1. Choice of fluid in sepsis University of Copenhagen Anders Perner Dept of Intensive Care, Rigshospitalet, University of Copenhagen Scandinavian Critical Care Trials Group www.ssai.info/research/SCCTG Intensive Care Medicine http://icmjournal.esicm.org/index.html COIs - Research support from B Braun, Fresenius, CSL Behring Honoraria from Ferring, LFP

2. CCM 2013;41:580 ICM 2013;39:165

3. 6S TRIAL

4. Investigator-initiated & publicly-funded 6S TRIAL

5. Investigator-initiated & publicly-funded High internal validity Pre-publiced protocol and SAP Five-fold blinding 100% follow-up 6S TRIAL

6. Investigator-initiated & publicly-funded High internal validity Pre-publiced protocol and SAP Five-fold blinding 100% follow-up High external validity Pragmatic design 50% non-university hospitals 66% inclusion rate, simple inclusion and few exclusion criteria 6S TRIAL

7. Inclusion criteria Adult patients in the ICU AND Fulfil severe sepsis criteria within 24 h AND Need for fluid resuscitation 6S TRIAL

8. 6S TRIAL Trial fluid # 1 Trial fluid # 2 Trial fluid # X Masked trial fluid up till 33 ml/IBW-kg/day Intervention 6% HES 130/0.42 in Ringer’s acetate (Tetraspan) or Ringer’s acetate (Sterofundin)

9. Baseline characteristics StarchRingers Numbers398400 Age66 (56-75)67 (56-76) Time from ICU admin to rando 4 (1-13) 4 (1-13) SAPS II50 (40-60)51 (39-62) Acute kidney injury36%35% Shock84%84% Values are medians (IQRs) or numbers (%) 6S TRIAL

10. Trial fluid StarchRingers Volume, ml Day 1 (14 h)1500 (1000-1500)1500 (1000-1550) Day 21000 (300-1500)1000 (500-1500) Day 3500 (0-1000)425 (0-500) Day 40 (0-500) Day 50 (0-500) Total (90 days)3000 (1500-5000)3000 (1800-5500) 6S TRIAL

11. Fluid volumes and balances 6S TRIAL

12. 180 g HES

13. Starch increased…. 6S TRIAL

14. Number needed to harm…. 13 6S TRIAL

15. 6S TRIAL ICM 2013; 39: 1936

16. Meta-analysis of HES130 vs. crystalloid/HA in sepsis Mortality RR 1.1 (1.0-1.2) BMJ 2013; 346: f839

17. Starch increased…. 6S TRIAL

18. ESICM 2013 6S TRIAL Earlier use of RRT with starch

19. RRT and risk of death 6S TRIAL NEJM 2012

20. RRT and risk of death 6S TRIAL NEJM 2012

21. Meta-analysis of HES130 vs. crystalloid/HA in sepsis RRT RR 1.4 (1.1-1.7) BMJ 2013; 346: f839

22. Starch increased bleeding 6S TRIAL ICM 2013 39(12):2126

23. 6S TRIAL P=0.001 Earlier bleeding with starch ICM 2013 39(12):2126

24. Bleeding and risk of death 6S TRIAL ICM 2013 39(12):2126

25. StarchRinger’s SF-36P value Physical component summary score 37 (29-48)40 (32-51)0.23 Mental component summary score 45 (36-55)53 (39-60)0.01 6S TRIAL Reduced QoL at 1-year with starch Critical Care 2013; 17: R58

26. The 6S summary 6S TRIAL Higest methodological standards Tested starch in clinical practice Included patients fairly early Gave fluid volumes early and well within the labelled dose Biological plausibility – Cause-and-effect

27. A ‘correct’ indication for starch?

28. Existing data do not support ‘correct’ indication for starch Haase et al. Critical Care 2013

29. A safe starch dose?

30. Lower volume Higher volume Cochrane CD007594

31. CHEST: HES 130/0.4 vs saline in 7,000 general ICU patients Increased use of RRT, RBCs and SAEs with mean 500 ml of starch Myburgh et al. NEJM 2012

32. Ratio CHESTNaCl vs 6% HES130 n=70001.2 6S trialRinger vs 6% HES130 n= 800 1.1 CRYSTMAS NaCl vs 6% HES130 n= 196 1.0 Crystalloid to HES volume ratio in blinded trials

33. New data

34. Open-label trial ICU patients in shock Randomisation by envelopes, fixed block size of 4 Any colloid (maily HES) vs. any crystalloid (maily saline) The CRISTAL trial JAMA Oct. 2013

36. Primary outcome

37. 90-day mortality

38. High risk of bias in 3 domains Unblinded Uncertain allocation concealment Baseline imbalance The CRISTAL trial JAMA Oct. 2013

39. The effect of bias on mortality in HES trials in sepsis RR 1.11 (1.01-1.23), p=0.03 Low risk of method. bias High risk of method. bias RR 0.49 (0.28-0.85), p=0.01 Test of heterogeneity p<0.01

40. CCM 2013;41:580 ICM 2013;39:165

41. CCM 2013;41:580 ICM 2013;39:165

42. Shall we use albumin in sepsis?

44. Fraud? HES comparator / Non-septic patient Kids

45. SAFE septic pts – outcome Finfer S. ICM 2010

46. Multivariate analyses Finfer S. ICM 2010

47. Coming trial results… EARSS - 20% HA vs saline in septic shock ALBIOS - 20% HA vs saline in severe sepsis Shall we use albumin in sepsis? Probably not

48. Until then..................... crystalloids for sepsis

49. www.NEJM.org Sept 24 th 2013

50. 3241

51. anders.perner@regionh.dk 6S TRIAL TRISS TRIAL