1. The recent big fluid trials Sibylle A. Kozek-Langenecker M.D. Professor MBA Department of Anaesthesia and Intensive Care Evangelical Hospital Vienna www.perioperativebleeding.org sibylle.kozek@aon.at

2. Honoraria for lectures and travel reimbursement: B. Braun Fresenius Kabi CSL Behring Conflicts of interest

3. European Medicines Agency EMA Pharmacovigilance Risk Assessment Committee PRAC

5. CMDh Statement: Information for healthcare professionals (1)Because of the risk of kidney injury and mortality HES solutions must no longer be used in patients with sepsis, burn injuries or critically ill patients. (2)HES solutions should only be used for the treatment of hypovolaemia due to blood loss when crystalloids alone are not considered sufficient. (3)There is a lack of robust long-term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against the uncertainties with regard to long-term safety, and other available treatment options should be considered. Additional studies will be performed with HES solutions in patients with trauma and in elective surgery. (4)HES solutions should be used at the lowest effective dose for the shortest period of time. Treatment should be guided by continuous haemodynamic monitoring so that the infusion is stopped as soon as appropriate haemodynamic goals have been achieved. (5)HES solutions are now contraindicated in patients with renal impairment or renal replacement therapy. The use of HES must be discontinued at the first sign of renal injury. An increased need for renal replacement therapy has been reported up to 90 days after HES administration. Patients’ kidney function should be monitored after HES administration. (6)HES solutions are contraindicated in severe coagulopathy. HES solutions should be discontinued at the first sign of coagulopathy. Blood coagulation parameters should be monitored carefully in case of repeated administration. CMDh: Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human

6. Contraindications of HES 130 (after PRAC/CMDh 10/2013): Sepsis Burn trauma Renal insufficiency or RRT intracranial or cerebral bleeding Critical illness (on ICU) Hyperhydratation, incl. pulmonary edema Dehydratation Severe coagulopathy Severe liver dysfunction

7. good drug kept in treatment repertoire medico-legal relevance of restrictions CI against initial volume resuscitation in sepsis irrational problem: „not bad drug but bad use of a drug“ problem: „only bad news are good news“ restrictions in surgery/trauma irrational & not practicable renal function 90 days postOP, severe coagulopathy … use of alternatives: less investigated/risky/expensive … Personal Interpretation

8. PopulationDesign VISEP 537 sepsis, septic shock multi-center, two-by-two factorial RCT Germany CRYSTMAS 196 severe sepsis multi-center, double blind RCT Germany, France 6S 804 severe sepsis multi-center, blinded, parallel group RCT Denmark, Norway, Finland, Island CHEST 7000 ICU patients multi-center, blinded, parallel group RCT Australia, New Zealand CRISTAL 3000 ICU patients multi-nationale, pragmatic, parallel group, open-label RCT; France, Canada, North-Africa BaSES 241 sepsis, septic shock single-center, double blind, RCT Swiss Recent big fluid trials in critical illness

9. Big trial in critical illness efficacy of initial colloidal volume therapy Annane. JAMA 2013;310:1809-17

10. ControlOutcome CRYSTMAS tetrastarch130/0.4 vs. NaCl 0,9% volume requirement: colloid* < crystalloid time until stabilisation: 12 vs. 14 h (NS) renal failure: 25 v. 20% (NS) AKIN, RIFLE, NGAL,  -NAG,  -microglobulin: (NS) 6S tetrastarch 130/0.42 vs. Ringer acetate 90 day-mortality: 43 vs. 51% (*colloid worse) 90 day- RRT: 16 vs. 22% (*colloid worse) severe bleeding: 6 vs. 10% (NS) CHEST tetrastarch 130/0.4 vs. NaCl 0,9% renal failure: 10 vs. 9% (NS) RRT: 5.8 vs.7.0% (*colloid worse); length of RRT (NS) FFP-requirements: colloid* > crystalloid (18 ml) volume requirements: colloid* < crystalloid (90ml/day) ICU-mortality: 17 vs. 18% (NS) CRISTAL crystalloids vs. colloidsvolume requirement: colloid = 2x crystalloid 90 day-mortality: 34 vs. 31% (*colloid better) RRT: 13 vs. 11% (NS) BaSES tetrastarch 130/0.4 vs. Ringer lactate/ NaCl 0,9% volume requirements: 5,6 l vs. 5,0 l (NS) ICU-mortality: 29 vs. 28% (NS) AKI: 44 v. 49% (NS) LOS: 28,5 vs. 20 days (*colloid better) Results ? cause of death ? ? RRT-trigger ?

