1975 14. LaRochelle GE, LaRochelle AG, Ratner RE, et al: Recovery of the hypothalamicpituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 95:258-264, 1993 15. Livanou T, Ferriman D, James VHT Recovery of hypothalamo-pituitary adrenal function after corticosteroid therapy. Lancet 2:85&859, 1967 16. Luger A, Deuster PA, Kyle SB, et al: Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. N Engl J Med 316:1309-1314, 1987 17. Magiakou MA, Chrousos GI? Corticosteroid therapy, non endocrine disease, and
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corticosteroid withdrawal. In Bardin CW (ed): Current Therapy in Endocrinology and Metabolism, ed 6. St. Louis, Mosby, 1997, pp 138-142 18. Malchoff CD, Carey RM: Adrenal insufficiency. In Bardin CW (ed): Current Therapy in Endocrinology and Metabolism, ed 6. St. Louis, Mosby, 1997, pp 142-147 19. Martin MM, Gaboardi F, Podolsky S, et a1 Intermittent steroid therapy. N Engl J Med 279:27>278, 1968 20. Morris DJ: The metabolism and mechanism of action of aldosterone. Endocr Rev 2234-247,1981 21. Munck A, Guyne PM, Holbrook NJ: Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25-44, 1984 22. Myles AB, Bacon PA, Daly J R Single daily dose corticosteroid treatment. Ann Rheum Dis 30:149-153, 1971 23. Naito Y, Fukata J, Tamai S, et al: Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab 73:111-117,1991 24. Nichols T, Nugent CA, Tyler F H Diurnal variation in suppression of adrenal function by glucocorticoids. J Clin Endocr 25:343, 1965 25. Oelkers W Adrenal insufficiency. N Engl J Med 335:1206-1212, 1996 26. Orth D N Diagnosis of adrenal insufficiency. UpToDate 8:l-9, 1997 27. Orth DN: Evaluation of the response to ACTH in adrenal insufficiency. UpToDate 81-9, 1998 28. Orth DN, Kovacs WJ: The adrenal cortex. In Wilson JD, Foster DW, Kronenberg HM, et a1 (eds): Wiilliams Textbook of Endocrinology, ed 9. Philadelphia, WB Saunders, 1998, pp 517-664 29. 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 65295298, 1987 30. Rasmuson S, Olsson T, Hagg E: A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 44:151-156, 1996 31. Rescini E, Catassia A, Giustina G: Plasma cortisol response to ACTH does not accurately indicate the state of hypothalamic-pituitary-adrenal axis. J Endocrinol Invest 5259-261, 1982 32. Rolih C, Ober K The endocrine response to critical illness. Med Clin North Am 79211-224, 1995 33. Salem M, Tainsh RE, Bromberg J, et al: Perioperative glucocorticoid coverage. Ann Surg 219:41M25, 1994 34. Spiegel RJ, Oliff AI,Bruton J, et al: Adrenal suppression after short-term corticosteroid therapy. Lancet L630-633, 1979 35. Bloom A: Letter: Steroid therapy and the adrenals. Lancet 2659, 1975 36. Tordjman K, Jaffe A, Grazas N, et al: The role of the low dose (1 mcg) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 80:1301-1305, 1995 37. Udelsman R, Norton JA, Jelenich SE, et a 1 Responses of the hypothalamic-pituitaryadrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metab 64:986-994, 1987 38. Vaughan GM, Becker RA, Allen JP, et al: Cortisol and corticotrophin in burned patients. J Trauma 2226>271, 1982 39. Werbel SS, Ober KP: Acute adrenal insufficiency. Endocrinol Metab Clin North Am 22:30>328, 1993 40. White PC, Pescovitz OH, Cutler GB: Synthesis and metabolism of corticosteroids. In Becker KL (ed): .Principles and Practice of Endocrinology and Metabolism, ed 2. Philadelphia, Lippincott, 1995, pp 647-662
Address reprint requests to Serge A. Jabbour, MD Jefferson Medical College 211 South 9th Street, Suite 600 Philadelphia, PA 19107 e-mail: [email protected]
0025-7125/01 $15.00
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STEROIDS AND THE SURGICAL PATIENT Serge A. Jabbour, MD
The primary role of the endocrine system is the maintenance of normal physiologic functioning of many organ systems of the body.31 The endocrine response to many forms of stress, including surgery, is complicated and comprehensive in scope. The adrenal cortex plays a crucial role in the endocrine response to major stress. Cortisol, the primary glucocorticoid secreted from the human adrenal gland, has long been recognized as a requirement for survival in critical illness.21,31 Case Study
