Department of Anesthesiology and Critical Care Medicine Hadassah

Department of Anesthesiology and Critical Care Medicine Hadassah Medical Center The use of steroids in septic shock patients Charles L. Sprung, M. D.

Treating the Septic Shock Patient- • • An interactive case A 65 year old man is admitted with septic shock. After two fluid challenges of a liter of normal saline each and noradrenaline 0. 02 mcg/kg/min, the BP was 95/45 mm. Hg after 30 minutes. This patient SHOULD receive adjunct therapy with intravenous hydrocortisone 50 mg every 6 hours for 5 -7 days. 1. Strongly agree 2. Agree 3. No opinion or Unsure 4. Disagree 5. Strongly disagree

Treating the Septic Shock Patient • The difference between the mortalities of patients and the steroid affect in the Annane (JAMA 2002) and the Corticus (NEJM 2008) studies were primarily due to: 1. The entry window of 8 hours vs. 72 hours 2. SBP < 90 mm. Hg greater than 1 hour or not 3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not

Treating the Septic Shock Patient • The following statements concerning the use of steroids for patients with septic shock are true according to the latest Surviving Sepsis Campaign guidelines (Crit Care Med 2008; 36: 296 -327). 1. Treat patients who still require vasopressors despite fluid replacement with hydrocortisone. 2. ACTH stimulation tests should be used to identify the subset of adults with septic shock who should receive hydrocortisone. 3. Fludrocortisone must be added to hydrocortisone 4. Wean the patient from steroid therapy once the septic shock has resolved 5. Hydrocortisone should be administered for severe sepsis without shock

Balancing Risks and Benefits of Steroids BENEFIT RISK

Used in Clinical Practice NO YES Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs „high-dose“ „low-dose“ Bollaert Weizmann Schumer Sprung VA-Coop Cronin review)) (review 1976 1984 Bone Lefering 1998 (meta_ analyses) 1974 1987 1995 Briegel Annane 1999 2002 Surviving Sepsis Campaign 2004 Corticus 2008

Surviving Sepsis Campaign (SSC) Guidelines- Steroids • • Treat patients who still require vasopressors despite fluid replacement with hydrocortisone 200 -300 mg/day, for 7 days in three or four divided doses or by continuous infusion Grade C Optional: - Adrenocorticotropic hormone (ACTH) stimulation test (250 -µg) - Continue treatment only in nonresponders (delta cortisol 9 µg/dl) Grade E Dellinger P. Crit Care Med 2004; 32: 858 -873

STUDY DESIGN ONSET OF SHOCK RANDOMIZATION H 0 H 8 HC (IV 50 mg q 6 h) + FC (PO 50 µg/d) FOR 7 D ELIGIBILITY AND ACTH TEST PLACEBO FOR 7 DAYS DAY 28 Annane D. JAMA 2002: 288: 862 -871

STEROID THERAPY OF SEPTIC SHOCK • • 18 YEARS OR OLDER DOCUMENTED INFECTION OR SUSPICION TEMPERATURE > 38. 3 OC OR < 35. 6 OC HEART RATE > 90 BEATS/MIN SBP < 90 mm. Hg > 1 HR DESPITE FLUID & VP UO < 0. 5 ml/kg/hr OR Pa. O 2/FIO 2 < 280 NEED FOR MECHANICAL VENTILATION ACTH STIMULATION TEST Annane D. JAMA 2002: 288: 862 -871

28 -Day Survival All PATIENTS Hazard Ratio: 0. 71 (95% CI, 0. 53 -0. 97) p = 0. 03 Annane JAMA 2002; 288: 862 -871

28 -Day Survival NON RESPONDER Hazard Ratio: 0. 67 (95% CI, 0. 47 -0. 95) p = 0. 02 Annane JAMA 2002; 288: 862 -871

28 -Day Survival RESPONDERS Log-Rank-Test, 2 = 0. 56 p = 0. 81 Annane JAMA 2002; 288: 862 -871

Sprung CL. 2008; 358: 111 -124

CORTICUS STUDY • Investigator-initiated, European double-blind PRCT • Patients enrolled from March ‘ 02 - Nov ‘ 05 • 52 enrolling centers • Intended sample size: 800 (80% power to detect 10% absolute fall in mortality) • Final enrollment: 500 patients • 499 patients analyzable Sprung CL. NEJM 2008; 358: 111 -124

CORTICUS INCLUSION CRITERIA 1. Clinical evidence of infection within previous 72 h Any of… • presence of neutrophils in normally sterile body fluid (excluding blood) • positive culture or Gram stain of blood, sputum, urine or normally sterile body fluid • identified focus of infection • other clinical evidence of infection - pneumonia, purpura fulminans, necrotising fascitis, etc.

