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Goals of Resuscitation: Early Versus Late Targets

Goals of Resuscitation: Early Versus Late Targets. Luciano Gattinoni. Energy Charge. ATP synthesis. Relative speed. ATP consumption. 0. 0.25. 0.5. 0.75. 1. Energy charge. During Glycolysis. For 1 mole of glucose, only 2 moles of ATP produced (efficiency = 5%).

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Goals of Resuscitation: Early Versus Late Targets

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  1. Goals of Resuscitation:Early Versus Late Targets Luciano Gattinoni

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

  3. During Glycolysis • For 1 mole of glucose, only 2 moles of ATP produced (efficiency = 5%) • No O2 is consumed and no CO2 is produced • No H+ is released into the medium • Lactate formation is essential for NADH re-oxidation

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

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

  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. Oxyconformers Fresh water turtle Hibernating frog

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

  9. Oxyregulators Cat Man

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

  11. Oxyregulators Metabolic shut down (Protein synthesis ) = VO2 / O2 dependency Hours Secondary mitochondrial damage Apoptosis Necrosis

  12. Metabolic Rearrangement Wenger RH J Exp Biol 2000; 203 Pt 8: 1253

  13. Gene Regulation Krebs enzymes Glycolytic enzymes Metabolic Rearrangement HFI - 1

  14. Mammalian Cell Response • 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 Necrosis Apoptosis

  15. Markers for Energy Failure • Oxygen debt concept • Venous oxygen saturation • Lactate and acidosis • Venous / tissue pCO2

  16. Measured as increased VO2 after muscle exercise VO2 (L/min) Time VO2 (L/min) Estimated in ICU as decreased VO2 Hypothetical baseline Time Oxygen Debt

  17. Long-Lasting Oxygen Debt? A debt of 25 mL O2 / 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 !!!

  18. VO2(mL/min) 1 SatvO2 = SataO2 - x Q (L/min) Hb (g/L) x 1.39 metabolism 1 - SatvO2 = Lung x haemodynamic carrier Physiological Background

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

  20. 100 Alkalosis Acidosis 80 60 Mortality distribution (%) 40 20 0 < 20 > 60 20 - 25 35 - 40 40 - 45 25 - 30 30 - 35 45 - 50 50 - 55 55 - 60 H+ [nanomoles/litre] Mortality and Acidosis at Entry 721 Critically Ill Patients

  21. Importance of Mixed Venous pCO2 CO2 content vs. CO2 tension CvCO2 = CaCO2 + VCO2/Q CvO2 = CaO2 - VO2/Q

  22. BE 0 BE -5 80 BE -10 BE -15 BE -20 60 CO2 content (mL%) 40 20 20 40 60 80 100 120 pCO2 (mm Hg) CO2 Dissociation Curve(Whole Blood) Each curve is described at constant Base Excess. As shown, for the same CO2 content, changing the Base Excess causes a great change of pCO2 (see the broken line parallel to axes)

  23. lemon drops CocaCola + CocaCola pCO2 + HCO3- pCO2 HCO3- The Coca Cola Effect

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

  25. VO2 Lactate  VO2 Lactate  Volume test VO2 Lactate  Dobutamine test VO2 Lactate  Haemodynamic and Mitochondrial Failure Haemodynamic failure Pump failure Energy failure BE - Lactate Pump failure or mitochondrial dysfunction Mitochondrial dysfunction

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

  27. 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 Survival Curves Probability of survival Days after randomization Patients at risk (N° of events) Gattinoni L et al.N Engl J Med 1995; 333: 1025

  28. SvO2 70% Early Goal Directed Therapy Control 49.2 Baseline SvO2 Treated 48.6 Mortality Rivers E et al.N Engl J Med 2001; 345: 1368

  29. Shoemaker Chest 1988 DO2 target C 38% T* 21% C 67.3 CI 68.2 SVO2 69.7 Gattinoni NEJM 1995 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% C T* 46.5 30.5 Rivers NEJM 2001 Haemodynamic Treatment in Critically Ill Patients Pre-operative ER ICU Day 7 Day 2 Time frame 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

  30. Percentage of Time Within 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 Gattinoni L et al.N Engl J Med 1995; 333: 1025

  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

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