Objectives. Pathophysiology of Steroids. Question 1. Pathophysiology 3/1/2010. Steroids in Septic Shock: An Update

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1 Objectives : An Update Michael W. Perry PharmD, BCPS PGY2 Critical Care Resident Palmetto Health Richland Hospital Review the history of steroids in sepsis Summarize the current guidelines for steroids in sepsis Identify new literature concerning steroids in sepsis Incorporate new literature into current practice Question 1 True or False Adrenal insufficiency during septic shock is solely due to decreased production of cortisol Pathophysiology of Steroids Steroids are synthesized in the adrenal cortex Mineralocorticoid - Aldosterone Glucocorticoid - Cortisol Androgens Dehydroepiandrosterone (DHEA) Synthesis is dependant on adrenocorticotropic hormone (ACTH) Stress Normal Hypothalamic Pituitary Axis (HPA) CRH: corticotropin releasing hormone ACTH: adrenocorticotropic hormone DHEA: dehydroepiandrosterone Aldosterone Hypothalamus CRH Anterior Pituitary ACTH Adrenal Cortex Diurnal Rhythm Aldosterone Cortisone Negative Feedback Pathophysiology Steroids are protein bound Cortisol binding protein Albumin 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) Inactivates cortisol to cortisone Kidney and liver 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) Converts cortisone to cortisol Liver, adipose, and bone tissue DHEA 1

2 Adrenal Insufficiency in Sepsis Stress Hypothalamus Diurnal Rhythm Septic shock leads to changes in the HPA Changes in secretion of cortisol Changes at the tissue level Binding Metabolism Anatomic damage Drug-induced adrenal insufficiency Hypothalamic Pituitary Axis (HPA) During Septic Shock CRH: corticotropin releasing hormone ACTH: adrenocorticotropic hormone DHEA: dehydroepiandrosterone CRH Anterior Pituitary ACTH Adrenal Cortex Negative Feedback Lost Cytokines Sympathetic Nervous System Current Pharmaceutical Design. 2008; 14: Aldosterone DHEA Aldosterone Cortisone Adrenal Insufficiency in Sepsis Question 2 Cortisol levels are increased during the acute phase of septic shock Conversion of cortisol to cortisone is decreased 11β-HSD1 activity increased Decreased hepatic and renal blood flow Reduced levels of cortisol binding protein Which of the following steroids has the highest anti-inflammatory potency? A. Triamcinolone B. Hydrocortisone C. Betamethasone D. Prednisolone Current Pharmaceutical Design. 2008; 14: The Early Years Case reports and animal studies had shown positive outcomes with high dose steroids in sepsis Two prospective, randomized, doubleblind, placebo-controlled trials of highdose methylprednisolone for severe sepsis and septic shock failed to show mortality benefits. The early years Bone et.al. Methylprednisolone 30 mg/kg vs. placebo 14 day Mortality methylprednisolone (46/78 [59 %]) placebo (17/58 [29 %]) p < 0.01 Increased secondary infection in treatment group N Engl J Med 1987; 317:

3 The Early Years Veterans Administration Study 223 patients with systemic sepsis Methylprednisolone 30 mg/kg bolus followed by infusion of 5 mg/kg/hr for 9 hours 14-day mortality placebo (22 %) methylprednisolone (21 %) (p = 0.97) High dose methylprednisolone does not reduce mortality significantly in patients with systemic sepsis N Engl J Med 1987; 317: The Revitalization: Briegel et.al. Prospective, randomized, double-blind, single-center study 40 patients with septic shock Placebo vs. hydrocortisone 100 mg bolus followed by a continuous infusion of 0.18 mg/kg/hr Hydrocortisone significantly reduced the time to cessation of vasopressor support 2 days in the hydrocortisone-treated group 7 days in the placebo group p = There was a trend to earlier resolution of the organ dysfunction in the hydrocortisone group. Overall shock reversal and mortality were not significantly different between the groups Crit Care Med 1999; 27: ) The Revitalization: Bollaert et.al. Prospective, randomized, double-blind, placebo-controlled study 41 patients with septic shock requiring catecholamines for >48 hrs Hydrocortisone 100 mg IV TID x 5 days vs. placebo 7-day shock reversal Hydrocortisone15 (68%) Placebo 4 (21%) 95% CI 17% to 77%; p = No significant differences in outcome in responders and nonresponders to a short corticotropin test. Administration of modest doses of hydrocortisone resulted in a significant improvement in hemodynamics and a beneficial effect on survival. The Revitalization: Annane et.al. Placebo-controlled, randomized, double-blind, parallel-group trial 300 patients with septic shock Hydrocortisone (50-mg IV Q6H) and fludrocortisone (50-μg PO daily) vs. placebo for 7 days. Patients were divided into either responders or non-responders after a short corticotropin test. These beneficial effects do not appear related to adrenocortical insufficiency. Crit Care Med 1998;26: JAMA. 2002;288(7): The Revitalization: Annane et.al. The Revitalization: Annane et.al. 28 Day Mortality Nonresponders Placebo 63% Treatment 53% p= 0.02 NNT=7 28 Day Mortality All patients Placebo 61% Treatment 55% p= 0.03 NNT = 8 JAMA. 2002;288(7): JAMA. 2002;288(7):

4 Surviving Sepsis Guidelines 2008 Corticosteroids The guideline committee suggests intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy. (Grade 2C) The guideline committee suggests the adrenocorticotropic hormone (ACTH) stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone. (Grade 2B) The guideline committee suggests that patients with septic shock should not receive dexamethasone if hydrocortisone is available. (Grade 2B) Surviving Sepsis Guidelines 2008 Update Corticosteroids The guideline committee suggests the daily addition of oral fludrocortisone (50 micrograms) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used. (Grade 2C) The guideline committee suggests clinicians wean the patient from steroid therapy when vasopressors are no longer required. (Grade 2D) Intensive Care Med 2008 Jan;34(1): Intensive Care Med 2008 Jan;34(1): Surviving Sepsis Guidelines 2008 Update The guideline committee recommends doses of corticosteroids comparable to >300 mg hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic shock. (Grade 1A) The guideline committee recommends corticosteroids not be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress-dose steroids if the patient's endocrine or corticosteroid administration history warrants. (Grade 1D) CORTICUS Multicenter, randomized, double-blind, placebo-controlled trial Hydrocortisone 50 mg IV Q6H vs. placebo The primary outcome was death at 28 days among patients who did not have a response to a corticotropin test Intensive Care Med 2008 Jan;34(1): CORTICUS CORTICUS P=0.69 P=

5 CORTICUS Conclusions Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin Hydrocortisone hastened reversal of shock in patients in whom shock was reversed There were more episodes of superinfection, including new sepsis and septic shock in the hydrocortisone group Critique of CORTICUS The study did not meet its goal of 800 patients The illness severity of the patients was less than that of previous trials The dosing regimen did not include fludrocortisone Meta-analysis 17 randomized trials investigating corticosteroid treatment included in analysis 28-day mortality treated 388/1099 (35.3%) control patients 400/1039 (38.5%) RR = 0.84; 95% [CI], ; 1 00; P= trials investigating prolonged low-dose corticosteroid treatment 28-day mortality for treated 236/629 (37.5%) control 264/599 (44%) RR= 0.84; 95% CI, ; P=.02). Meta-analysis 28-day shock reversal 6 trials;treatment 322/481 [66.9%] vs Control 276/471 [58.6%] RR, 1.12; 95% CI, ; P=0.02 Risk of gastroduodenal bleeding 13 trials;treatment 65/800 [8.1%] vs Control 56/764 [7.3%]; P=0.50 Risk of superinfection 14 trials; Treatment184/998 [18.4%] vs Control 170/950 [17.9%]; P=0.92 Risk of neuromuscular weakness 3 trials; Treatment 4/407 [1%] vs Control 7/404 [1.7%]; P=0.58 JAMA. 2009;301(22): JAMA. 2009;301(22): Current Practice Who should receive low dose steroids? Current Practice Should fludrocortisone be added to hydrocortisone therapy. Should steroids be weaned off? JAMA. 2010;303(4):

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