1. Nicolai Haase, MD, PhD Department of Intensive Care Copenhagen University Hospital - Rigshospitalet Resuscitating sepsis – how I do it after 6S 4th International Fluid Academy Days 2014 No financial conflicts of interest

2. 6S background Hydroxyethyl starches (HES) Used for > 30 years Physiology and small studies show improved short term hemodynamics Popularity was largely based on fraudulent evidence No data to show improved patient outcome Safety concerns have existed for many years

3. 6S background – the VISEP trial Blinded, multicenter RCT 10% HES 200/0.5 vs. Ringer’s lactate in patients with severe sepsis / septic shock Stopped early: 537 patients Use of RRT: Increased by 63% (P=0.001) 90d-mortality: Increased by 21% (P=0.09) Hypothesized weaknesses – 10% HES 200/0.5 and not 6% HES 130/0.4 – Some patients were overdosed Brunkhorst et al. New Engl J Med 2008

4. The Scandinavian Starch for Severe Sepsis / Septic Shock (6S) Trial Scandinavian Critical Care Trials Group Funded by public funds and supported by B Braun Melsungen AG

5. Design 6% HES 130/0.42 in Ringer’s acetate Ringer’s acetate 800 ICU-patients with severe sepsis who needed fluid resuscitation Double-blind, multicenter, randomised clinical trial Max. dose 33 ml/kg/day

6. Fluid volumes Perner, Haase et al. New Engl J Med 2012

7. Mortality at 90 days Perner, Haase et al. New Engl J Med 2012 RR 1.17 (1.01-1.36), P=0.03 Number needed to harm: 13

8. Any Renal Replacement Therapy Perner, Haase et al. New Engl J Med 2012 and unpublished data RR 1.35 (1.01-1.80), P = 0.04

9. Hemostasis - post-hoc Haase et al. Intensive Care Med 2013 Relative risk P-Value (95%-CI) Bleeding episode 1.55 (1.16-2.08) 0.003 RBC transfusion 1.28 (1.12-1.47) <0.001

10. Strengths State-of-the-art method Centralised randomisation Allocation concealment Blinding Pre-published protocol and statistical analysis plan Intention-to-treat analyses Pragmatic design No specific fluid algorithm Resembles the clinical use of HES Real world evidence Group differences indicate a very strong signal

11. Conclusion – the 6S trial In patients with severe sepsis the use of 6% HES 130/0.42 vs. Ringer’s acetate – Did not significantly reduce the amount of fluid given – Impaired renal function – Probably induced bleeding – Increased the risk of death

12. 6S versus VISEP VISEP 10% solution HES 200/0.5 Some overdosing 6S 6% solution HES 130/0.42 No overdosing Despite a ‘better’ design the 6S trial confirmed that HES induces renal impairment and increase mortality in sepsis.

13. Hypothesized weaknesses of 6S No protocol for RRT Inclusion of fully resuscitated patients Lack of specific fluid algorithm to prevent HES-induced hypervolemia

14. Hypothesized weaknesses of 6S No protocol for RRT inclusion of fully resuscitated patients lack of specific fluid algorithm to prevent HES-induced hypervolemia Randomisation should balance potential differences No group difference in KDIGO-stages at initiation of RRT Unpublished data Randomisation should balance potential differences No group difference in KDIGO-stages at initiation of RRT Unpublished data

15. Hypothesized weaknesses of 6S No protocol for RRT Inclusion of fully resuscitated patients Lack of specific fluid algorithm to prevent HES-induced hypervolemia

16. Hypothesized weaknesses of 6S No protocol for RRT Inclusion of fully resuscitated patients Lack of specific fluid algorithm to prevent HES-induced hypervolemia ICU-clinicians judged fluid resuscitation to be needed 84% had septic shock Mean arterial pressure < 70 mmHg Lactate > 4 mmol/l Vasopressor treatment ICU-clinicians judged fluid resuscitation to be needed 84% had septic shock Mean arterial pressure < 70 mmHg Lactate > 4 mmol/l Vasopressor treatment

17. Müller, Haase et al. ICM 2013

18. Hypothesized weaknesses of 6S No protocol for RRT Inclusion of fully resuscitated patients Lack of specific fluid algorithm to prevent HES-induced hypervolemia

19. Hypothesized weaknesses of 6S No RRT-protocol The harm seen with HES is due to the inclusion of fully resuscitated patients lack of specific fluid algorithm to prevent HES-induced hypervolemia No specific fluid algorithm ≠ no targets for resuscitation What happened in 6S (and other pragmatic trials), is what happens in the clinic every day! If the therapeutic window of HES is too small, HES may not be safe to use at all. No specific fluid algorithm ≠ no targets for resuscitation What happened in 6S (and other pragmatic trials), is what happens in the clinic every day! If the therapeutic window of HES is too small, HES may not be safe to use at all.

