Steroids: Benefits vs. Risks Risk/Benefit: Where are we now? Charles L. Sprung, M.D.

1. Department of Anesthesiology and Critical Care MedicineHadassah Medical Center Steroids: Benefits vs. Risks Risk/Benefit: Where are we now? Charles L. Sprung, M.D.

2. Balancing Risks and Benefits of Steroids BENEFIT RISK

3. STEROIDS BENEFIT OR HARM PATIENTS • Increased survival or mortality • Benefits - reversal or prevention of shock - improve organ system dysfunction - improve oxygenation • Complications - superinfection - neuromuscular weakness

4. STEROID THERAPY FOR THE CRITICALLY ILL PATIENT • Sepsis and Septic Shock • ARDS • COPD • Immunosuppression • Actual or relative adrenal insufficiency • Critical illness Related Corticosteroid Insufficiency- CIRCI • Etomidate treatment • Severe community-acquired pneumonia • Weaning from mechanical ventilation • Cardiac surgery • Critically ill patients with liver disease

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

6. 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

7. 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

8. STEROID THERAPY OF SEPTIC SHOCK • 18 YEARS OR OLDER • DOCUMENTED INFECTION OR SUSPICION • TEMPERATURE > 38.3OC OR < 35.6OC • HEART RATE > 90 BEATS/MIN • SBP < 90 mmHg > 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

9. 28-Day Survival All PATIENTS Hazard Ratio: 0.71 (95% CI, 0.53-0.97) p = 0.03 Annane JAMA 2002;288:862-871

10. 28-Day Survival NON RESPONDER Hazard Ratio: 0.67 (95% CI, 0.47-0.95) p = 0.02 Annane JAMA 2002;288:862-871

11. 28-Day Survival RESPONDERS Log-Rank-Test, 2= 0.56 p = 0.81 Annane JAMA 2002;288:862-871

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

13. CORTICUS INCLUSION CRITERIA 3. Evidence of shock • Systolic BP < 90 mmHg or >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 > 90mmHg • Hypoperfusion or organ dysfunction attributable to sepsis within previous 72h including one of: • sustained oliguria (<0.5 ml/kg/h for >1 hr) • metabolic acidosis [pH <7.3, base deficit ≥ 5, lactate >2] • platelets ≤ 100,000/mm3 • GCS < 14 (or acute change from baseline) 4. Informed consent 5. ACTH stimulation test

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

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

16. RESULTS Reversal of shock Sprung CL. NEJM 2008;358:111-124

17. RESULTS: Time to reversal of shock Median time in days (95% CI) Sprung CL. NEJM 2008;358:111-124

18. COMPLICATIONS OF STEROID USE • We must not forget about the complications of steroid use in septic shock patients • The complications outweigh the advantages of steroid use in most septic shock patients

19. COMPLICATION OF STEROID USE- WEAKNESS ICU acquired paresis and muscle weakness has been associated with corticosteroid use in the ICU Herridge MS. NEJM 2003;348:683-693 De Jonge B. JAMA 2002;288:2859-2867

20. COMPLICATION OF STEROID USE- WEAKNESS • ICU acquired paresis 25% • Risk factorsOR (95% CI) • Female sex 4.66 (1.2-18.3) • Number days > 2 organ dysfunction 1.28 (1.1-1.5) • Mechanical ventilation 1.10 (1.0- 1.2) • Corticosteroids 14.9 (3.2-70.8) • 29% 9-month mortality with paresis De Jonghe B. JAMA 2002;288:2859-2867

21. STEROIDS FOR ARDS • MP was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS • MP increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy • As compared with placebo, MP did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness • 9 had neuromuscular weakness; all occurred in patients receiving MP, p < 0.05 ARDSnet NEJM 2006; 354:1671-1684

22. Frequency of superinfections 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

23. Adverse events

24. CMV MORE COMMON IN SEPTIC PATIENTS • 56 ICU patients with SAPS II score > 40 and anti-HCMV IgG seropositivity were studied • 20 (36%) developed an active HCMV infection • HCMV infected patients • had higher mortality (55% vs. 36%) • ICU duration (30 vs. 23 days) • Multivariate analysis: only sepsis independently associated with active HCMV infection Heininger A. Crit Care Med 2001;29:541-547

25. COMPLICATIONS OF STEROID USE- CMV • 237 ICU nonimmunosuppressed patients with fever > 72 hours, without positive cultures and with CMV antigenemia assays • 40 (17%) had positive CMV assays • CMV diagnosis in 20 + 12 days • CMV mortality higher (50% vs. 28%) (p < 0.02), longer ICU LOS (41 vs. 31 days) (p < 0.04), longer MV (35 vs. 24 days) (p < 0.03) • CMV infection was linked to steroid use (p < 0.04) and renal failure (p < 0.02) Jaber S. Chest 2005;127: 233-241

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

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

28. 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

29. Some steroid believers are religious in their beliefs

30. Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids Dellinger P et al. Crit Care Med. 2008;36:296-327

31. 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

32. Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids • Wean the patient from steroid therapy once the septic shock has resolvedGrade 2DKeh AJRCCM 2003; 167:512-520 • Do not use corticosteroids >300 mg/day of hydrocortisone to treat septic shock Grade 1ABone, 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

33. International Task Force on Clinical Practice Guidelines for the Diagnosis and Treatment of Adrenal Insufficiency in the ICU • The committee voiced concern about as yet undiscovered harmful effects of hydrocortisone exposure occurring subsequent to its current widespread use in patients with septic shock Marik P et al. Crit Care Med. 2008;36:1937-1949

34. NO FREE LUNCH

35. Balancing Risks and Benefits of Steroids BENEFIT RISK