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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
Relative speed
ATP synthesis
ATP consumption
0
0.25
0.5
0.75
Energy charge
1
Glucose
+ 2 ATP
Lactate - piruvate
Krebs cycle
30 ATP
During glycolysis
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
Matrix
COMPLEX I
COMPLEX II
COMPLEX III
COMPLEX IV
2H+
NADH + H+
NAD+
succinate
4H+
fumarate
½O2
H2O
QH2
Q
4H+
Inter-membrane space
Inner
4H+
QH2
Q
2Cyt c
2H+
2H+
Matrix
ATP SYNTHASE
ATP
ADP + Pi
Inner
membrane
3H+
H+
H+
Inter-membrane space
H+
H+
3H+
H+
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 turtle
Hybernating 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 )
=
Hours
VO2/O2 dependency
Secondary mitochondrial
damage
Necrosis
Apoptosis
Bickler PE and Donohoe PH, J Exp Biol 205, 3579-3586 (2002)
Metabolic re-arrangement
HFI - 1
Gene regulation
Glycolitic
enzymes
Krebs
enzymes
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
Markers of energy failure
Oxygen debt concept
Venous oxygen saturation
Lactate and acidosis
Venous/tissue PCO2
VO2 (L/min)
Oxygen debt
After muscle exercise
measured as increased
VO2
VO2 (L/min)
Time
Hypothetical beseline
In ICU estimated as
decreased VO2
Time
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 !!!
Physiological background
SatvO2= SataO2 -
SatvO2 =
Lung
-
VO2 (mL/min)
Q (L/min)
metabolism
hemodynamic
*
*
1
Hb (gr/L) * 1.39
1
carrier
SID approach
Concentrations (mEq/L)
160
140
120
OH-
OHA-
A-
HCO3
HCO3-
100
80
60
40
20
0
DSID = Actual SID – Reference SID
BE = Actual BB – Reference BB
DSID = BE
Mortality at entry
721 critically ill
% 100
Alkalosis
Acidosis
80
60
40
20
0
H+ [nanomoles/liter]
The importance
of
mixed venous
PCO2
CO2 content vs CO2 tension
CvCO2 = CaCO2 + VCO2/Q
CvO2 = CaO2 - VO2/Q
CO2 content (mL%)
80
BE 0
BE -5
BE -10
BE -15
BE -20
60
40
20
20
40
60
80
PCO2 (mmHg)
100
120
PCO2
+
HCO-3
lemon
+ drops
CocaCola
CocaCola
Coca Cola effect
PCO2
HCO-3
Indeed…
Low SatvO2  may indicate or may not
energy failure
• Low pH
• High lactate
• Negative BE
• Decreased SID
• High PvCO2
All indicate energy
failure
Hemodynamic and mitochondrial failure
Hemodynamic
failure
VO2 
Lactate 
Energy
failure
BE - Lactate
Volume
test
VO2 
Lactate 
Pump failure
or
mitochondrial
dysfunction
Pump failure
VO2 
Lactate 
Dobutamine
test
VO2 
Lactate 
Mitochondrial
dysfunction
Dobutamine
test (stress test)
Absence of
energy
failure
VO2
Lactate
=
VO2
Lactate
= Good reserve
Reserve at
limit
1.0
Cardiac index group (156 events)
Probability of survival
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
Days after randomization
135
180
Patients at risk (N° of events)
253 (133)
102 (8)
90 (4)
86 (3)
83
257 (133)
106 (16)
89 (4)
85 (1)
84
252 (129)
108 (13)
94 (4)
90 (3)
87
Gattinoni L et al. N Engl J Med 333;1025-32, 1995
Early goal direct therapy
Baseline SvO2
SvO2 70%
Control 49.2
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
Preoperative
ER
ICU
Day 2
Shoemaker
Chest 1994
DO2
target
T*
21%
C
CI SVO2
67.3 68.2 69.7
Gattinoni
NEJM 1995
Rivers
NEJM 2001
C
38%
SVO2
49.2% 48.6%
SVO2
65.3% 70.3%
C
T*
46.5 30.5
Day 7
C
CI
70.7
72.1
48.4% 48.6%
SVO2
71.7
52.1%
% of time within the 70% SatvO2 target
Mortality (%)
100
80
60
40
20
0
Patients
84
60
88
127
376
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