11. HEScrystalloid RRT 235196 no RRT 31173179 p = 0.044 HEScrystalloid RRT 234197 no RRT 31183178 p = 0.054 X² Test CHEST: Statistical concerns J. Kreutziger, AIC 2013

12. HEScrystalloid RRT 8765 no RRT 311335 p = 0.044 HEScrystalloid RRT 876 no RRT 311334 p = 0.054 X² Test 6S: Statistical concerns J. Kreutziger, AIC 2013

13. Randomisation AFTER initial stabilisation CHEST 6S NEJM 2012; 367;124-34 NEJM 2012;367:1901-11

14. Recommendations against initial colloidal volume resuscitation cannot be derived from 6S, CHEST, VISEP

15. ethics committee approval: use in known contraindication informed consent to use in known contraindication financial and intellectual conflicts of interest EMA: no data inspection before suspension/restriction NEJM, meta-analyses, Cochrane review: no concerns on ethics, methodological & statistical concerns Open questions

16. Lesson learned from VISEP, CHEST and 6S: prolonged colloidal volume therapy without indication according to preload a/o in the presence of contraindications must be avoided

17. Not only 1 single magic bullet … ? surgery with muscle relaxant only ? ? infusion therapy with colloids only ?

18. No indication for colloids absence of intravascular hypovolaemia „indiscriminate drug administration“ misuse, ban, prohibition …

19. Indication for colloids hypovolaemia with impaired tissue perfusion „goal-directed therapy (GDT)“ tailor drug administration in its indication CHALLENGE of MONITORING intravascular filling status, microcirculation in organs, endothelial barrier function…

20. Eur J Anaesthesiol 2013; 30: 270-382 http://esa.perioperativebleeding.org

21. We recommend avoiding hypervolemia with crystalloids or colloids to a level exceeding the interstitial space in steady state, and beyond an optimal cardiac preload 1B Avoid hypervolaemia Eur J Anaesthesiol 2013; 30: 270-382

22. Preload optimization We recommend aggressive and timely stabilisation of cardiac preload throughout the surgical procedure, as this appears beneficial to the patient 1B Eur J Anaesthesiol 2013; 30: 270-382

23. Tissue perfusion We recommend repeated measurements of a combination of Hk/Hb, serum lactate, and base deficit in order to monitor tissue perfusion, tissue oxygenation and the dynamics of blood loss during acute bleeding. These parameters can be extended by measurement of cardiac output, dynamic parameters of volume status (e.g. SVV, PPV) and central venous saturation 1C Eur J Anaesthesiol 2013; 30: 270-382

24. Monitoring MAP, CVP, HR: Crystalloid:colloid ratios cannot be derived from 6S, CHEST, VISEP

25. Systematic reviews and meta-analyses: pooling of study limitations not helpful Zarychanski R. JAMA. 2013;309(7):678-688 Patel A. Intensive Care Med 2013; DOI 10.1007/s00134-013-2863-6 Haase N. BMJ 2013;346:f839 doi: 10.1136/bmj.f839 …

26. EVIDENCE from Cochrane Analyses 2013: „… hard to see how the use of colloids can be justified …“

27. „… no evidence that one colloid solution is more effictive or safe than any other…“

28. „… hard to see how the use of albumin can be justified …“

29. Crit Care 2013; 17: R166

30. Fluids In Resuscitation in Severe Trauma James. Br J Anaesth 2011;107:693 The FIRST Study: Lactate clearance similar static hemodynamic measurements between groups superior tissue perfusion after HES compared to saline

31. CI, cardiac index CVP central venous pressure SVV, stroke volume variation PEEP, positive end-expiratory pressure Vt, tidal volume Benes. Crit Care 2010;14;R118

32. GDT: improved tissue perfusion Benes. Crit Care 2010;14;R118

33. GDT: less complications Benes. Crit Care 2010;14;R118

34. Van der Linden. Anaesth Analg 2013;116:35-48 n = 4.529 Big trial in elective surgery colloidal volume therapy & patient safety

35. risk difference acute renal failure serum creatinine extreme values Big trial in elective surgery colloidal volume therapy & renal function Martin. Anesthesiology 2013; 118: 387-94 n = 1.230 in 17 studies

37. …….. Coriat, Guidet, de Hert, Kochs, Kozek, van Aken 71 co-signatories …….. Coriat, Guidet, de Hert, Kochs, Kozek, van Aken 71 co-signatories

38. Alternatives? Perfusion monitoring?

39. www.perioperativebleeding.org sibylle.kozek@aon.at Thank you for your attention !