Didier Payen, MD, Ph D DAR Lariboisière Université Paris 7 Unité INSERM 1160

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1 Assessing response to therapy: SvO 2, lactate, PCO 2 gap, others Didier Payen, MD, Ph D DAR Lariboisière Université Paris 7 Unité INSERM 1160 dpayen1234@orange.fr

2 How can we see the question? Some useful concept have to mentioned What means therapeutic response? SvO 2 :regional? Sup VCaval? Mixed SvO 2 Lactate: a marker or a mechanistic index or both? CO2 level within tissue

3 ALL IS LINKED!!! Glucose, lactate, inflammation, cellular metabolism, O 2 use and CO 2 production

4 Metabolic assessment can be seen as a part of inflammation

5 NADPH

6 glucose GLYCOLYSIS lactate LDH PDH pyruvate CYTOSOL pyruvate dehydrogenase MITOCHONDRION fatty acid oxidation acetyl CoA ATP synthase O 2 e - H + cytochrome oxidase IV ATP ADP H + RESPIRATORY CHAIN e - III H + II e - I e - NADH dehydrogenase NAD + NADH NAD + CITRIC ACID CYCLE

7 Energy consuming functions of immune cells Synthesis of macromolecule & ion transport; O 2 is mainly used by mitochondria, non-mitochondrial O 2 consumption is negligible 98% of VO 2 is related to Phos OX. In acute situation 20 to 40% is non mitochondrial ROS+++

8 Mitochondrial VO 2 becomes more decoupled after incubation in septic plasma.

9 Energy metabolism: interorgan cooperation Erythrocytes Glucose Recycling Glucose CO H 2 O 2 CO CO CO H 2 O Liver Glucose 6-P 1 Pyruvate ADP 2ATP 4 Lactate Glucose Pyruvate 4 The liver respires for anaerobic erythrocytes (Leverve 1998) 1 6ADP 6ATP O O 2 2 O 2 O 2 O 2 O 2 oxidation of fatty acids

10 Otto Warburg effect In oncology, the Warburg concept or effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in normal cells. The latter process is aerobic. Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin, even if oxygen is plentiful.

11 Neutro Macro Dend C Effector T Cell Memory T C Treg Cell Macro M2

12 The effect of systemic vascular tone changes on microcirculation. Arteriolar constriction and dilatation.

13 How can we see the question? Some useful concept have to mentioned What means therapeutic response? SvO 2 :regional? Sup VCaval? Mixed SvO 2 Lactate: a marker or a mechanistic index or both? CO2 level within tissue

14 What is tissue perfusion? How to asses it? - microvessels abnormalities : Microflow Index, MVDensity using (SDF/OPS imaging) - microcirculatory blood flow (Laser Doppler) - tissue micro-perfusion (PCO 2 gap) - micro-oxygenation? (StO 2 ) - all of them multimodal monitoring?

15 What is the problem? Is the systemic hemodynamic resuscitation able to change microcirculation? Is the regional blood flow related to microcirculatory flow? Is the tissue oxygenation well assessed by perfusion? What about the ICU clinical situations? SEPSIS THE EXAMPLE;

16 Macro-circulation responder vs non responders MacroR Increase in CO > 15% after fluid MacroNR Increase in CO < 15% after fluid

17 % variation 80 CO Variation RS Variation Macro-NR n=28 Macro-R n=21 Micro-R n=24 Micro-NR n=25

18 Coherence after fluid or «coherent» patients n=28 (57%) or «non coherent» patients n=21 (43%)

19 What is the problem? Is the systemic hemodynamic resuscitation able to change microcirculation? Is the regional blood flow related to microcirculatory flow? Is the tissue oxygenation well assessed by perfusion? What about the ICU clinical situations? SEPSIS THE EXAMPLE;

21 How to improve perfusion? by downstream dilatation (shear stress ) by upstream increase inflow pressure

22 How can we see the question? Some useful concept have to mentioned What means therapeutic response? SvO 2 :regional? Sup VCaval? Mixed SvO 2 Lactate: a marker or a mechanistic index or both? CO2 level within tissue

23 Rationale for monitoring SvjO 2 Cerebral tissue is highly susceptible to oxygen deficit Oxygen delivery is dependent on CBF+++ CBF and CMRO 2 are coupled: CBF has to match the demand. In brain injury, blood flow regulation could be lost SvjO 2 informs on: the ability of the brain to extract oxygen. the O 2 extraction adequacy CBF-CMRO 2 and may guide therapy. As long as Hb and SaO 2 remain constant SvjO 2 is THE KEY between CMRO 2 and CBF.