A 42-year-old white woman was admitted for resection of a potentially malignant right ovarian cyst. A medical consultation was requested for preoperative clearance. The patient’s past medical history was significant for a car accident 3 months previously that resulted in a major cerebral contusion, which was treated with dexamethasone, 16 mg/d for 4 weeks. Otherwise, the patient had no other medical problems. She was not taking any medications. She did not smoke or drink. The review of systems was positive for an intermittent right lower quadrant pain from the ovarian cyst. The patient had no other complaints. The patient’s vital signs showed a blood pressure of 120/60 mm Hg and a heart rate of 76 beats/min. The physical examination was unremarkable except for a mild tenderness on palpation of the right lower quadrant. After receipt of normal results for the preoperative routine laboratory studies, electrocardiogram, and chest radiograph, the patient was cleared for surgery. Soon after the cyst was resected, in the recovery room, the patient became hypotensive with a blood pressure of 80/42 mm Hg. Saline, 2 L, was infused
From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
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without improvement. Hydrocortisone, 100 mg, was given as an intravenous bolus, with subsequent normalization of the blood pressure. KEY POINTS
The case study raises a few questions: 1. What is the effect of surgery on the hypothalamic-pituitary-adrenal (HPA) axis? How can the HPA axis be affected by previous steroid intake? 2. What are the dose and duration of any steroid treatment capable of inducing suppression of the HPA axis, leading to secondary adrenal insufficiency? 3. How should patients who have undergone steroid treatment be managed when exposed to stress, including surgery? DISCUSSION Normal Physiology
The production of glucocorticoids by the adrenal cortex is regulated predominantly by adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary under the influence of hypothalamic corticotropin-releasing hormone (CRH). ACTH and CRH are under direct negative feedback from cortisol. Normal daily production of cortisol is approximately 15 to 20 mg/d.28Glucocorticoids play an important role in the metabolism of carbohydrates, lipids, and proteins and have profound regulatory effects on immune and circulatory function.40Glucocorticoids increase glucose production through gluconeogenesis and antagonism of insulin action. Lipolysis is stimulated as well as proteolysis, making amino acid substrates available for gluconeogenesis. Glucocorticoids have a positive inotropic influence on the heart and a permissive effect on the actions of epinephrine and norepinephrine.4o Aldosterone secretion by the adrenal gland is regulated mainly by the reninangiotensin system. Aldosterooe acts by promoting sodium reabsorption and stimulating the excretion of potassium and hydrogen ions in the kidney.20 Patients with primary adrenal insufficiency (Addison’s disease) have defects in cortisol and aldosterone secretion. In secondary adrenal insufficiency (e.g., from previous steroid intake), aldosterone secretion is intact. Effect of Surgery
Acute physical or psychologic stress activates the HPA axis, resulting in increased plasma ACTH and cortisol concentrations. Physical stresses include severe trauma, burns, major surgery, hypoglycemia, fever, hypotension, exercise, and cold exposure.1o, 16, 37, 38 Surgery is one of the most potent and best-studied activators of the HPA axis.I2The degree of activation depends on the type of surgery5and a n e s t h e ~ i aDuring . ~ ~ a major surgical procedure, CRH, ACTH, and cortisol levels rise significantlyu Plasma ACTH concentrations increase at the time of incision and during the surgery, but the greatest ACTH secretion occurs during reversal of anesthesia, during extubation, and during the immediate
