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Can “goal directed therapy” reduce mortality on the ICU

Can “goal directed therapy” reduce mortality on the ICU. 2006, Paris. Luciano Gattinoni, MD, FRCP Università di Milano Fondazione IRCCS- “ Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena” Milan, Italy. ATP synthesis. Relative speed. ATP consumption. 0. 0.25. 0.5. 0.75. 1.

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Can “goal directed therapy” reduce mortality on the ICU

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

  2. ATP synthesis Relative speed ATP consumption 0 0.25 0.5 0.75 1 Energy charge

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

  4. For 1mole of glucose only 2moles of ATP produced (efficiency 5%) No O2 is consumed and no CO2 is produced No H+ are released in the medium Lactate formation is essential for NADH reoxydation During glycolysis

  5. succinate NADH + H+ 2Cyt c Matrix COMPLEX I COMPLEX II COMPLEX III COMPLEX IV 2H+ 4H+ fumarate NAD+ ½O2 H2O 4H+ QH2 QH2 Inner Q Q 4H+ 2H+ 2H+ Inter-membrane space

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

  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 turtle Hybernating 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 ) = VO2/O2 dependency Hours Secondary mitochondrial damage Apoptosis Necrosis

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

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

  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 Necrosis Apoptosis

  16. Oxygen debt concept Venous oxygen saturation Lactate and acidosis Venous/tissue PCO2 Markers of energy failure

  17. After muscle exercise measured as increased VO2 VO2 (L/min) Time VO2 (L/min) Hypothetical beseline In ICU estimated as decreased VO2 Time Oxygen debt

  18. Long lasting Oxygen debt ??? A debt of 25 mL O2/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 Oxygen conformance is mandatory !!!

  19. Physiological background VO2(mL/min) 1 SatvO2= SataO2 - * Q (L/min) Hb (gr/L) * 1.39 metabolism 1 - SatvO2 = Lung * hemodynamic carrier

  20. OH- OH- A- A- SID BB SID BB HCO3- HCO3- Positive charges Negative charges Negative charges SID approach 160 140 120 100 Concentrations (mEq/L) 80 60 40 20 0 DSID = Actual SID – Reference SID BE = Actual BB – Reference BB DSID = BE

  21. % 100 Alkalosis Acidosis 80 60 40 20 0 < 20 > 60 20 - 25 25 - 30 30 - 35 35 - 40 40 - 45 45 - 50 50 - 55 55 - 60 H+ [nanomoles/liter] Mortality at entry 721 critically ill

  22. The importance of mixed venous PCO2

  23. CO2 content vs CO2 tension CvCO2 = CaCO2 + VCO2/Q CvO2 = CaO2 - VO2/Q

  24. BE 0 BE -5 BE -10 BE -15 BE -20 80 60 40 CO2 content (mL%) 20 20 40 60 80 100 120 PCO2 (mmHg)

  25. lemon drops + CocaCola CocaCola PCO2 HCO-3 PCO2 + HCO-3 Coca Cola effect

  26. Low pH • High lactate • Negative BE • Decreased SID • High PvCO2 Indeed… Low SatvO2  may indicate or may not energy failure All indicate energy failure

  27. VO2 Lactate  VO2 Lactate  Energy failure Volume test VO2 Lactate  Dobutamine test BE - Lactate VO2 Lactate  Hemodynamic and mitochondrial failure Hemodynamic failure Pump failure Pump failure or mitochondrial dysfunction Mitochondrial dysfunction

  28. Dobutamine test (stress test) VO2 Reserve at limit = Lactate VO2 = Good reserve Lactate Absence of energy failure

  29. 1.0 Cardiac index group (156 events) 0.9 Oxygen-saturation group (164 events) 0.8 Control group (157 events) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 45 90 135 180 252 (129) 108 (13) 94 (4) 90 (3) 87 253 (133) 102 (8) 90 (4) 86 (3) 83 257 (133) 106 (16) 89 (4) 85 (1) 84 Probability of survival Days after randomization Patients at risk (N° of events) Gattinoni L et al. N Engl J Med 333;1025-32, 1995

  30. Early goal direct therapy SvO2 70% Control 49.2 Baseline SvO2 Treated 48.6 Mortality Control therapy n° 133 Treatment n° 130 P In hospital 46.5% 30.5% 0.009 28 days 49.2% 33.3% 0.01 60 days 56.9% 44.3% 0.03 Rivers et al. N Engl J Med 2001; 345:1368-77

  31. Shoemaker Chest 1994 DO2 target C 38% T* 21% C 67.3 CI 68.2 SVO2 69.7 Gattinoni NEJM 1995 Rivers NEJM 2001 C 70.7 48.4% CI 72.1 48.6% SVO2 71.7 52.1% SVO2 49.2% 48.6% SVO2 65.3% 70.3% CT* 46.5 30.5 Preoperative ER ICU Day 7 Day 2

  32. % of time within the 70% SatvO2 target 100 80 60 Mortality (%) 40 20 0 0-20 20-40 40-60 60-80 80-100 Patients 376 84 60 88 127

  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

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