1. Department of Anesthesiology and Critical Care Medicine Hadassah 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. 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

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 > 38.3 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

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

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

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

13. 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

14. 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

15. 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

16. 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

17. 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

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 factors OR (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 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)

23. 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)

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

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

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

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 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

33. 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 International Task Force on Clinical Practice Guidelines for the Diagnosis and Treatment of Adrenal Insufficiency in the ICU Marik P et al. Crit Care Med. 2008;36:1937-1949

34. NO FREE LUNCH

35. Balancing Risks and Benefits of Steroids BENEFIT RISK