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

2. 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 mmHg 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

3. 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 mmHg greater than 1 hour or not 3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not

4. 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

5. Balancing Risks and Benefits of Steroids BENEFIT RISK

6. Used in Clinical Practice Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs Weizmann(review)1974Schumer1976Sprung1984VA-CoopBone1987 Cronin Lefering (meta_ analyses) 1995 Bollaert1998 Briegel1999 Annane2002 NO YES Surviving Sepsis Campaign 2004 „high-dose“ „low-dose“ Corticus 2008

7. 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

8. STUDY DESIGN H0 H8 ONSET OF SHOCK RANDOMIZATION ELIGIBILITY AND ACTH TEST HC ( IV 50 mg q 6h) + FC ( PO 50 µ g/d ) FOR 7 D PLACEBO FOR 7 DAYS DAY 28 Annane D. JAMA 2002:288:862-871

9. STEROID THERAPY OF SEPTIC SHOCK 18 YEARS OR OLDER DOCUMENTED INFECTION OR SUSPICION TEMPERATURE > 38.3 O C OR < 35.6 O C HEART RATE > 90 BEATS/MIN SBP 1 HR DESPITE FLUID & VP UO < 0.5 ml/kg/hr OR PaO2/FIO2 < 280 NEED FOR MECHANICAL VENTILATION ACTH STIMULATION TEST Annane D. JAMA 2002:288:862-871

10. 28-Day Survival All PATIENTS Hazard Ratio: 0.71 (95% CI, 0.53-0.97) p = 0.03 Annane JAMA 2002;288:862-871

11. Hazard Ratio: 0.67 (95% CI, 0.47-0.95) p = 0.02 NON RESPONDER 28-Day Survival Annane JAMA 2002;288:862-871

12. RESPONDERS Annane JAMA 2002;288:862-871 Log-Rank-Test,  2 = 0.56 p = 0.81 28-Day Survival

13. Sprung CL. 2008;358:111-124

14. 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 CORTICUS STUDY Sprung CL. NEJM 2008;358:111-124

15. 1.Clinical evidence of infection within previous 72h 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

16. 2. Systemic response to infection … as defined by ≥2 of following signs within previous 72h: fever (>38.3 0 C) or hypothermia (<35.6 0 C) tachycardia (>90 bpm) tachypnea (> 20 breaths/min, PaCO 2 <32mmHg).or patient requires mechanical ventilation WBC count >12,000 or 10% immature neutrophils CORTICUS INCLUSION CRITERIA

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

18. 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 EXCLUSION CRITERIA

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

20. RESULTS Demographics Steroids (n=251)Placebo (n=248) Age (y)63 ± 1463 ± 15 Male166 (66%)166 (67%) Medical 80 (32%) 93 (38%) Emergency surgical138 (55%)132 (54%) Elective surgical 31 (12%) 21 (9%) SAPS II Score49.5 ± 17.848.6 ± 16.7 Sprung CL. NEJM 2008;358:111-124

21. RESULTS Source of infection Steroids (n=251)Placebo (n=248) Lung76 (30%)95 (38%) GI tract123 (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

22. RESULTS: ACTH stimulation test Steroids (n=251) Placebo (n=248) All (n=499) Non-responders125 (49.8%)108 (43.5%)233 (46.7%) Responders118 (47%)136 (54.8%)254 (50.9%) Unknown8 (3.2%)4 (1.6%)12 (2.4%) Sprung CL. NEJM 2008;358:111-124

23. RESULTS: 28-day mortality - all patients P = 0.51 0 20 40 60 80 100 % mortality steroids (n=251) 86 (34.3%) placebo (n=248) 78 (31.5%) Sprung CL. NEJM 2008;358:111-124

24. 0 20 40 60 80 100 steroids (n=125) placebo (n=108) Non-responders % mortality 0 20 40 60 80 100 steroids (n=118) placebo (n=136) Responders % mortality P =0.69P = 1.000 49 (39.2%) RESULTS: 28-day mortality - by response to ACTH stimulation 34 (28.8%) 39 (28.7%) 39 (36.1%) Sprung CL. NEJM 2008;358:111-124

25. P value for log rank test: 0.753 RESULTS: 28 day survival curves - all patients placebo steroid survival 0 0.25 0.50 0.75 1.00 0510152025 30 day Sprung CL. NEJM 2008;358:111-124

26. P value for log rank test: 0.786 placebo steroid survival 0 0.25 0.50 0.75 1.00 0510152025 30 day RESULTS: 28 day survival curves - ACTH non-responders Sprung CL. NEJM 2008;358:111-124