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postoperative recovery period.29,37 From a normal secretion of 15 to 20 mg/d, cortisol production rates increase to 75 to 150 mg/d,'3 leading to mean cortisol values ranging from 30 to 50 mg/dL.5 The increase in cortisol production is believed to enhance survival through increased cardiac contractility, cardiac output, sensitivity to catecholamines, work capacity of skeletal muscles, and ability to mobilize energy sources through gluconeogenesis, proteolysis, and lipolysis.40 Patients who have suppression of the HPA axis from previous steroid therapy cannot increase ACTH and cortisol production during surgery, leading to hypotensive shock. To prevent such a disastrous situation, these patients need to be given stress doses of glucocorticoids around the surgical period. Hypothalamic-Pituitary-AdrenalAxis Suppression
After long-term treatment with glucocorticoids, there is a suppression of the HPA axis. After cessation of ACTH secretion, the adrenocortical fascicular and reticular zones undergo functional and anatomic atrophy within few weeks, leading to secondary adrenal insufficiency.28 Most studies have shown that steroid doses equivalent to 5 mg/d or less of prednisone given for any length of time (even years) once daily in the morning generally are not associated with HPA axis suppression when prednisone is withdrawn.3,14,15,34 Any dose of glucocorticoid given for less than 3 weeks does not lead to clinically significant suppression of the HPA axis." Prednisone or dexamethasone given to patients as a single bedtime dose (even at physiologic doses) are associated more commonly with HPA axis suppression because the 24 negative feedback from steroids on ACTH and CRH becomes more potent!, Long-term alternate-day glucocorticoid therapy produces less suppression of the HPA function.z,7, l9 The situations in which the patient should be assumed to have suppression of the HPA function include: Any patient who has received more than 20 mg of prednisone daily (or equivalent dose of other glucocorticoids) for more than 3 weeks, within the previous year.6 Any patient who has clinical Cushing's syndrome (from any steroid dose). Such patients do not need testing to evaluate the HPA axis but should be treated similar to any patient with secondary adrenal insufficiency undergoing surgery. The intermediate category of patients includes patients taking more than 5 mg/d but less than 20 mg/d of prednisone for more than 3 weeks within the previous year. These patients may have suppression of HPA function, depending on the dose, duration of steroid therapy, and the individual patient. If there is an acute stress, such as surgery, one can test for the responsiveness of the adrenals if time permits or give stress doses of glucocorticoids prophylactically." After cessation of steroid therapy, recovery of the HPA axis can take 12 months or longer17,28; hypothalamic-pituitary function returns to normal before adrenocortical function.**During the recovery period, patients may be asymptomatic unless exposed to stress, such as surgery, which can precipitate an acute adrenal insufficiency crisis. The main symptoms are fatigue, anorexia, nausea, vomiting, abdominal pain, fever, hypoglycemia, hypotension, and circulatory ~ollapse.'~, z8 Hyponatremia can be seen in secondary adrenal insufficiency (from decreased water clearance and increased antidiuretic hormone release), but po-
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tassium and bicarbonate concentrations remain normal because aldosterone secretion is intact.28 In the case presented, 16 mg/d of dexamethasone (equivalent to 160 mg of prednisone) given for 1 month is enough to suppress the HPA function for a long time. The lack of cortisol production in response to surgery led to the postoperative hypotension. The glucocorticoid equivalencies between different corticosteroid preparations are shown in Table l . I 7 Testing of the Hypothalamic-Pituitary-AdrenalAxis