25 SEVERE HEAD TRAUMA Evolution of SvjO 2, ICP, MAP, MCA blood flow velocity after a fast i.v. bolus of Mannitol before ICP=33 mmhg MAP=89 mmhg CPP=56 mmhg SvjO2<60%

26 SEVERE HEAD TRAUMA Evolution of SvjO 2, ICP, MAP, MCA blood flow velocity after a fast i.v. bolus of Mannitol before ICP=33 mmhg MAP=89 mmhg CPP=56 mmhg SvjO2<60% Mannitol after ICP=20 mmhg MAP=89 mmhg CPP=69 mmhg SvJO2>60%

27 How can we see the question? Some useful concept have to mentioned What means therapeutic response? SvO 2 :regional? Sup VCaval? Mixed SvO 2 Lactate: a marker or a mechanistic index or both? CO2 level within tissue

28 Normal lactate turnover: 1300 mmol/day mostly RBC (1/3) Major sources: muscle, RBCs-WBCs, gut, (lung, eye, tumor cells), epinephrine, dysfunction of PDH: normal L/P hypoxia: increased L/P Clearance: liver (kidney, lung, heart, gut) 2/3 oxidized in citric acid cycle 1/3 gluconeogenesis (Cori cycle)

29 LACTATE & CATECHOLAMINES THE LANCET Vol 354 August 7, 1999 adrenaline AMPc + "glycolytic" Compartment glycogene glycogenolysis "oxydative" Compartment 2K 3Na Na/K pump + ADP ATP glucose 6-P glycolysis O 2 lactate lactate pyruvate mitochondria (James JH et al, Lancet 1999)

30 Sepsis: lactate clearance vs production 20 Lactate fluxes (mmol/h) LPS Control Release 10 0 Uptake -10 Lung Kidney Gut Liver Muscle (adapted from Bellomo, Chest 1996)

31 How can we see the question? Some useful concept have to mentioned What means therapeutic response? SvO 2 :regional? Sup VCaval? Mixed SvO 2 Lactate: a marker or a mechanistic index or both? CO2 level within tissue

83 CO 2 60 SO2 -.86 CO 2 55 CO 2 70 mmhg SO2 -.

32 Microvascular Blood Flow shunting & stagnant CO 2 in Severe Sepsis and/or high PvO 2 Arterial blood SO CO 2 40 SO CO 2 70 mmhg SO SO SO CO 2 60 SO CO 2 55 CO 2 70 mmhg SO Venous blood Increased SvO 2 from shunting area will enrich central SvO 2 Stagnant tissue kco 2 k CO 2 gradient with ETCO 2

34 From Vallée et al; Réanimation Schematic view for tissue PCO 2 Tonometry Normal conditions Shock with low systemic flow Resuscitated shock with Microcirculation failure

36 Gradient threshold: 16 mm d'hg for outcome; Spe 100%; Se 88% (AUC ROC: 0.97). Diagnostic tool 1- Patients in SShock at admission (n=30) : gradient P(tc-et) CO 2 patients vs controls (n=15) : 31±12 versus 11±4 mm Hg, p<

37 Pronostic value 2- Survivals increased P(tc-etCO 2 ) within the 1st 36 hrs after admission compared to NS: H0: 31±13 versus 29±12 mm Hg, NS; H36: 21±5 (S) vs 40±17 (NS), p<0.0001

38 Therapeutic test 3- D P(tc-et)CO 2 after fluid challenge (correlated negatively with cutaneous BF (Laser BF): R²= 0.68, p< 0.001): the more the Laser BF k the lower will be the P(tc-et)CO 2 gradient.

39 The Warming test Abnormal gradient questions: 1- is it related to macrocirculation abnormality? 2- is it related to microvessel disease?

40 Hypotheses Elevated tissue PCO 2 stagnant flow Vascular reactivity can be assessed by the heatinginduced vasodilatation Possible patterns Low flow but normal reactivity kpcco 2 & nl PIndex Low flow with abnormal microvessels kpcco 2 & abnl PIndex microvessel disease

41 Heat Challenge Δ HC PcCO 2 = PcCO 2 end - PcCO 2 start Δ HC PI max/min = PI max / PI min

42 To conclude No tool can be recommended for all situations A sufficient understanding of basic concepts and of pathologic situation is essential Metabolism is a witness more than a cause of organ dysfunction Metabolism is linked to all functions Lactate is a marker of «stress intensity» more than ischemic marker SvO 2 is interesting if it is lower than normal value; CO 2 gap is a marker of tissue perfusion; coupling with a vascular reactivity test it may help to make a decision and to assess the therapy.

43 Un example of acute inflammation in human beings: Liver transplantation

44 Day 4 after OLT

Mitochondria and ATP Synthesis

Mitochondria and ATP Synthesis Mitochondria and ATP Synthesis 1. Mitochondria are sites of ATP synthesis in cells. 2. ATP is used to do work; i.e. ATP is an energy source. 3. ATP hydrolysis releases energy