Perioperative Corticosteroids: Who, Why and When? A rational approach.

1. Perioperative Corticosteroids: Who, Why and When?A rational approach. 14 Nov 2003

2. Objectives • History • Hypothalamic-Pituitary-Adrenal (HPA) Axis • Adrenal Insufficiency • HPA Axis Tests • HPA Axis Response to Surgical Stress • Perioperative Supplementation Recommendations

3. Case (this really happened) 68 year-old, 85 kg male with COPD (75 pack-years), RA, CAD with a single LUL mass suspicious for carcinoma scheduled for left thoracotomy with wedge resection vs. lobectomy. He takes prednisone 5 mg BID for the past 2 years along with a host of other meds. He took his usual prednisone dose the morning of surgery.

4. Case (this really happened, too) He was induced with fentanyl 150 mcg, propofol 100 mg, and rocuronium 80 mg. SBP dropped to 60’s after induction. Phenylephrine, ephedrine, fluids given with some improvement in BP. SBP hovered in 90-100’s. Noticeable improvement in BP after administration of hydrocortisone.

5. History • Sir Thomas Addison reports adrenal gland destruction by TB in 1855. • Cortisone used clinically in late 1940’s. • Hench, Kendall and Reichstein share Nobel Prize in Medicine after describing benefits of cortisone in RA in 1949.

6. History: How it all started • Exogenous cortisone introduced in the late 1940’s • 1952--Fraser, et al. • Fatal post-op adrenal insufficiency (AI) in a 34-year old male with rheumatoid arthritis chronically treated with cortisone. • Cortisone withheld 2 days prior to hip arthroplasty. JAMA 1952:149:1542-3.

7. History • The patient died 3 hours after surgery after developing hypotension refractory to volume, vasopressors and “adrenal cortical extract.” • Autopsy showed marked atrophy of the adrenal glands. JAMA 1952:149:1542-3.

8. History • 1953—Lewis and colleagues report the death of a patient who died several hours after a knee flexion contracture repair. • Had been taking cortisone daily for 5 months prior to surgery. • Cortisone discontinued the day before surgery. • Autopsy: adrenal atrophy and hemorrhage. Ann Intern Med 1953; 39:116-26.

9. History • Early perioperative recommendations for steroid use were based on anecdotal evidence and incomplete understanding of the HPA axis and its response to physiological stress. • High doses were given with a long (2-4 week) taper. • Perspective: Cushing’s patients average cortisol production is 36 mg/day. • Increased risk for infection due to hyperglycemia and immunosuppression and delayed wound healing. Ann Surg 1994;219:416-25 Hosp Phys. Oct 2003:39-44.

10. Corticosteroids ZG: Mineralocorticoids aldosterone ZF & ZR: Glucocorticoids cortisol ZF & ZR: Androgens Medulla: Epi & Norepi Guyton’s Physiology, 8th Ed: 843. Adrenal Physiology

11. Adrenal Physiology • Aldosterone: • Electrolyte (Na, K) and fluid balance • Glucocorticoids: • Stress responses • Increase blood glucose • Gluconeogenesis, protein & fat mobilization • Immune modulation ** Cortisol has only 1/400 the mineralocorticoid activity as aldosterone but about 80 times as much cortisol as aldosterone is secreted so cortisol’s mineralocorticoid activity is significant. Have you ever treated AI with aldosterone?? Guyton’s Physiology, 8th Ed: 844

12. Glucocorticoids are regulated by a negative feedback system involving the Hypothalamic-Pituitary-Adrenal (HPA) Axis Guyton’s Physiology, 8th Ed: 850. Adrenal Physiology

13. Adrenal Physiology Mineralocorticoids (aldosterone) secretion controlled by (in descending order): 1. [K] of extracellular fluid (ECF). 2. Renin-angiotensin system. 3.  [Na] of ECF. 4. ACTH (although total absence of ACTH can significantly decrease aldosterone secretion). Guyton’s Physiology, 8th Ed: 846.

14. Adrenal Insufficiency • Primary (Addison’s Disease): inability of gland to produce hormone • Anatomic destruction of gland • “Idiopathic” atrophy (Autoimmune, Adrenoleukodystrophy) • Surgical removal • Infection (especially AIDS patients, TB) • Hemorrhage • Metastatic Invasion • Metabolic failure of hormone production • Congenital adrenal hyperplasia • Enzyme inhibitors (metyrapone, ketoconazole, Etomidate) • Cytotoxic agents Harrison’s Principles of Internal Medicine. 14th Edition:2051

15. Adrenal Insufficiency • Secondary: inadequate ACTH formation or release. • Hypopituitarism • Suppression of hypothalamic-pituitary axis • Exogenous systemic steroid • High-dose inhaled steroids • Exogenous steroid from tumor (paraneoplastic) Harrison’s Principles of Internal Medicine. 14th Edition:2051

16. Adrenal Insufficiency • Chronic systemic corticosteroid therapy is the most common cause of AI. • COPD/Asthma • Arthritis (RA/OA) • Autoimmune disease (Crohn’s, UC, SLE, Sjogren’s, Sarcoidosis, Vasculitides, etc.) • s/p transplant (immunosuppression) Harrison’s Principles of Internal Medicine. 14th Edition:2051