As mentioned previously, if patients are in the intermediate category (prednisone >5 mg/d but <20 mg/d), testing of adrenal responsiveness can be performed before the surgery, if time permits, to assess the need for stress-dose steroids. Many tests are available, each with some limitations. The best test of the response to stress, when done carefully, is measurement of plasma cortisol levels during insulin-induced hyp~glycemia.~~ This is probably the most sensitive test of adrenal suppression and is most frequently abnormal for long periods after corticosteroid use.15,l9 This test is difficult to perform, however, and carries some risk if not done properly. It is not used commonly in clinical practice. The response to administration of synthetic ACTH (cosyntropin) is the preferred method to assess adrenocortical function. Different protocols are available, using cosyntropin at a dose of 250 pg or 1 pg. The classic test described in most textbooks uses 250 pg. It can be performed at any time of the day. Cosyntropin (Cortrosyn),which comes in vials of 250 pg, is given intravenously or intramuscularly; plasma cortisol is measured before and 60 minutes after the injection. Adrenal function is considered to be normal if the basal or the postcosyntropin plasma cortisol concentration is at least 20 ~ g / d L Criteria .~~ that require a minimal increment in plasma cortisol are invalidz8because patients who have a high basal plasma cortisol, caused by either normal circadian rhythmicity or acute stress, may be stimulated nearly maximally and unable to increase cortisol secretion further. If the patient is stressed by the procedure, the basal cortisol level may exceed the postcosyntropin stimulation level?* It is useful to obtain baseline and postcosyntropin samples for accurate assessment of adrenal function. Some limitations of the 250-pg test have been reported. Cases of partial adrenal insufficiency may be missed because a cosyntropin dose of 250 p,g provides a supraphysiologic stimulus that can stimulate a partially diseased
Table 1. GLUCOCORTICOID EQUIVALENCIES Glucocorticoids
Hydrocortisone (Cortef, Solu-Cortef) Cortisone (Cortone) Prednisone (Deltasone) Methylprednisolone (Medrol, Soh-Medrol) Dexamethasone (Decadron)
Equivalent Dose (mg)
Biologic Half-Life (h)
20
&12
25 5 4
8-12 18-36 18-36
0.5
36-54
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adrenal?Sz6It has been shown that ACTH levels during the 250-pg test are much higher than those attained in response to the most severe stressful situations9; that would explain the reports of false normal results of the 250-pg test, in which steroid-suppressed patients responded normally to the cosyntropin (250 pg) while clinically in adrenal insufficiency.1,4, 30, 36 ACTH levels obtained with the l-pg test are equivalent to ACTH levels after stressful situations, such as surgery or hyp~glycemia.~ Many studies showed a much better correlation between the insulin-induced hypoglycemia and the 1pg test than with the 250-pg test.', 32, 36 A subgroup of patients on long-term steroids may have a diminished response to 1 pg of cosyntropin, although they still respond to 250 pg9 It is recommended by many experts that the 1-pg test replace the conventional 250-pg test as the screening test for assessment of patients with probable HPA axis suppression from steroid therapy.', 9, 36 The test is performed by injecting 1 pg of cosyntropin intravenously, not intramuscularly (because 1 pg may not be enough to reach the systemic circulation if given in the muscle). Because cosyntropin comes in vials of 250 pg, one can prepare the 1-pg solution by injecting the 250-1-1.8vial into a 250-mL bottle of saline and drawing 1 mL for injection. Plasma cortisol levels are measured before and 30 minutes after the injection. A normal response is a plasma cortisol concentration at least 18 pg/dL at 30 minutes.z7 In all tests performed, cross-reaction between all glucocorticoids except dexamethasone and the cortisol assay can occur, leading to falsely high cortisol values. Steroids taken at the time of the testing should be stopped (except dexamethasone) for at least 24 hours.18 In the case presented, testing was not necessary because adrenal insufficiency was almost certain with the high doses of dexamethasone given to the patient a few months previously. Stress-dose steroids should have been given to the patient to prevent an adrenal crisis precipitated by the surgery. Management
