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

Energy charge Relative speed ATP synthesis ATP consumption

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

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

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

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

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

Oxyconformers Fresh water turtleHybernating frog

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

Oxyregulators Cat Man

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

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

Bickler PE and Donohoe PH, J Exp Biol 205, (2002)

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

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

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

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

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

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 -

Concentrations (mEq/L) 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

Mortality at entry 721 critically ill < > % H+ [nanomoles/liter] Alkalosis Acidosis

The 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

BE 0 BE -5 BE -10 BE -15 BE -20 CO 2 content (mL%) PCO 2 (mmHg)

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

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

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

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

Probability of survival Days after randomization 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; , 1995

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% Rivers et al. N Engl J Med 2001; 345:

PreoperativeERICU Day 2 Day 7 Shoemaker Chest 1994 DO 2 target C 38% T* 21% C % CI % SVO % Gattinoni NEJM 1995 C 67.3 CI 68.2 SVO Rivers NEJM 2001 SVO % 48.6% SVO % 70.3% C T*

Mortality (%) Patients % of time within the 70% Sat v O 2 target

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