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

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

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 • 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 From Navickis R et al. J Thorac Cardiovasc Surg 144:223-230e5, 2012.

5. HES Solutions For Cardiovascular Surgery: A Systematic Review of Randomized Trials • 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) Boldt’ studies not retrieved ! From Shi XY et al. Eur J Clin Pharmacol 67:767-82, 2011.

6. Perioperative Fluid Therapy in Cardiac Surgery • 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 From Bayer O et al. Crit Care Med 41:2532-42, 2013.

7. Perioperative Fluid Therapy in Cardiac Surgery • 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 From Bayer O et al. Crit Care Med 41:2532-42, 2013.

8. Perioperative Fluid Therapy in Cardiac Surgery • 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) * * * From Bayer O et al. Crit Care Med 41:2532-42, 2013. * p<0.01 vs colloids

9. Perioperative Fluid Management in Cardiac Surgery Tissue Fluid accumulation Tissue O2 delivery optimization

10. Fluid Overload Predicts Mortality after Cardiac Surgery • Prospective cohort study (N=502) • Fluid overload and creatinine levels recorded daily in ICU 17 patients died during their ICU stay 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 From Stein A et al. Crit Care 16:R99, 2012.

11. Optimization of Circulatory Status After Cardiac Surgery • Randomized controlled trial • Conventional hemodynamic management (N=85) • Protocol (N=89): stroke index > 35 ml/m2 (esophageal doppler) • Primary outcome: hospital length of stay From McKendry M et al. BMJ 329:258-62, 2004.

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

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

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

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 9 9 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] From Russel JA et al. J Cardiothorac Vasc Anesth 18:429-437, 2004.

17. Colloids Vs. Crystalloids as Priming Solutions for Cardiopulmonary Bypass • 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. From Himpe D. Acta Anaesthesiol Belg 54:20-15, 2003.

18. Albumin Vs. Gelatins as Priming Solutions for Cardiopulmonary Bypass • 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) * * * From Himpe D et al. J Cardiothorac Vasc Anesth 5:457-66, 1991 * p<0.05 vs gelatins

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

22. % p<0.005 p<0.001 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 From Verheij J et al. Intensive Care Med 32: 1030-8, 2006.

23. Effects of 6% HES 130/0.4 & 4% Gelatin On Hemodynamics After Cardiac Surgery • 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.

24. Effects of 6% HES 130/0.4 & 4% Gelatin On Hemodynamics After Cardiac Surgery • 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 From Schramko A et al. Perfusion 25:283-91, 2010; Br J Anaesth 104:691-7, 2010.

25. Gelatin vs HES 130/0.4 in Cardiac Surgery Propspective randomized single-blind study 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 2nd objective: efficacy in maintaining hemodynamics PAOP: 8-15 mmHg; CI > 2.5L/min.m²; diuresis > 0.5 ml/kg.h From Van der Linden P et al. Anesth Analg 101: 629-34, 2005.

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

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

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

30. Gelatin vs HES 130/0.4 in Cardiac Surgery p<0.05 p<0.01 From Van der Linden P et al. Anesth Analg 101: 629-34, 2005.

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 • 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 p=0.0001 • No difference in creatinine clearance at 72 hours • No difference in ICU and hospital length of stay From Tiryakioglu O et al. J Cardiothorac Surg 3:45, 2008.