1. Can “goal directed therapy” reduce mortality on the ICU Luciano Gattinoni, MD, FRCP Università di Milano Fondazione IRCCS- “Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena” Milan, Italy 2006, Paris

2. Energy charge Relative speed 00.250.50.751 ATP synthesis ATP consumption

3. Glucose + 2 ATP Krebs cycle 30 ATP Lactate - piruvate Glycolisis

4. During glycolysis For 1mole of glucose only 2moles of ATP produced (efficiency 5%) No O 2 is consumed and no CO 2 is produced No H + are released in the medium Lactate formation is essential for NADH reoxydation

5. Matrix Inter-membrane space NADH + H + NAD + Q QH 2 succinate fumarate Q QH 2 2H + 2Cyt c 2H + 4H + 2H + ½O 2 H2OH2O COMPLEX ICOMPLEX IICOMPLEX IIICOMPLEX IV Inner

6. 3H + ADP + Pi ATP Matrix Inter-membrane space Inner membrane H+H+ H+H+ H+H+ H+H+ H+H+ ATP SYNTHASE

7. To maintain energy charge 1) Supply for ATP synthesis sufficient to compensate for: - mechanical work - active transport (ions and molecules) - synthesis of biomolecules 2) Mitochondria must be structurally and functionally intact

8. Oxyconformers Fresh water turtleHybernating frog

9. Oxyconformers Metabolic shut down Protein synthesis , half life  Channel arrest (  ion motive ATPases) Decrease electron transport and proton leaks 90 – 95% decrease of demand

10. Oxyregulators Cat Man

11. Oxyregulators Flow redistribution Partial oxygen conformance (shut down) Metabolic rearrangement (Pasteur)

12. Oxyregulators Metabolic shut down (Protein synthesis  ) = VO 2 /O 2 dependency Secondary mitochondrial damage Necrosis Apoptosis Hours

13. Bickler PE and Donohoe PH, J Exp Biol 205, 3579-3586 (2002)

14. Metabolic re-arrangement HFI - 1 Glycolitic enzymes Krebs enzymes Gene regulation

15. Indeed, the mammalian cells respond to energy failure by Increased glycolysis (Lactate and acidosis) Oxygen conformance ( Protein synthesis) both are short term lasting mechanisms Secondary mitochondrial dysfunction ApoptosisNecrosis

16. Markers of energy failure Venous/tissue PCO 2 Lactate and acidosis Venous oxygen saturation Oxygen debt concept

17. Oxygen debt Time VO 2 (L/min) After muscle exercise measured as increased VO 2 Time VO 2 (L/min) In ICU estimated as decreased VO 2 Hypothetical beseline

18. A debt of 25 mL O 2 /min to be payed by anaerobic ATP production Would imply 0.017 mol ATP/min = 0.017 mol Lactate /min 12.240 mmol Lactate/24 hours Long lasting Oxygen debt ??? Oxygen conformance is mandatory !!! =

19. Physiological background Sat v O 2 = Sat a O 2 - VO 2 (mL/min) Q (L/min) 1 Hb (gr/L) * 1.39 * Sat v O 2 = metabolism hemodynamic 1 carrier * Lung -

20. Concentrations (mEq/L) 0 20 40 60 80 100 120 140 160 Negative charges HCO 3 - A-A- OH - Positive charges Negative charges HCO 3 - A-A- OH - SID BB  SID = Actual SID – Reference SID BE = Actual BB – Reference BB  SID = BE SID approach

21. Mortality at entry 721 critically ill < 20 20 - 2525 - 3030 - 3535 - 4040 - 4545 - 5050 - 5555 - 60 > 60 0 20 40 60 80 100 % H+ [nanomoles/liter] Alkalosis Acidosis

22. The importance of mixed venous PCO 2

23. CO 2 content vs CO 2 tension CvCO 2 = CaCO 2 + VCO 2 /Q CvO 2 = CaO 2 - VO 2 /Q

24. 20406080100120 20 40 60 80 BE 0 BE -5 BE -10 BE -15 BE -20 CO 2 content (mL%) PCO 2 (mmHg)

25. Coca Cola effect lemon drops + CocaCola PCO 2 + HCO - 3 CocaCola PCO 2 HCO - 3

26. Indeed… Low Sat v O 2  may indicate or may not energy failure All indicate energy failure Low pH High lactate Negative BE Decreased SID High PvCO 2

27. Energy failure BE - Lactate Pump failure or mitochondrial dysfunction Hemodynamic failure Pump failure Volume test VO 2  Lactate  Mitochondrial dysfunction VO 2  Lactate  Dobutamine test VO 2  Lactate  VO 2  Lactate  Hemodynamic and mitochondrial failure

28. Absence of energy failure Reserve at limit Good reserve Dobutamine test (stress test) VO 2 Lactate = VO 2 Lactate =

29. 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 333;1025-32, 1995

30. Early goal direct therapy S v O 2 70% Baseline S v O 2 Control 49.2 Treated 48.6 In hospital 28 days 60 days Control therapy n° 133 Treatment n° 130 P Mortality 46.5%30.5% 49.2% 56.9% 33.3% 44.3% 0.009 0.01 0.03 Rivers et al. N Engl J Med 2001; 345:1368-77

31. PreoperativeERICU Day 2 Day 7 Shoemaker Chest 1994 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

32. 0-20 20-4040-6060-80 80-100 Mortality (%) 0 20 40 60 80 100 846088127 376 Patients % of time within the 70% Sat v O 2 target

33. Conclusion Energy failure may be due to primitive hemodynamic inadequacy and/or mitochondrial dysfunction Volume and dobutamine test may help in the diagnosis Prolonged energy failure leads to irreversible mitochondrial dysfunction (necrosis - apoptosis) Early intervention may prevent irreversible secondary damages