20. CRYSTMAS N196 DesignSpecific targets Intervention6% HES 130/0.4 Study fluid to stabilization 300 ml less Total study fluidNo difference AKI, relative risk1.22 RRT, relative risk1.83 Mortality at 90 d, relative risk 1.20 Sponsored by Fresenius 196 ICU-patients with severe sepsis Voluven (HES 130/0.4) vs. Saline for up to 4 days Specific resuscitation targets R.O.S.E concept

21. HES in sepsis - summary VISEP6SCRYSTMAS N537798196 DesignPragmatic Specific targets Intervention10% HES 200/0.56% HES 130/0.426% HES 130/0.4 Study fluid to stabilization --300 ml less Total study fluid1:1.3No difference AKI, relative risk1.531.181.22 RRT, relative risk1.631.351.83 Mortality at 90 d, relative risk 1.211.171.20 P-values < 0.05 are marked with bold

22. Conclusion – HES in sepsis HES vs. crystalloid – Reduces fluid use slightly – Short term hemodynamic improvement – Impairs renal function – Increase mortality – Certainly no overall benefit

23. We need to take the discussion further -Are the results plausible? -Can the results be applied to other patient groups?

24. Tissue deposition Profound even in healthy volunteers and surgical patients Up to 40% of ‘modern’ HES Almost any organ Even after low doses Lasting for years (>8 years) Renal deposits is associated with renal failure Bellmann et al., Clin Pharmacokinet 2012 Wiedermann et al., ICM 2014

25. Critically ill in general - CHEST 7,000 critically ill ICU patients HES 130/0.4 vs. Saline HES:crystalloid = 1:1.2 Total HES dose < 30 ml/kg RRT increased by 21 % Mortality increased by 6% (NS) Conclusion: Less use of fluid did not improve clinical outcome Renal toxicity at very low doses Too few patients to evaluate mortality Myburgh et al. New Engl J Med 2012

26. RCTs comparing any HES vs. other fluids in any type of patient Data from > 9.000 patients 30 % increased risk of RRT 10 % increased risk of death Most data from ICU-trials – limited trials in surgery No support for different effects according to HES-type and type of patient Systematic reviews by independent authors Perel & Roberts, Cochrane 2013; Mutter at al., Cochrane 2013; Zarychanski et al. JAMA 2013

27. Suggesting a safe use of HES – if used ‘correctly’ No data support Remains pure speculation

28. CRISTAL suggests benefit with colloids Important sources of bias Doesn’t outweigh other evidence against the use of HES Annane et al. JAMA 2013

29. Conclusion Improved hemodynamics with HES do not lead to improved outcome HES is harmful in sepsis, but HES toxicity seems to be independent of septic disease The ability to resist HES-toxicity may depend only on comorbidity and severity of disease A true benefit with HES remains to be shown and even elective surgical patients will be at risk of adverse effects

30. Resuscitating sepsis – how I do it after 6S I do not use HES at all - neither in sepsis nor in anyone else. High-quality real world evidence show that crystalloid is a far better alternative than HES. Thank you very much for your attention.

32. Exclusions 6 Age < 18 years 0 Allergy towards IMP 138 Renal Replacement Therapy 1 Organ transplant 5 Burn injury >10% 9 Intracraniel bleeding 21 S-K + >6 mM 25 Other trial 15 No active therapy 152 >1000 ml synthetic colloid 51 No informed consent 804 randomised patients Inclusion criteria fulfilled 1211 Post-randomisation exclusions 4 deleted from database during the trial (Violation of in-/exclusion criteria AND no trial fluid given) 2 consent withdrawn after end of trial both in the HES group 798 patients analysed 100% follow-up

33. Results - baseline characteristics GroupHESRinger’s Numbers398400 Age66 (56-75)67 (56-76) Surgical reason for admission29%29% Source of sepsis Lungs212 (53)229 (57) Abdomen130 (33)133 (33) SAPS II50 (40-60)51 (39-62) Shock84%84% Values are medians (IQRs) or %

34. The harm seen with HES is due to by the inclusion of patients with renal impairment the inclusion of fully resuscitated patients lack of specific fluid algorith to prevent HES-induced hypervolemia Hypothesized weaknesses of 6S

35. 1 year mortality Perner, Haase et al., Intensive Care Med 2014

36. Coagulopathy Hypocoagulopathy as assessed by TEG/ROTEM Hartog et al. ICM 2011 Potential clinical relevance? Increased bleeding with HES vs. albumin in cardiac surgery (meta-analysis) Navickis et al. J Thorac Cardiovasc Surg. 2012 Excess bleeding in 6S