17. Adrenal Insufficiency • Clinical Manifestations • Mineralocorticoid Deficiency •  Na, Cl • Hypovolemia/Hypotension/ Cardiac Output • Metabolic Acidosis •  K • Glucocorticoid Deficiency • Weakness/Fatigue • Hypoglycemia • Hypotension (insensitivity to catecholamines) • Weight Loss

18. Guyton’s Physiology, 8th Ed: 851 Circadian Secretion of Cortisol: “natural caffeine”

19. HPA Axis Testing • Cosyntropin Stim Test • A synthetic analog of ACTH. • 250 mcg IV or IM. • Plasma cortisol & aldosterone levels drawn at baseline, 30 and 60 minutes later. • Useful for diagnosing primary AI; if the gland is destroyed, no increase in cortisol will occur.

20. HPA Axis Testing Cosyntropin Stim Test • May miss secondary AI if the gland is still able to synthesize cortisol. Consider other tests. • Normal response is doubling of baseline level at 60 minutes.

21. HPA Axis Testing • Metyrapone test • Inhibits 11ß-hydroxylase (blocks conversion of 11-deoxycortisol to cortisol). • HP axis senses low cortisol and secretes more ACTH. • Assesses entire HPA axis. • Etomidate suppression test??

22. HPA Axis Testing • Insulin-induced hypoglycemia test • 0.05-0.1 unit regular insulin/kg given IV to induce hypoglycemia >50% below basal. • Normal response is increase in cortisol. • CRH stimulation test • 1 mcg ovine CRH/kg IV. • Stimulates secretion of ACTH.

23. Perioperative Adrenal Crisis • Extremely rare! • In a series of 62,473 anesthetics, 419 cases (0.7%) received glucocorticoids. • Only 3 episodes of hypotension due to inadequate glucocorticoids. Ann Surg 1994;219:416-25

24. Minor: herniorraphy Mod: cholecystectomy Major: colectomy Hosp Phys. October 2003:39-44. Surgical Stress

25. Surgical Stress • Baseline cortisol production is approximately 10 mg/day (range 5-25). J Clin Endocrinol Metab 2001;86:5920-4. • Normal individuals produce 75 to 150 mg/day of cortisol in response to major surgical stress. • They rarely produce more than 200 mg in the 24 hours after major surgery. Ann Surg 1994:219:416-25.

26. Who’s at Risk? • Primary AI • Secondary AI • Chronic exogenous steroid users • How much? • How long? • How long ago? • Type of surgery?

27. How much? How long?(Short term) • 75 patients received 25 mg prednisone daily for between 5-30 days for various reasons. • After discontinuation, 1 mcg corticotropin (CRH) given IV. • Adrenal response suppressed in 34 patients and normal in 41. • All but 2 patients had normal tests 2 weeks after stopping prednisone. 2 patients remained suppressed for several months. Lancet 2000;355:542-5.

28. How much? How long?(Long term) • 1993—LaRochelle, et al. • Retrospective chart review. • Patients currently on prednisone (or equivalent), </= 10 mg, for >24 months. • Patients received cosyntropin (ACTH) stim test. Am Journ Med 1993;95:258-63.

29. How much? How long?(Long term) • 1993—LaRochelle, et al (Cont). • >7.5 mg prednisone daily (or equivalent): HPA axis suppressed, therefore, cover with steroids. • 5-7.5 mg: equivocal, therefore, test administer ACTH stim test and treat accordingly. • <5 mg: HPA axis expected to be normal. Give normal daily steroid dose. • “Duration of therapy, total steroid dose, and highest steroid dose need not be considered since they do not affect HPAA recovery. Relying on these factors to make a decision as to the status of the HPAA would be unwise.” Am Journ Med 1993;95:258-63.

30. How much? How long?(Long term) • 1967—Livanou, et al. • >7.5 mg prednisone delays HPAA recovery. • Duration of therapy has “inconclusive effects” on the HPAA. Lancet 1967; Oct 21;2:856-9.

31. Minor: herniorraphy Mod: cholecystectomy Major: colectomy Hosp Phys. October 2003:39-44. Physiologic Stress Dosing

32. Physiologic Stress Dosing “The routine administration of stress doses equivalent to 200-300 mg of hydrocortisone when a patient undergoes any procedure or has any medical illness should be discouraged.” JAMA 2002;287:236-239. “Normal individuals produce 75-150 mg/day of cortisol in response to major surgical stress and rarely produce more than 200 mg in the 24 hours following major surgery.” Ann Surg 1994;219:416-25

33. Recommendations *Data are based on extrapolation from the literature, expert opinion, and clinical experience. Patients receiving 5 mg/d or less of prednisone should receive their normal daily replacement, but do not require supplementation. Patients who receive >5 mg/d of prednisone should receive the above therapy in addition to their maintenance therapy. JAMA 2002;287:236-239.

34. Summary • Determine who is at risk for adrenal crisis. • How much? • How long? • How long ago? • Type of surgery? • When you decide to “stress dose,” give physiologic doses.