1. High Fluid Need During Cardiac Surgery: Can We Do Without HES? Philippe Van der Linden MD, PhD CHU Brugmann-HUDERF, Free University of Brussels

2. Fees for lectures, advisory board and consultancy: Fresenius Kabi GmbH B Braun Medical SA

3. High Fluid Need During Cardiac Surgery: Can We Do Without HES?

4. Effects of Hydroxyethyl Starch on Bleeding After Cardiopulmonary Bypass From Navickis R et al. J Thorac Cardiovasc Surg 144:223-230e5, 2012. Meta-analysis including 18 trials (N=970) Compared to albumin, HES:  postop blood loss by 33% (18.2-48.3%)  risk of reoperation RR:2.24 (1.14-4.40)  risk of RBC transfusion by 28.4% (12.2-44.6%)  risk of FFP transfusion by 30.6% (8.0-53.1%)  risk of platelet transfusion by 29.8% (3.4-56.2%) No difference between HES 450/0.7 and HES 200/0.5…but mix of 6% and 10% solutions Insufficient data available for HES 130/0.4 versus albumin

5. HES Solutions For Cardiovascular Surgery: A Systematic Review of Randomized Trials From Shi XY et al. Eur J Clin Pharmacol 67:767-82, 2011. Quantitative and qualitative analysis of all pertinent randomized controlled trials (up to December 2010) 52 randomized trials; 3234 patients (23 trials with HES130/0.4) Blood loss NStd mean diff (95% CI) HES 130/0.4 vs albumin 7-0.61 (-0.82, -0.40) HES 130/0.4 vs gelatin 10-0.02 (-0.16, 0.12) HES 130/0.4 vs crystalloids 3-0.19 (-0.45, 0.08) Transfusion NRR (95% CI) p HES 130/0.4 vs albumin 40.77 (0.62, 0.94)0.01 HES 130/0.4 vs gelatin 41.03 (0.86, 1.24)0.74 HES 130/0.4 vs crystalloids 10.67 (0.13, 3.44)0.63 Boldt’ studies not retrieved !

6. Perioperative Fluid Therapy in Cardiac Surgery From Bayer O et al. Crit Care Med 41:2532-42, 2013. Observational cohort study: fluid therapy in the operating room and on the ICU directed at preset hemodynamic goals HES (predominantly 130/0.4) in 2004-2006 (N=2137) 4% Gelatin in 2006-2008 (N=2324) Only crystalloids in 2008-2010 (N=2017) Clinical outcomes RRT more common with HES and gelatins than crystalloids Hospital mortality: HES = crystalloids, but higher with gelatin ICU length of stay longer for HES than for gelatin and crystalloids

7. Perioperative Fluid Therapy in Cardiac Surgery From Bayer O et al. Crit Care Med 41:2532-42, 2013. Observational cohort study: fluid therapy in the operating room and on the ICU directed at preset hemodynamic goals HES (predominantly 130/0.4) in 2004-2006 (N=2137) 4% Gelatin in 2006-2008 (N=2324) Only crystalloids in 2008-2010 (N=2017) Clinical outcomes RRT more common with HES and gelatin than crystalloids… in patients who already had an intermediate or high risk for RRT Mean SOFA score higher with crystalloids than with HES or gelatin Duration of mechanical ventilation shorter with HES

8. Perioperative Fluid Therapy in Cardiac Surgery From Bayer O et al. Crit Care Med 41:2532-42, 2013. Observational cohort study: fluid therapy in the operating room and on the ICU directed at preset hemodynamic goals HES (predominantly 130/0.4) in 2004-2006 (N=2137) 4% Gelatin in 2006-2008 (N=2324) Only crystalloids in 2008-2010 (N=2017) * p<0.01 vs colloids * * * “Colloid” period“Crystalloid” period 6% HES 130/0.4500 ml1000 ml Ringer’s lactate750 ml250 ml 15% mannitol250 ml

