CORTICOSTEROID USE IN SEPTIC SHOCK THE ONGOING DEBATE DIEM HO, PHARMD PGY1 PHARMACY RESIDENT VALLEY BAPTIST MEDICAL CENTER BROWNSVILLE

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1 CORTICOSTEROID USE IN SEPTIC SHOCK THE ONGOING DEBATE DIEM HO, PHARMD PGY1 PHARMACY RESIDENT VALLEY BAPTIST MEDICAL CENTER BROWNSVILLE 1

2 ABBREVIATIONS ACCP = American College of Chest Physicians ARF = acute respiratory failure ICU = intensive care unit IV = intravenous ITT = intention to treat NE = norepinephrine RCT = randomized control trial DAA = drotrecogin alfa, activated SOFA = Sequential Organ Failure Assessment SCCM = Society of Critical Care Medicine RRT = renal replacement therapy PNA = pneumonia SIRS = systemic inflammatory response syndrome CNS = central nervous system GCS = Glasglow Coma Scale HPA = hypothalamic-pituitary-adrenal CRH = corticotropin releasing hormone ACTH = adrenocorticotropic hormone IVP = intravenous push CIF = continuous infusion MICU = medical ICU SICU = surgical ICU LOS = length of stay 2

3 OBJECTIVES 1. Differentiate sepsis versus septic shock and describe current recommendation for management. 2. Describe the clinical evidence behind current guideline recommendation for adjunctive corticosteroid use in septic shock. 3. Evaluate APROCCHSS and ADRENAL trials. 4. Select appropriate patient population for the use of adjunctive corticosteroid. 3

4 PATIENT CASE MA is a 65 year-old female admitted to the ICU for sepsis and ARF secondary to PNA requiring mechanical ventilation On admission: Lactate = 7.2 mmol/l Received Hour-1 Bundle After 2 hours: NE drip started Lactate = 6.3 mmol/l After 4 hours: NE drip at 50 mcg/min Vasopressin drip started Lactate = 5.5 mmol/l 4

5 WHICH CORTICOSTEROID REGIMEN WOULD YOU RECOMMEND FOR PATIENT MA? A. Hydrocortisone 50 mg IVP q6h x7 days B. Hydrocortisone 200 mg CIF x7 days C. Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg via PEG tube daily x7 days. D. None 5

6 SEPSIS AND SEPTIC SHOCK THE 1991 AND 2001DEFINITIONS Definition ACCP & SCCM 1991 International Sepsis Definition Conference 2001 Sepsis SIRS + infection Expanded on signs of system inflammation in response to infection Severe sepsis Septic shock Sepsis + organ dysfunction or hypoperfusion or hypotension Sepsis + hypotension despite adequate fluid resuscitation Unchanged Persistent hypotension unexplained by other causes Bone RC et al. Crit Care Med. 1992;20(6): Levy MM et al. Intensive Care Med. 2003;29(4):

7 SEPSIS AND SEPTIC SHOCK SEPSIS Sepsis: Life threatening organ dysfunction caused by a dysregulated host response to infection Acute increase of SOFA 2 points Severe sepsis: Removed Septic shock: Underlying circulatory and cellular or metabolic abnormalities Vasopressors to maintain MAP 65 mmhg Lactate > 2 mmol/l Singer M et al. JAMA. 2016;315(8):

8 SEPSIS-3 ORGAN DYSFUNCTION MEASURED BY SOFA SCORE System Respiration PaO 2 /FiO 2, mmhg, (kpa) Coagulation Platelets, x10 3 /µl Liver Bilirubin, mg/dl 400 (53.3) <400 (53/3) <300 (53.3) <200 (26.7) w/ respiratory support <100 (13.3) w/ respiratory support 150 < 150 < 100 < 50 < 20 < >12.0 Cardiovascular, mmhg MAP 70 MAP < 70 Dopamine <5 or dobutamine Dopamine or epinephrine 0.1 or NE 0.1 Dopamine >15 or epinephrine >0.1 or NE>0.1 CNS, GCS score <6 Renal, SCr (mg/dl) < >5.0 Urine output, ml/d < 500 <200 Singer M et al. JAMA. 2016;315(8):

9 MANAGEMENT OF SEPSIS AND SEPTIC SHOCK Initial resuscitation and infection management: IV crystalloids IV broad spectrum antibiotic within 1 hour Source control Hemodynamic support: IV vasopressors Inotropic therapy Rhodes A et al. Intensive Care Med. 2017;43(3):