Patients with known or suspected secondary adrenal insufficiency should receive stress doses of steroid when undergoing surgery. For minor surgical stress ( e g , hand surgery, hemorrhoidectomy, inguinal herniorrhaphy), 100 mg of hydrocortisone is given intravenously with the induction of anesthesia, followed by usual maintenance dose (approximately 20 mg/d of hydrocortione).^^,^^ For major surgical stress (e.g., chest or abdominal surgery), it is recommended to give hydrocortisone, 100 mg intravenously, starting with induction of anesthesia and to continue the same dose every 8 hours for at least the first 24 h o ~ r ~ When . ~ ~ the , ~ major ~ , ~stress ~ of the postoperative period is resolved, and the patient is stable and free of complications (fever, vomiting), hydrocortisone can be tapered during a few days to the usual maintenance dose. Table 2 provides an example of steroid tapering. SUMMARY
In patients undergoing surgery, a thorough history is important to obtain, including use of any steroid therapy within the previous year. If there is a history of steroid use, and if time permits, testing of the HPA axis should be performed. If adrenal unresponsiveness is documented or if clinical suspicion of
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Table 2. POSTOPERATIVE STEROID TAPERING
Day 1 Hydrocortisone, 100 mg N q 8 h, starting with induction of anesthesia Day 2 if patient stable and major postoperative stress resolved, lower dose of hydrocortisone to 50 mg q 8 h Day 3 Hydrocortisone, 25 mg q 8 h Dav 4 Hydrocortisone, 25 mg bid Day 5 Maintenance dose (12-15 mg hydrocortisone/mz/d): 15-20 mg A.M. and 5-10 mg P.M.
N
= intravenously,
q = every, bid = twice a day.
adrenal insufficiency is high (without testing), a stress dose of steroids should be administered during the perioperative period to prevent an adrenal crisis. References 1. Abdu TAM, Elhadd TA, Neary R, et a1 Comparison of the low dose short synacthen test (1 mcg), the conventional dose short synacthen test (250 mcg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 84S38-843, 1999 2. Ackerman GL, Nolan CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 278:405-409, 1968 3. Axelrod L: Glucocorticoid therapy. Medicine 55:39-65, 1976 4. Borst GC, Michenfelder HJ, OBrian JT: Discordant cortisol response to exogenous ACTH and insulin-induced hypoglycemia in patients with pituitary disease. N Engl J Med 3061462-1464, 1982 5. Chernow 8, Alexander HR, Smallridge RC, et al: Hormonal responses to graded surgical stress. Arch Intern Med 1471273-1278, 1987 6. Christy NP:Corticosteroid withdrawal. In Bardin CW (ed): Current Therapy in Endocrinology and Metabolism, ed 3. Toronto, BC Decker, 1988, p 113 7. Dale DC, Fauci AS, Wolff SM: Alternate-day prednisone. N Engl J Med 291:11541158, 1974 8. Danowski TS, Bonessi JV, Sabeh G, et al: Probabilities of pituitary-adrenal responsiveness after steroid therapy. Ann Intern Med 61:ll-26, 1964 9. Dickstein G, Arad E, Shechner C: Low-dose ACTH stimulation test. Endocrinologist 7285-293, 1997 10. Fish HR, Chernow 8, OBrian JT Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia. Metabolism 35:763-780, 1986 11. Furst .DE, Saag KG, Orth D N Glucocorticoid withdrawal regimens. UpToDate 8:l-8, 1999 12. Hume DM, Bell CC, Bartter F: Direct measurement of adrenal secretion during operative trauma and convalescence. Surgery 52:174-187,1962 13. Kehlet H: A rational approach to dosage and preparation of parenteral glucocorticoid substitution therapy during surgical procedure. Acta Anaesth Scand 19:260-264, 1975 14. LaRochelle GE, LaRochelle AG, Ratner RE, et al: Recovery of the hypothalamicpituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 95:258-264, 1993 15. Livanou T, Ferriman D, James VHT Recovery of hypothalamo-pituitary adrenal function after corticosteroid therapy. Lancet 2:85&859, 1967 16. Luger A, Deuster PA, Kyle SB, et al: Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. N Engl J Med 316:1309-1314, 1987 17. Magiakou MA, Chrousos GI? Corticosteroid therapy, non endocrine disease, and
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