9. Perioperative Fluid Management in Cardiac Surgery Tissue Fluid accumulation Tissue O 2 delivery optimization

10. Fluid Overload Predicts Mortality after Cardiac Surgery From Stein A et al. Crit Care 16:R99, 2012. Prospective cohort study (N=502) Fluid overload and creatinine levels recorded daily in ICU Black circle: non survival with Δcreat < 0.6 mg/dl White circle: survival with with Δcreat < 0.6 mg/dl Black square: non survival with Δcreat ≥ 0.6 mg/dl White square: survival with with Δcreat ≥ 0.6 mg/dl Black circle: non survival with Δcreat < 0.6 mg/dl White circle: survival with with Δcreat < 0.6 mg/dl Black square: non survival with Δcreat ≥ 0.6 mg/dl White square: survival with with Δcreat ≥ 0.6 mg/dl 17 patients died during their ICU stay

11. Optimization of Circulatory Status After Cardiac Surgery From McKendry M et al. BMJ 329:258-62, 2004. Randomized controlled trial Conventional hemodynamic management (N=85) Protocol (N=89): stroke index > 35 ml/m 2 (esophageal doppler) Primary outcome: hospital length of stay

12. Perioperative Fluid Management in Cardiac Surgery Pre-bypass On-bypass Post-bypass

13. Physiopathology of Cardiopulmonary Bypass Interstitial fluid accumulation Complement activation Capillar permeability HYPOVOLEMIA Catecholamine release Hypothermia Vasoconstriction Venous capacitance Hemodilution Plasma COP Interstitial COP Translocation of interstitial albumin

14. Interstitial Volume (ISFV) During Cardiac Surgery Olthof CG et al. Acta Anaesthesiol Scand 39:508-12, 1995. Start CPB 10 min CPB End CPB End Operation 0 20 40 60 80 100 120 Changes compared to pre-op values (%) COP (%)ISFV (%) ISFV: measured by a non-invasive conductivity technique * p<0.05 vs pre-op * * * * * * Start CPB 10 min CPB End CPB End Operation 0 1,000 2,000 3,000 4,000 5,000 Changes compared to pre-op values Fluid balance (ml) * * * *

15. Fluid Management in Pediatric Cardiac Surgery: On-bypass Albumin in the prime: precoats the CPB circuit surface To delay the absorption of circulating fibrinogen To reduce surface activation and adhesion of platelets

16. Albumin vs Crystalloids for Pump Priming in Cardiac Surgery Meta-analysis of controlled trials (adult & pediatric patients): 21 studies, 1346 patients Albumin prime reduces: The on-bypass drop in platelet count pooled WMD: -23,8 10 /L [-42,8 to -4,7 10 /L] The colloid oncotic pressure decline pooled WMD: -3,6 mmHg [-4,8 to -2,3 mmHg] The on-bypass positive fluid balance pooled WMD: -584 ml [-819 to -348 ml] The postoperative weight gain pooled WMD: -1,0 kg [-0,6 to -1,3 kg] 99 From Russel JA et al. J Cardiothorac Vasc Anesth 18:429-437, 2004.

17. Colloids Vs. Crystalloids as Priming Solutions for Cardiopulmonary Bypass From Himpe D. Acta Anaesthesiol Belg 54:20-15, 2003. Meta-analysis of prospective randomized trials: N=17 (997 patients). Wide variations in priming fluid regimens Colloids in the prime resulted in higher COP and lower positive fluid balance. No difference between albumin- based priming and synthetic-based priming No difference in postoperative bleeding between crystalloids and colloids-based priming. No difference between albumin-based priming and synthetic-based priming.