10 NORMAL HPA AXIS ACTIVATION IN ACUTE ILLNESS Hypothalamus CRH Annane. Front Endocrinol. 2016;7:70. Cooper et al. N Engl J Med. 2003; 348: Pituitary ACTH Adrenal glands Cortisol Tissue 10

11 NORMAL HOST RESPONSE IN ACUTE ILLNESS Sepsis HPA axis activated, releasing cortisol Improve cardiac function Attenuate inflammation Sympathetic nervous system Endogenous catecholamines Annane. Front Endocrinol. 2016;7:70. 11

12 DISRUPTION OF HPA FUNCTION IN ACUTE ILLNESS Hemorrhage or necrosis of neuroendocrine cells Infection Hypoxia Coagulopathy Inactivation by high level of cytokines Decreased cortisol delivery to local tissues Increased cortisol clearance Decreased cortisol synthesis Enzymes inhibition Depleted lipid droplets storage Decreased cholesterol production Annane. Front Endocrinol. 2016;7:70. Cooper et al. N Engl J Med. 2003; 348:

13 FRENCH TRIAL 2002 STUDY DESIGN Objective Assess 28-day survival benefits of low-dose corticosteroids in patients with septic shock and relative adrenal insufficiency Design Single center, double-blind, parallel, RCT in 19 ICU from 10/9/95 to 02/23/99 Population N = 300; Septic shock patients with documented infection requiring mechanical ventilation within 8 hours of shock onset Intervention Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg daily for 7 days Placebo Short corticotropin test prior to randomization Nonresponders 9 mcg/dl Outcomes Primary: 28-day survival in nonresponders to corticotropin test Secondary: 28-day survival in responders and all patients, 28-day, ICU, hospital and 1- year mortality rates; time to vasopressor withdrawal Annane D et al. JAMA. 2002;288:

14 FRENCH TRIAL RESULT Primary Outcome: 28-day mortality Placebo (%) Corticosteroids (%) Adjusted OR Nonresponders 73/115 (63) 60/114 (53) 0.54 ( ) 10 Responders 18/34 (53) 22/3 (61) 0.97 ( ) - All patients 91/149 (61) 82/150 (55) 0.65 ( ) - Adverse events 33/149 (22) 32/150 (21) - - NNT Nonresponder Placebo Corticosteroids HR P-value Time to vasopressor withdrawal (median) 10 day 7 day 1.91 ( ) day vasopressor withdrawal (%) 46/115 (40) 65/114 (57) - - Annane D et al. JAMA. 2002;288:

15 CORTICUS STUDY DESIGN Objective Evaluate the efficacy and safety of low-dose hydrocortisone therapy in patients with septic shock Design Multicenter, double-blind, placebo, RCT from 03/2002 to 11/2005 Population N = 499 (needed 800) Septic shock patients randomized within 72 hours of onset. Intervention Hydrocortisone 50 mg IVP q6h for 5 days then 6 day taper Placebo Short corticotropin test prior to randomization Nonresponders 9 mcg/dl Outcomes Primary: 28-day mortality in nonresponders to corticotropin test Secondary: 28-day mortality in responders and all patients, 28-day, ICU, hospital and 1- year mortality; time to shock reversal, ICU and hospital LOS Sprung CL et al. N Engl J Med. 2008;358:

16 CORTICUS RESULT Primary Outcome 28-day mortality Placebo (%) Hydrocortisone (%) P-value Nonresponders 39/108 (36.1) 49/125 (39.2) 0.69 Responders 39/136 (28.7) 34/118 (28.8) 1.00 All patients 78/248 (31.5) 86/251 (34.3) 0.51 Hyperglycemia (BG 150 mg/dl) 67/232 (29) 42/234 (18) 1.18 ( ) Outcome Placebo (%) Hydrocortisone (%) P-value Time to shock reversal (median) Nonresponders Responders All patients 6.0 days 5.8 days 5.8 days 3.9 days 3.3 days 2.8 days 0.06 <0.001 <0.001 Sprung CL et al. N Engl J Med. 2008;358:

17 ADJUNCTIVE MANAGEMENT OF SEPTIC SHOCK We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day. (Weak recommendation, low quality of evidence) Rhodes A et al. Intensive Care Med. 2017;43(3):

18 APROCCHSS STUDY DESIGN & METHODS Objective Evaluate the mortality benefit of hydrocortisone plus fludrocortisone in patients with septic shock Design Multicenter, double-blinded, RCT Initially 2x2 factorial designed to evaluate corticosteroids and DAA Inclusion ICU with septic shock < 24 hours Infection SOFA 3 or 4 for at least 2 organs and at least 6 hours in duration Vasopressor for at least 6 hours targeting SBP>90 mmhg or MAP>65 mmhg Exclusion Septic shock > 24 hours, high bleeding risk, pregnancy, lactation, limited short-term survival, previous treatment with corticosteroid Annane D et al. N Engl J Med. 2018; 378:

19 APROCCHSS STUDY DESIGN & METHODS Settings 34 ICUs September 2008 June Suspended Oct 2011 May > DAA withdrawal July 2014 October > interim analysis Intervention Placebo + DAA placebo or DAA Corticosteroid + DAA placebo or DAA Corticosteroid = hydrocortisone 50 mg IV q6h & fludrocortisone 50 mcg NGT daily for 7 days Short 250 mcg corticotropin test prior to randomization: Nonresponders 9 mcg/dl Annane D et al. N Engl J Med. 2018; 378:

20 APROCCHSS STUDY DESIGN & METHODS Outcomes Primary: 90 days all-cause mortality Secondary: All-cause mortality at ICU discharge, hospital discharge, day 28, day 180. % of patients weaned from vasopressor, mechanical ventilation, reach total SOFA score < 6, organ-failure free-day, ICU discharge, hospital discharge at day 28 and 90 Safety: Superinfection day 180, GI bleeding day 28, hyperglycemia day 7 Statistical analysis ITT analysis 45% 90-day mortality; 320 pts in each group to detect 10% difference. Alpha = 0.05 Annane D et al. N Engl J Med. 2018; 378:

21 APROCCHSS BASELINE CHARACTERISTICS Characteristics Placebo (n=627) Corticosteroids (n=614) Age, year 66 ± ± 14 Medical ward admission 499/616 (81%) 495/601 (82.4) SAPS II 56 ± ± 19 SOFA score 11 ± 3 12 ± 3 Site of infection lung 363/626 (58%) 373/614 (60.7) Adequate antimicrobial therapy 602/626 (96.2%) 595/614 (96.9%) Receipt of NE NE dose, mcg/kg/min 552/ ± / ± 1.61 Mechanical ventilation 569/623 (91.3%) 567/614 (92.3) Annane D et al. N Engl J Med. 2018; 378:

22 APROCCHSS MORTALITY Annane D et al. N Engl J Med. 2018; 378:

23 APROCCHSS MORTALITY Outcome 90-day all cause mortality (%) Nonresponders Responders Placebo (n=627) 308 (49.1) 115/228 (50.4) 67/170 (39.4) Corticosteroi ds (n=614) 264 (43) 101/198 (51.0) 61/184 (33.2) Relative risk (95% CI) 0.88 ( ) 1.01 ( ) 0.84 ( ) P values 28-day all cause mortality (%) 244 (38.9) 207 (33.7) 0.87 ( ) day all cause mortality (%) 328/625 (52.5) 285/611(46.6) 0.89 ( ) All-cause mortality at ICU discharge (%) All-cause mortality at hospital discharge (%) /627 (41) 217/613 (35.4) 0.86 ( ) /627 (45.3) 239/613 (39.0) 0.86 ( ) NN T Annane D et al. N Engl J Med. 2018; 378:

24 APROCCHSS MORTALITY Primary Outcome Placeboplacebo DAAplacebo Cortico steroidplacebo Cortico steroid- DAA DAA Effects P value Corticosteroid Effects Interaction 90-day all cause mortality 257/524 (49.0) 51/103 (49.5) 215/509 (42.2) 49/105 (46.7) Annane D et al. N Engl J Med. 2018; 378:

25 APROCCHSS SECONDARY OUTCOMES Outcomes Placebo (n=627) Corticosteroids (n=614) P values % Weaned off vasopressor at day 28 Mean vasopressor-free day to day 28 Median (IQR) 505/626 (80.7) 15 ± (1-26) 520/611 (85.1) 17.1± (5-26) 0.04 < % Organ-failure-free at day 28 Mean organ failure free day to day 28 Median (IQR) 408/622 (65.5) 12 ± (0-24) 448/612 (73.2) 14 ± (0-25) Ventilator free day at day 28 Mean ventilator free day to day 28 Median (IQR) 348/622 (55.9) 10 ± 11 4 (0-21) 383/611 (62.7) 11 ± 11 1 (0-22) Annane D et al. N Engl J Med. 2018; 378:

26 APROCCHSS ADVERSE EVENTS Adverse events Placebo (n=627) Corticosteroids (n=614) Relative risk (95% CI) P values GI bleeding 45/626 (7.2) 39/614 (6.4) 0.88 ( ) 0.56 Superinfection 178/626 (28.4) 191/614 (31.1) 1.09 ( ) 0.30 Hyperglycemia 1 episode of BG 150 mg/dl by day 7 Mean # of days with 1 episode of BG 150 mg/dl by day 7 Median (IQR) 520/626 (83.1) 3.4 ± (1-6) 547//614 (89.1) 4.3 ± (2-6) 1.07 ( ) < Annane D et al. N Engl J Med. 2018; 378:

27 APROCCHSS AUTHORS CONCLUSION Hydrocortisone plus fludrocortisone lowered 90-day-all-cause-mortality in patients with septic shock compared to placebo. Strengths Multi-centered RCT ITT Appropriate antibiotic used Appropriate fluid resuscitation Limitations Sample size originally calculated for a 2x2 factorial design 461 pts did not receive short corticotropin test due to shortage Treatment based on Surviving Sepsis 2008 Guideline Annane D et al. N Engl J Med. 2018; 378:

28 APROCCHSS PRESENTER S CONCLUSION Hydrocortisone 50 mg IVP q6h and fludrocortisone 50 mcg daily for 7 day can be used as adjunctive therapy in patients with refractory shock requiring mechanical ventilation and IV vasopressor to improve mortality benefit The addition of low-dose corticosteroid use may facilitate IV vasopressor and ventilator weaning, as well as decreasing the time to reverse organ failure. Annane D et al. N Engl J Med. 2018; 378:

29 ADRENAL STUDY DESIGN & METHODS Objective Evaluate the mortality benefit of hydrocortisone plus fludrocortisone in patients with septic shock Design Double-blinded, multicenter, placebo, parallel-group RCT Stratified based on medical vs. surgical admission Inclusion ICU adults patients with septic shock requiring mechanical ventilation Infection documented or strong suspicion 2 out of 4 SIRS criteria Vasopressor or inotropes for at least 4 hours targeting SBP > 90 mmhg or MAP > 60 mmhg or physician s target. Exclusion Met all exclusion criteria >24 hours prior to study, corticosteroids for another indication, prior treatment with etomidate or amphotericin B, cerebral malaria or strongloides infection, inevitable death or expected death in 90 days Settings 69 MICU/SICUs in Australia, UK, NZ, Saudi Arabia and Denmark March 2013 April 2017 Venkatesh et al. N Engl J Med. 2018; 378:797 29

30 ADRENAL STUDY DESIGN & METHODS Intervention Hydrocortisone 200 mg daily CIf for 7 days or until ICU discharge Placebo Outcomes Primary: 90-day all-cause mortality Secondary: 28-day all-cause mortality Time to resolution of shock; recurrence of shock; ICU LOS; hospital LOS; frequency and duration of mechanical ventilation, RRT New onset of bacteremia or fungemia between day 2-14 Receipt of blood transfusion Statistical analysis ITT 33% mortality; 3800 pts to detect 5% ARR with 90% power, allowing 1% rate of withdrawal and loss. Alpha = 0.05 Venkatesh et al. N Engl J Med. 2018; 378:797 30

31 ADRENAL BASELINE CHARACTERISTICS Characteristics Placebo (n=1853) Hydrocortisone (n=1860) Age, year 62.3 ± ± 15.2 Medical ward admission 1273/1849 (68.8) 1266/1857 (68.2) APACHE II Site of infection lung Abdominal 623/1844 (33.8) 477/1844 (25.9) 677/1854 (36.5) 467/1854 (25.2) Receipt of antimicrobial therapy 602/626 (96.2) 595/614 (96.9) Receipt of NE 1823/1853 (98.4) 1821/1860 (97.9) Mechanical ventilation 1845/1849 (99.8) 1855/1857 (99.9) Time from shock onset to randomization 20.9 ± ± 83.4 Venkatesh et al. N Engl J Med. 2018; 378:797 31

32 ADRENAL RESULTS Venkatesh et al. N Engl J Med. 2018; 378:797 32

33 ADRENAL RESULTS Outcome Hydrocortisone (n=1860) Placebo (n=1853) OR (95% CI) P values 90-day all cause mortality (%) 511/1832 (27.9) 526/1826 (28.8) 0.95 ( ) day all cause mortality (%) 410/1841 (22.3) 338/1840 (24.3) 0.89 ( ) 0.13 Median time to resolution of shock (IQR, day) Median time to discharge from ICU (IQR, day) Median time to cessation of ventilation (IQR, day) 3 (2-5) 4 (2-9) 1.32 ( )* < (5-30) 12(6-42) 1.14 ( )* < (3-18) 7 (3-24) 1.13 ( )* < New-onset bacteremia or fungemia 262 (14.1) 262 (14.1) 1.00 ( ) 0.96 * Hazard ratio Venkatesh et al. N Engl J Med. 2018; 378:797 33

