1. ABC Advanced Bleeding Care Goals of Resuscitation: Early Versus Late Targets Luciano Gattinoni

2. © TPWG May 2004 ABC Advanced Bleeding Care 2 Energy Charge Energy charge Relative speed 00.250.50.751 ATP synthesis ATP consumption

3. © TPWG May 2004 ABC Advanced Bleeding Care 3 During Glycolysis For 1 mole of glucose, only 2 moles of ATP produced (efficiency = 5%) No O 2 is consumed and no CO 2 is produced No H+ is released into the medium Lactate formation is essential for NADH re-oxidation

4. © TPWG May 2004 ABC Advanced Bleeding Care 4 Matrix Inter-membrane space NADH + H + NAD + 4H + Q QH 2 succinatefumarate Q QH 2 2H + 2Cyt c 2H + 4H + 2H + ½O 2 H2OH2O COMPLEX ICOMPLEX IICOMPLEX IIICOMPLEX IV Inner Glycolysis

5. © TPWG May 2004 ABC Advanced Bleeding Care 5 Matrix 3H + ADP + Pi ATP Inter-membrane space Inner membrane H+H+ H+H+ H+H+ H+H+ H+H+ ATP SYNTHASE ATP Synthesis

6. © TPWG May 2004 ABC Advanced Bleeding Care 6 To Maintain Energy Charge ATP synthesis sufficient to compensate for -Mechanical work -Active transport (ions and molecules) -Synthesis of biomolecules Mitochondria must be structurally and functionally intact

7. © TPWG May 2004 ABC Advanced Bleeding Care 7 Fresh water turtleHibernating frog Oxyconformers

8. © TPWG May 2004 ABC Advanced Bleeding Care 8 Metabolic shut-down Protein synthesis, half-life Channel arrest ( ion-motive ATPases) Decreased electron transport and proton leaks 90 – 95% decrease in demand Oxyconformers

9. © TPWG May 2004 ABC Advanced Bleeding Care 9 CatMan Oxyregulators

10. © TPWG May 2004 ABC Advanced Bleeding Care 10 Flow redistribution Partial oxygen conformance (shut-down) Metabolic rearrangement (Pasteur) Oxyregulators

11. © TPWG May 2004 ABC Advanced Bleeding Care 11 Metabolic shut down (Protein synthesis ) = VO 2 / O 2 dependency Secondary mitochondrial damage Necrosis Apoptosis Hours Oxyregulators

12. © TPWG May 2004 ABC Advanced Bleeding Care 12 Metabolic Rearrangement Wenger RH J Exp Biol 2000; 203 Pt 8: 1253

13. © TPWG May 2004 ABC Advanced Bleeding Care 13 HFI - 1 Glycolytic enzymes Krebs enzymes Gene Regulation Metabolic Rearrangement

14. © TPWG May 2004 ABC Advanced Bleeding Care 14 Mammalian cells respond to energy failure with -Increased glycolysis -Lactate and acidosis -Oxygen conformance -Decreased protein synthesis -Both are short-term mechanisms Secondary Mitochondrial Dysfunction ApoptosisNecrosis Mammalian Cell Response

15. © TPWG May 2004 ABC Advanced Bleeding Care 15 Markers for Energy Failure Oxygen debt concept Venous oxygen saturation Lactate and acidosis Venous / tissue pCO 2

16. © TPWG May 2004 ABC Advanced Bleeding Care 16 Estimated in ICU as decreased VO 2 Time VO 2 (L/min) Hypothetical baseline Oxygen Debt Measured as increased VO 2 after muscle exercise Time VO 2 (L/min)

17. © TPWG May 2004 ABC Advanced Bleeding Care 17 A debt of 25 mL O 2 / min to be paid by anaerobic ATP production would imply 0.017 mol ATP / min = 0.017 mol Lactate /min 12.240 mmol Lactate / 24 hours Oxygen conformance is mandatory !!! = Long-Lasting Oxygen Debt?