27. P value for log rank test: 0.937 placebo steroid survival 0 0.25 0.50 0.75 1.00 0510152025 30 day RESULTS: 28 day survival curves - ACTH responders Sprung CL. NEJM 2008;358:111-124

28. RESULTS Reversal of shock Steroids (n=251)Placebo (n=248)p All200 (79.7%)184 (74.2%)0.18 Non-responders95 (76.0%)76 (70.4%)0.41 Responders100 (84.7%)104 (76.5%)0.13 Sprung CL. NEJM 2008;358:111-124

29. RESULTS: Time to reversal of shock Median time in days (95% CI) Steroids (n=251)Placebo (n=248)P All3.3 (2.9-3.9)5.8 (5.2-6.9)< 0.001 Non-responders3.9 (3.0-5.2)6.0 (4.9-9.0)0.056 Responders2.8 (2.1-3.3)5.8 (5.2-6.9)< 0.001 Sprung CL. NEJM 2008;358:111-124

30. Frequency of superinfections Steroids (n=234)Placebo (n=232) Superinfection 78 (33%) 61 (26%) No superinfection156 (67%)171 (74%) SI- Relative risk (95% CI) = 1.27 (0.96-1.68) Sprung CL. NEJM 2008;358:111-124 SI+ new S + SS- Relative risk (95% CI) = 1.37 (1.05-1.79)

31. Adverse events Steroids (n=234) Placebo (n=232) RR (95% CI) Critical illness polyneuropathy 2 (1%)4 (2%) 0.50 (0.09-2.68) Bleeding - any site21 (9%)16 (7%) 1.3 (0.70-2.43) MSOF 34 (15%)33 (14%) 1.02 (0.66-1.59) New sepsis6 (3%)2 (1%) 2.97 (0.61-14.59) New septic shock14 (6%)5 (2%) 2.78 (1.02-7.58) Repeat shock 72 (31%)57 (25%) 1.25 (0.93-1.68) Renal7 (3%)6 (3%) 1.16 (0.39-3.39) Pulmonary8 (3%)13 (6%) 0.61 (0.26-1.44) Glucose >8.3 mmol/l (day 1-7) 186 (85%)161 (72%) 1.18 (1.07-1.31)

32. Responder Central Nonresponder Central Total Responder Local154 (36%)23 (5%)177 (42%) Nonresponder Local 76 (18%)172 (40%)248 (58%) 230 (54%) 195 (46%)425 Corticus Harmonization Study Central Method: Roche Briegel J. Am J Resp CCM 2007, 175: A436

33. 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

34. 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

35. 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 Conclusions

36. 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 Recommendations

37. 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%)

38. Entry window 8 hours 72 hours SBP 1 hour < 1 hour Treatment Fludrocortisone None Treatment duration 7 days 11 days Weaning NoYes Practice/Guidelines None Steroids used SAPS II 59 + 21 49 + 17 Non-responders 229 (77%) 233 (47%) STUDY DIFFERENCES Annane Corticus

39. 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

40. 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

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

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

43. 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

44. 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

45. 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 2C Annane JAMA 2002;288:862-871 Sprung CL. NEJM 2008;358:111-124 Dellinger P. Crit Care Med. 2008;36:296-327

46. 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 2B Sprung CL. NEJM 2008;358:111-124 Briegel AJRCCM (abst). 2007: 175:A436 Oral fludrocortisone (50 µg) is considered optional if hydrocortisone is used Grade 2C Annane JAMA 2002;288:862-871 Sprung CL. NEJM 2008;358:111-124 Dellinger P. Crit Care Med. 2008;36:296-327

47. Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids Wean the patient from steroid therapy once the septic shock has resolved Grade 2D Keh AJRCCM 2003; 167:512-520 Do not use corticosteroids >300 mg/day of hydrocortisone to treat septic shock Grade 1A 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 1D 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 1D Dellinger P. Crit Care Med 2008;36:296-327

48. Corticosteroids in Septic Shock Déjà vu

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

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

51. Used in Clinical Practice Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs Weizmann(review)1974Schumer1976Sprung1984VA-CoopBone1987 Cronin Lefering (meta_ analyses) 1995 Bollaert1998 Briegel1999 Annane2002 NO YES Surviving Sepsis Campaign 2004 „high-dose“ „low-dose“ Corticus 2008

52. 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 mmHg 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

53. 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 mmHg greater than 1 hour or not 3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not

54. 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