34 ADRENAL ADVERSE EVENTS Adverse events Hydrocortisone (n=1835) Placebo (n=1829) Number of patients with adverse events 21 6 Hyperglycemia 6 3 Bleeding 2 1 Hypernatremia 3 0 Venkatesh et al. N Engl J Med. 2018; 378:797 34

35 ADRENAL AUTHORS CONCLUSION Continuous hydrocortisone infusion did not result in lower 90-day mortality in septic shock patients requiring mechanical ventilation. Strengths Multi-centered ITT Largest RCT to date Limitations Appropriate use of antibiotic not assessed Greater rate of loss to follow up and withdrawal Used 2001 septic shock definition Venkatesh et al. N Engl J Med. 2018; 378:797 35

36 ADRENAL PRESENTER S CONCLUSION Did not improve 90-day mortality in patients with septic shock requiring mechanical ventilation, However, time to resolution of shock, ICU discharge, and ventilator cessation, which are important patient-centered outcomes, was significantly less in hydrocortisone group Venkatesh et al. N Engl J Med. 2018; 378:797 36

37 APROCCHSS VS. ADRENAL COMPARSION Characteristics APROCCHSS ADRENAL Time to onset of shock for inclusion 24 h 24 h Mean age Mechanical ventilation 91.8% 99.9% NE dose at enrollment 2.1 mcg/kg/min 0.2 mcg/kg/min (assuming 70kg) Severity of illness SAPS II score: 56 APACHE II score: 24 Site of infection lung 60% 33-36% Venkatesh et al. N Engl J Med. 2018; 378:797 Annane D et al. N Engl J Med. 2018; 378:809 37

38 APROCCHSS VS. ADRENAL ADDITION OF FLUDROCORTISONE Characteristics APROCCHSS ADRENAL Intervention Hydrocortisone 50 mg IVP q6h and fludrocortisone 50 mcg daily x7 days Hydrocortisone 200 mg CIF daily for 7 days or until ICU discharge COIITSS 2010: Multicenter, 2x2 factorial design, RCT in 11 ICUs Objective: evaluate in-hospital mortality benefits of tight glycemic control and of fludrocortisone in septic shock patients receiving corticosteroid Intervention: hydrocortisone IVP 50 mg IVP q6h Arm 1: BG target mg/dl vs. < 150 mg/dl Arm 2: fludrocortisone 50 mcg daily vs. no fludrocortisone Outcomes: There is no significant difference between the fludrocortisone group vs placebo in addition to hydrocortisone Venkatesh et al. N Engl J Med. 2018; 378:797 Annane D et al. N Engl J Med. 2018; 378:809 Annane. JAMA 2010; 303(4):

39 APROCCHSS VS. ADRENAL COMPARSION Characteristics APROCCHSS ADRENAL Mechanical ventilator Use Reduce Reduce Shock resolution/free of organ failure Faster to achieve Faster to achieve IV vasopressor use Reduce Not assessed Hyperglycemia Increase Increase Superinfection No significant difference No significant difference Venkatesh et al. N Engl J Med. 2018; 378:797 Annane D et al. N Engl J Med. 2018; 378:809 39

40 WHICH CORTICOSTEROID REGIMEN WOULD YOU RECOMMEND FOR PATIENT MA? A. Hydrocortisone 50 mg IVP q6h x7 days B. Hydrocortisone 200 mg CIF x7 days C. Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg via PEG tube daily x7 days. D. None 40

41 WHICH CORTICOSTEROID REGIMEN WOULD YOU RECOMMEND FOR PATIENT MA? A. Hydrocortisone 50 mg IVP q6h x7 days B. Hydrocortisone 200 mg CIF x7 days C. Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg via PEG tube daily x7 days. D. None 41

42 TAKE HOME POINTS Sepsis: Infection + acute SOFA score change 2 Septic shock: Sepsis + circulatory and metabolic abnormalities Septic shock management: Prompt fluid resuscitation, IV antibiotic, source control IV vasopressor Hydrocortisone 50mg IVP q6h for 7 days Refractory septic shock Mechanical ventilator Within 24 hours of septic shock onset High dose NE Risks: hyperglycemia Benefit: Reduce vasopressor use Facilitate ventilator weaning 42