18. © TPWG May 2004 ABC Advanced Bleeding Care 18 Physiological Background Sat v O 2 = Sat a O 2 - VO 2 (mL/min) Q (L/min) 1 Hb (g/L) x 1.39 x Sat v O 2 = metabolism haemodynamic 1 carrier x Lung -

19. © TPWG May 2004 ABC Advanced Bleeding Care 19 Negative charges SID Approach Concentration (mEq/L) 0 20 40 60 80 100 120 140 160 HCO 3 - A-A- Positive charges HCO 3 - A-A- OH - SID BB DSID = Actual SID – Reference SID BE = Actual BB – Reference BB DSID = BE Negative charges OH -

20. © TPWG May 2004 ABC Advanced Bleeding Care 20 Alkalosis Acidosis Mortality and Acidosis at Entry 721 Critically Ill Patients < 20 0 20 - 25 25 - 3030 - 35 35 - 4040 - 45 45 - 5050 - 5555 - 60 > 60 20 40 60 80 100 H + [nanomoles/litre] Mortality distribution (%)

21. © TPWG May 2004 ABC Advanced Bleeding Care 21 Importance of Mixed Venous pCO 2 CO 2 content vs. CO 2 tension CvCO 2 = CaCO 2 + VCO 2 /Q CvO 2 = CaO 2 - VO 2 /Q

22. © TPWG May 2004 ABC Advanced Bleeding Care 22 20406080100120 20 40 60 80 CO 2 content (mL%) pCO 2 (mm Hg) CO 2 Dissociation Curve (Whole Blood) BE 0 BE -5 BE -10 BE -15 BE -20 Each curve is described at constant Base Excess. As shown, for the same CO 2 content, changing the Base Excess causes a great change of pCO 2 (see the broken line parallel to axes)

23. © TPWG May 2004 ABC Advanced Bleeding Care 23 lemon drops + CocaCola pCO 2 + HCO 3 - The Coca Cola Effect CocaCola pCO 2 HCO 3 -

24. © TPWG May 2004 ABC Advanced Bleeding Care 24 Low Sat v O 2 may or may not indicate energy failure All indicate energy failure Low pH High lactate Negative BE Decreased SID High PvCO 2 Indeed…

25. © TPWG May 2004 ABC Advanced Bleeding Care 25 Energy failure BE - Lactate Pump failure or mitochondrial dysfunction Haemodynamic failure Pump failure Volume test VO 2 Lactate Mitochondrial dysfunction VO 2 Lactate Dobutamine test VO 2 Lactate VO 2 Lactate Haemodynamic and Mitochondrial Failure

26. © TPWG May 2004 ABC Advanced Bleeding Care 26 Absence of energy failure Reserve at limit Good reserve Dobutamine test (stress test) VO 2 Lactate = VO 2 Lactate =

27. © TPWG May 2004 ABC Advanced Bleeding Care 27 Probability of survival Days after randomization 04590135180 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Patients at risk (N° of events) 257 (133)106 (16)89 (4)85 (1)84 Oxygen-saturation group (164 events) 252 (129)108 (13)94 (4)90 (3)87 Control group (157 events) 253 (133)102 (8)90 (4)86 (3)83 Cardiac index group (156 events) Gattinoni L et al. N Engl J Med 1995; 333: 1025 Survival Curves

28. © TPWG May 2004 ABC Advanced Bleeding Care 28 S v O 2 70% Baseline S v O 2 Control 49.2 Treated 48.6 Mortality Early Goal Directed Therapy Control therapy n = 133 Treatment n = 130 P In hospital46.5%30.5%0.009 28 days49.2%33.3%0.01 60 days56.9%44.3%0.03 Rivers E et al. N Engl J Med 2001; 345: 1368

29. © TPWG May 2004 ABC Advanced Bleeding Care 29 Pre-operativeERICU Day 2 Day 7 Shoemaker Chest 1988 DO 2 target C 38% T* 21% C 70.7 48.4% CI 72.1 48.6% SVO 2 71.7 52.1% Gattinoni NEJM 1995 C 67.3 CI 68.2 SVO 2 69.7 Rivers NEJM 2001 SVO 2 49.2% 48.6% SVO 2 65.3% 70.3% C T* 46.5 30.5 Shoemaker WC et al. Chest 1988; 94: 1176; Gattinoni L et al. N Engl J Med 1995; 333: 1025; Rivers E et al. N Engl J Med 2001; 345: 1368 Haemodynamic Treatment in Critically Ill Patients Time frame

30. © TPWG May 2004 ABC Advanced Bleeding Care 30 0-20 20-4040-6060-80 80-100 Mortality (%) 0 20 40 60 80 100 846088127 376 Patients Percentage of Time Within 70% Sat v O 2 Target Gattinoni L et al. N Engl J Med 1995; 333: 1025

31. © TPWG May 2004 ABC Advanced Bleeding Care 31 Conclusion Energy failure may be due to primitive haemodynamic inadequacy and/or mitochondrial dysfunction Volume and dobutamine test may help in diagnosis Prolonged energy failure leads to irreversible mitochondrial dysfunction (necrosis - apoptosis) Early intervention may prevent irreversible secondary damage