CORTICUS INCLUSION CRITERIA 2. Systemic response to infection … as defined by ≥ 2 of following signs within previous 72 h: • fever (>38. 30 C) or hypothermia (<35. 60 C) • tachycardia (>90 bpm) • tachypnea (> 20 breaths/min, Pa. CO 2<32 mm. Hg) . or patient requires mechanical ventilation • WBC count >12, 000 or < 4000 cells/mm 3 or >10% immature neutrophils

CORTICUS INCLUSION CRITERIA 3. Evidence of shock • Systolic BP < 90 mm. Hg or >50 mm. Hg fall despite adequate fluid or need for pressors >1 h (dopamine 5 g/kg/min or any dose of adr, noradr, vasopressin or phenylephrine) to maintain SBP > 90 mm. Hg • Hypoperfusion or organ dysfunction attributable to sepsis within previous 72 h including one of: • • sustained oliguria (<0. 5 ml/kg/h for >1 hr) metabolic acidosis [p. H <7. 3, base deficit ≥ 5, lactate >2] platelets ≤ 100, 000/mm 3 GCS < 14 (or acute change from baseline) 4. Informed consent 5. ACTH stimulation test

CORTICUS EXCLUSION CRITERIA • Chronic corticosteroid therapy in last 6 months or acute steroid therapy (any dose) within 4 months (including inhaled steroids) • Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks • Presence of advanced directive to withhold or withdraw life sustaining treatment • Moribund patients likely to die within 24 hours • In ICU >2 months at time of onset of septic shock • HIV positivity

CORTICUS STUDY MEDICATION IV bolus • 50 mg hydrocortisone q 6 h x 5 days (days 1 -5) • 50 mg hydrocortisone q 12 h x 3 days (days 6 -8) • 50 mg hydrocortisone q 24 h x 3 days (days 9 -11) no repeat dose or “real” steroids no fludrocortisone Sprung CL. NEJM 2008; 358: 111 -124

RESULTS Demographics Steroids (n=251) Placebo (n=248) Age (y) 63 ± 14 63 ± 15 Male 166 (66%) 166 (67%) Medical 80 (32%) 93 (38%) Emergency surgical 138 (55%) 132 (54%) Elective surgical 31 (12%) 21 (9%) SAPS II Score 49. 5 ± 17. 8 48. 6 ± 16. 7 Sprung CL. NEJM 2008; 358: 111 -124

RESULTS Source of infection Steroids (n=251) Placebo (n=248) Lung 76 (30%) 95 (38%) GI tract 123 (49%) 116 (47%) Urinary tract 20 (8%) 17 (7%) Soft tissue 17 (7%) Other 50 (20%) 48 (19%) Sprung CL. NEJM 2008; 358: 111 -124

RESULTS: ACTH stimulation test Steroids (n=251) Placebo (n=248) All (n=499) Non-responders 125 (49. 8%) 108 (43. 5%) 233 (46. 7%) Responders 118 (47%) 136 (54. 8%) 254 (50. 9%) Unknown 8 (3. 2%) 4 (1. 6%) 12 (2. 4%) Sprung CL. NEJM 2008; 358: 111 -124

RESULTS: 28 -day mortality - all patients Sprung CL. NEJM 2008; 358: 111 -124 % mortality 100 80 60 40 20 0 86 (34. 3%) steroids (n=251) 78 (31. 5%) placebo (n=248) P = 0. 51

RESULTS: 28 -day mortality by response to ACTH stimulation Sprung CL. NEJM 2008; 358: 111 -124 % mortality 100 Responders 100 80 80 60 60 40 40 20 0 34 (28. 8%) steroids (n=118) 39 (28. 7%) placebo (n=136) P = 1. 000 20 0 Non-responders 49 (39. 2%) 39 (36. 1%) steroids (n=125) placebo (n=108) P =0. 69

RESULTS: 28 day survival curves - all patients survival 1. 00 0. 75 0. 50 0. 25 steroid placebo 0 0 5 10 15 20 25 30 day Sprung CL. NEJM 2008; 358: 111 -124 P value for log rank test: 0. 753

