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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
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ATP synthesis
Relative speed
ATP consumption
0
0.25
0.5
0.75
1
Energy charge
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Glucose
Krebs cycle
30 ATP
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During glycolysis
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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
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Matrix
ATP SYNTHASE
ATP
ADP Pi
3H
Inner membrane
H
H
H
H
H
3H
Inter-membrane space
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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
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Oxyconformers
Fresh water turtle
Hybernating frog
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Oxyconformers
Metabolic shut down
Protein synthesis ?, half life ?
Channel arrest (? ion motive ATPases)
Decrease electron transport and proton leaks
90 95 decrease of demand
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Oxyregulators
Cat
Man
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Oxyregulators
Flow redistribution
Partial oxygen conformance (shut down)
Metabolic rearrangement (Pasteur)
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Oxyregulators
Metabolic shut down (Protein synthesis
?) VO2/O2 dependency
Hours
Secondary mitochondrial damage
Apoptosis
Necrosis
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Bickler PE and Donohoe PH, J Exp Biol 205,
3579-3586 (2002)
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Metabolic re-arrangement
HFI - 1
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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
Apoptosis
Necrosis
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Markers of energy failure
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Oxygen debt
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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 !!!
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Physiological background
VO2 (mL/min)
1
SatvO2 SataO2 -

Q (L/min)
Hb (gr/L) 1.39
metabolism
1
-
SatvO2
Lung

hemodynamic
carrier
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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
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Mortality at entry
721 critically ill
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The importance of mixed venous PCO2
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CO2 content vs CO2 tension
CvCO2 CaCO2 VCO2/Q
CvO2 CaO2 - VO2/Q
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80
60
40
CO2 content (mL)
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20
40
60
80
100
120
PCO2 (mmHg)
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Coca Cola effect
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Indeed
Low SatvO2 ? may indicate or may not energy
failure
All indicate energy failure
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Hemodynamic and mitochondrial failure
Hemodynamic failure
Pump failure
Pump failure or mitochondrial dysfunction
Mitochondrial dysfunction
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Absence of energy failure
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Probability of survival
Days after randomization
Patients at risk (N of events)
Gattinoni L et al. N Engl J Med 3331025-32, 1995
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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 3451368-77
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Preoperative
ER
ICU
Day 2
Day 7
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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
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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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