18. Albumin Vs. Gelatins as Priming Solutions for Cardiopulmonary Bypass From Himpe D et al. J Cardiothorac Vasc Anesth 5:457-66, 1991 Prospective randomized trial: elective CABG patients Randomization according to the priming volume (2200 ml) 3% albumin (N=35) 3.5% urea-linked gelatin (N=35) 3% balanced modified fluid gelatin (N=35) * p<0.05 vs gelatins ** *

21. Fluid Loading in Cardiovascular Hypovolemic Patients From Verheij J et al. Intensive Care Med 32:1030-8, 2006. Prospective randomized trial: treatment of hypovolemic hypotension after cardiac and major vascular surgery (N=63) Fluids administered < strict fluid challenge protocol

22. Cardiac Response to Fluid Loading After Cardiac or Vascular Surgery Single-blinded RCT (N=67) 90 min filling pressure-guided challenge - 0.9% saline - Colloids: 4%GEL, 6% HES, or 5% alb More saline than colloids infused Saline: ↓ COP; colloids: ↑ COP Colloids equally effective % p<0.001 p<0.005 From Verheij J et al. Intensive Care Med 32: 1030-8, 2006.

23. Prospective randomized single-blind study Elective surgery – crystalloid-based pump prime; no TXA Fluid administration immediately after ICU admission: 6% HES 130/ 0.4 (N=15) 4% Modified fluid gelatin (N=15) Ringer’s acetate (N=15) Hemodynamic monitoring: PAC, thermodilution cardiac output Hemodynamics & blood transfusion guided by strict protocols 3 bolus of 7 mL/kg + 7 mL/kg over 12h From Schramko A et al. Perfusion 25:283-91, 2010; Br J Anaesth 104:691-7, 2010. Effects of 6% HES 130/0.4 & 4% Gelatin On Hemodynamics After Cardiac Surgery

24. Prospective randomized single-blind study Intermittent thermodilution cardiac output measurements No difference in HR, MAP and CVP between the groups * * * # *p <0.05 Vs. Colloids # p<0.05 Vs. HES # * * * Effects of 6% HES 130/0.4 & 4% Gelatin On Hemodynamics After Cardiac Surgery From Schramko A et al. Perfusion 25:283-91, 2010; Br J Anaesth 104:691-7, 2010.

25. 1st objective: to compare the effects on total blood losses of two synthetic colloids: 3% modified fluid gelatin (N=64) or 6% HES 130/0.4 (N=68) in patients undergoing coronary artery surgery (up to 20 h postop) Max dose 50 ml/kg PAOP: 8-15 mmHg; CI > 2.5L/min.m²; diuresis > 0.5 ml/kg.h Gelatin vs HES 130/0.4 in Cardiac Surgery From Van der Linden P et al. Anesth Analg 101: 629-34, 2005. Propspective randomized single-blind study 2nd objective: efficacy in maintaining hemodynamics

26. From Van der Linden P et al. Anesth Analg 101: 629-34, 2005. Gelatin vs HES 130/0.4 in Cardiac Surgery

27. From Van der Linden P et al. Anesth Analg 101: 629-34, 2005.

28. Gelatin vs HES 130/0.4 in Cardiac Surgery Gel group: 21/64 were transfused (0 [0-6] units) HES 130/0.4: 24/68 were transfused (0 [0-6] units)

29. From Van der Linden P et al. Anesth Analg 101: 629-34, 2005. Gelatin vs HES 130/0.4 in Cardiac Surgery

30. From Van der Linden P et al. Anesth Analg 101: 629-34, 2005. p<0.05 p<0.01

31. Conclusions Primary goal of fluid volume therapy: To correct absolute or relative volume deficit in order to optimize tissue oxygen delivery The optimal amount at the right moment with a combination of crystalloids AND colloids Choice between the different solutions Physiological compartment that needs to be restored (intravascular, interstitial, intracellular) Characteristics of the solutions Pharmacokinetic and pharmacodynamic properties Side effects Costs

32. Thank you very much for your attention

33. HES 130/0.4 Vs. Ringer Solution For Cardiopulmonary Bypass Prime From Tiryakioglu O et al. J Cardiothorac Surg 3:45, 2008. Prospective randomized controlled trial (N=140) Prime volume -1500 ml Ringer solution (Ringer group: N=70) - 1500 ml HES 130/0.4 (HES group: N=70) p=0.0001 No difference in creatinine clearance at 72 hours No difference in ICU and hospital length of stay