RESULTS: 28 day survival curves - ACTH non-responders survival 1. 00 0. 75 0. 50 0. 25 steroid placebo 0 0 5 10 15 20 25 30 day Sprung CL. NEJM 2008; 358: 111 -124 P value for log rank test: 0. 786

RESULTS: 28 day survival curves - ACTH responders survival 1. 00 0. 75 0. 50 0. 25 steroid placebo 0 0 5 10 15 20 25 30 day Sprung CL. NEJM 2008; 358: 111 -124 P value for log rank test: 0. 937

RESULTS Reversal of shock Steroids (n=251) Placebo (n=248) p All 200 (79. 7%) 184 (74. 2%) 0. 18 Non-responders 95 (76. 0%) 76 (70. 4%) 0. 41 Responders 100 (84. 7%) 104 (76. 5%) 0. 13 Sprung CL. NEJM 2008; 358: 111 -124

RESULTS: Time to reversal of shock Median time in days (95% CI) Steroids (n=251) Placebo (n=248) P All 3. 3 (2. 9 -3. 9) 5. 8 (5. 2 -6. 9) < 0. 001 Non-responders 3. 9 (3. 0 -5. 2) 6. 0 (4. 9 -9. 0) 0. 056 Responders 2. 8 (2. 1 -3. 3) 5. 8 (5. 2 -6. 9) < 0. 001 Sprung CL. NEJM 2008; 358: 111 -124

Frequency of superinfections Steroids (n=234) Placebo (n=232) Superinfection 78 (33%) 61 (26%) No superinfection 156 (67%) 171 (74%) SI- Relative risk (95% CI) = 1. 27 (0. 96 -1. 68) SI+ new S + SS- Relative risk (95% CI) = 1. 37 (1. 05 -1. 79) Sprung CL. NEJM 2008; 358: 111 -124

Adverse events Steroids (n=234) Placebo (n=232) RR (95% CI) Critical illness polyneuropathy 2 (1%) 4 (2%) Bleeding - any site 21 (9%) 16 (7%) 34 (15%) 33 (14%) New sepsis 6 (3%) 2 (1%) New septic shock 14 (6%) 5 (2%) 72 (31%) 57 (25%) Renal 7 (3%) 6 (3%) Pulmonary 8 (3%) 13 (6%) 186 (85%) 161 (72%) 0. 50 (0. 09 -2. 68) 1. 3 (0. 70 -2. 43) 1. 02 (0. 66 -1. 59) 2. 97 (0. 61 -14. 59) 2. 78 (1. 02 -7. 58) 1. 25 (0. 93 -1. 68) 1. 16 (0. 39 -3. 39) 0. 61 (0. 26 -1. 44) 1. 18 (1. 07 -1. 31) MSOF Repeat shock Glucose >8. 3 mmol/l (day 1 -7)

Corticus Harmonization Study Central Method: Roche Responder Central Nonresponder Central Responder Local 154 (36%) 23 (5%) 177 (42%) Nonresponder Local 76 (18%) 172 (40%) 248 (58%) 230 (54%) 195 (46%) Briegel J. Am J Resp CCM 2007, 175: A 436 Total 425

Conclusions Hydrocortisone Rx • did not decrease mortality in non-responders, responders or all patients • did not reverse shock in non-responders, responders or all patients • did decrease the time to shock reversal in non-responders, responders and all patients

Conclusions Hydrocortisone Rx • was not associated with an increased incidence of polyneuropathy • was associated with an increased incidence of superinfection and new sepsis and septic shock

Conclusions • The short corticotropin test does not appear useful for guiding steroid therapy • The gain achieved by earlier shock reversal in patients receiving hydrocortisone was counterbalanced by later superinfections and new sepsis and septic shock

Recommendations • Hydrocortisone therapy cannot be recommended as routine adjuvant therapy for septic shock nor can corticotropin testing • Hydrocortisone may have a role among patients who are treated early after the onset of septic shock who remain hypotensive despite the administration of high-dose vasopressors

28 -day Mortality Annane Corticus Steroids 82/150 (55%) 86/251 (34. 3%) Placebo 91/149 (61%) 78/248 (31. 5%) Total 173/299 (58%) 164/499 (32. 9%)

STUDY DIFFERENCES Annane Corticus Entry window 8 hours 72 hours SBP < 90 mm. Hg > 1 hour < 1 hour Treatment Fludrocortisone None Treatment duration 7 days 11 days Weaning No Practice/Guidelines None Yes Steroids used SAPS II 59 + 21 49 + 17 Non-responders 229 (77%) 233 (47%)

Meta-analysis of treatment with hydrocortisone on shock reversal at day 7 in patients with septic shock Marik P et al. Crit Care Med. 2008; 36: 1937 -1949

Meta-analysis of treatment with hydrocortisone on 28 -day survival in patients with septic shock Marik P et al. Crit Care Med. 2008; 36: 1937 -1949

Steroids and ARDS prevention Peter, J. V. et al. BMJ 2008; 336: 1006 -1009

Steroids and ARDS mortality Peter, J. V. et al. BMJ 2008; 336: 1006 -1009

STEROID USE • Doctors see the reversal of shock very quickly and associate the improvement to steroid use • Doctors do not associate the late complications with steroids as they are not temporally related • These include superinfections, new sepsis, new septic shock, CMV and ARDS mortality

Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock Updated Guidelines Dellinger P et al. Crit Care Med. 2008; 36: 296 -327

Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids • We suggest 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 2 C Annane JAMA 2002; 288: 862 -871 Sprung CL. NEJM 2008; 358: 111 -124 Dellinger P. Crit Care Med. 2008; 36: 296 -327

Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids • We suggest the ACTH stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone Grade 2 B Sprung CL. NEJM 2008; 358: 111 -124 Briegel AJRCCM (abst). 2007: 175: A 436 • Oral fludrocortisone (50 µg) is considered optional if hydrocortisone is used Grade 2 C Annane JAMA 2002; 288: 862 -871 Sprung CL. NEJM 2008; 358: 111 -124 Dellinger P. Crit Care Med. 2008; 36: 296 -327

Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids • Wean the patient from steroid therapy once the septic shock has resolved Grade 2 D Keh AJRCCM 2003; 167: 512 -520 • Do not use corticosteroids >300 mg/day of hydrocortisone to treat septic shock Grade 1 A Bone, et al. NEJM 1987; 317 -658 VA Sepsis Study Group. NEJM 1987; 317: 659 -665 • • In the absence of shock, corticosteroids should not be administered for the treatment of sepsis Grade 1 D There is no contraindication to continuing maintenance steroid therapy or to using stress does steroids if the patient’s endocrine or corticosteroid administration history warrants Grade 1 D Dellinger P. Crit Care Med 2008; 36: 296 -327

Corticosteroids in Septic Shock Déjà vu

Sprung CL. N Engl J Med 1984; 11: 1137 -43; 358: 111 -124

MORTALITY REVERSAL OF SHOCK SPRUNG CL. N ENGL J MED 1984; 311: 1137 -1143

Used in Clinical Practice NO YES Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs „high-dose“ „low-dose“ Bollaert Weizmann Schumer Sprung VA-Coop Cronin review)) (review 1976 1984 Bone Lefering 1998 (meta_ analyses) 1974 1987 1995 Briegel Annane 1999 2002 Surviving Sepsis Campaign 2004 Corticus 2008

Treating the Septic Shock Patient- • • An interactive case A 65 year old man is admitted with septic shock. After two fluid challenges of a liter of normal saline each and noradrenaline 0. 02 mcg/kg/min, the BP was 95/45 mm. Hg after 30 minutes. This patient SHOULD receive adjunct therapy with intravenous hydrocortisone 50 mg every 6 hours for 5 -7 days. 1. Strongly agree 2. Agree 3. No opinion or Unsure 4. Disagree 5. Strongly disagree

Treating the Septic Shock Patient • The difference between the mortalities of patients and the steroid affect in the Annane (JAMA 2002) and the Corticus (NEJM 2008) studies were primarily due to: 1. The entry window of 8 hours vs. 72 hours 2. SBP < 90 mm. Hg greater than 1 hour or not 3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not

Treating the Septic Shock Patient • The following statements concerning the use of steroids for patients with septic shock are true according to the latest Surviving Sepsis Campaign guidelines (Crit Care Med 2008; 36: 296 -327). 1. Treat patients who still require vasopressors despite fluid replacement with hydrocortisone. 2. ACTH stimulation tests should be used to identify the subset of adults with septic shock who should receive hydrocortisone. 3. Fludrocortisone must be added to hydrocortisone 4. Wean the patient from steroid therapy once the septic shock has resolved 5. Hydrocortisone should be administered for severe sepsis without shock