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Goals of Resuscitation:Early Versus Late Targets
Luciano Gattinoni
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Energy Charge
Energy charge
Rel
ativ
e sp
eed
0 0.25 0.5 0.75 1
ATP synthesis
ATP consumption
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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
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Matrix
Inter-membrane space
NADH + H+ NAD+
4H+
Q
QH2
succinate fumarate
Q
QH2
2H+2Cyt c
2H+
4H+
4H+
2H+
½O2 H2O
COMPLEX I COMPLEX II COMPLEX III COMPLEX IV
Inn
er
Glycolysis
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Matrix
3H+
3H+
ADP + Pi
ATP
Inter-membrane space
Inn
er
mem
bra
ne
H+ H+H+ H+
H+
ATP SYNTHASE
ATP Synthesis
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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
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Fresh water turtle Hibernating frog
Oxyconformers
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Metabolic shut-down
Protein synthesis , half-life
Channel arrest ( ion-motive ATPases)
Decreased electron transport and proton leaks
90 – 95% decrease in demand
Oxyconformers
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Cat Man
Oxyregulators
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Flow redistribution
Partial oxygen conformance (shut-down)
Metabolic rearrangement (Pasteur)
Oxyregulators
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Metabolic shut down(Protein synthesis )
=VO2 / O2 dependency
Secondary mitochondrial damage
Necrosis Apoptosis
Hours
Oxyregulators
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Metabolic Rearrangement
Wenger RH J Exp Biol 2000; 203 Pt 8: 1253
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HFI - 1
Glycolyticenzymes
Krebsenzymes
Gene Regulation
Metabolic Rearrangement
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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
ApoptosisNecrosis
Mammalian Cell Response
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Markers for Energy Failure
Oxygen debt concept
Venous oxygen saturation
Lactate and acidosis
Venous / tissue pCO2
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Estimated in ICU as decreased VO2
Time
VO
2 (L
/min
)
Hypothetical baseline
Oxygen Debt
Measured as increased VO2
after muscle exercise
Time
VO
2 (L
/min
)
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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 !!!
=
Long-Lasting Oxygen Debt?
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Physiological Background
SatvO2 = SataO2 -VO2 (mL/min)
Q (L/min)
1
Hb (g/L) x 1.39x
SatvO2 = metabolism
haemodynamic
1
carrierxLung -
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19N
egat
ive
char
ges
SID Approach
Co
nc
entr
ati
on
(m
Eq
/L)
0
20
40
60
80
100
120
140
160
HCO3-
A-
Po
siti
ve c
har
ges
HCO3-
A-
OH-
SID
SID
BB
BB
DSID = Actual SID – Reference SIDBE = Actual BB – Reference BB
DSID = BE
Neg
ativ
e ch
arg
es
OH-
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Alkalosis Acidosis
Mortality and Acidosis at Entry
721 Critically Ill Patients
< 200 20 - 25
25 - 30
30 - 35
35 - 40
40 - 45
45 - 50
50 - 55
55 - 60
> 60
20
40
60
80
100
H+ [nanomoles/litre]
Mo
rta
lity
dis
trib
utio
n (
%)
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Importance of Mixed Venous pCO2
CO2 content vs. CO2 tension
CvCO2 = CaCO2 + VCO2/Q
CvO2 = CaO2 - VO2/Q
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20 40 60 80 100 120
20
40
60
80
CO
2 c
on
ten
t (
mL
%)
pCO2 (mm Hg)
CO2 Dissociation Curve(Whole Blood)
BE 0BE -5BE -10BE -15BE -20
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)
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lemondrops+
Coc
aCol
a
pCO2+
HCO3-
The Coca Cola Effect
Coc
aCol
a
pCO2
HCO3-
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Low SatvO2 may or may not indicate energy failure
All indicate energy failure
• Low pH
• High lactate• Negative BE• Decreased SID• High PvCO2
Indeed…
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Energy failure
BE - Lactate
Pump failure or mitochondrial dysfunction
Haemodynamic failure
Pump failure
Volume test
VO2 Lactate
Mitochondrial dysfunction
VO2 Lactate
Dobutaminetest
VO2 Lactate
VO2 Lactate
Haemodynamic and Mitochondrial Failure
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Absence of energy failure
Reserve at limit
Goodreserve
Dobutamine test(stress test)
VO2
Lactate=
VO2
Lactate=
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Pro
bab
ilit
y o
f su
rviv
al
Days after randomization0 45 90 135 180
0.00.10.20.30.40.50.60.70.80.91.0
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 1995; 333: 1025
Survival Curves
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SvO2 70%
Baseline SvO2 Control 49.2
Treated 48.6
Mortality
Early Goal Directed Therapy
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 E et al. N Engl J Med 2001; 345: 1368
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Pre-operative ER ICUDay 2 Day 7
ShoemakerChest 1988
DO2 target
C38%
T*21%
C70.7
48.4%
CI72.1
48.6%
SVO2
71.752.1%
GattinoniNEJM 1995
C67.3
CI68.2
SVO2
69.7
RiversNEJM 2001 SVO2
49.2% 48.6%SVO2
65.3% 70.3%C T*
46.5 30.5
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
Haemodynamic Treatment in Critically Ill Patients
Time frame
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0-2020-40
40-6060-80
80-100
Mo
rtal
ity
(%)
0
20
40
60
80
100
84 60 88 127 376Patients
Percentage of Time Within 70% SatvO2 Target
Gattinoni L et al. N Engl J Med 1995; 333: 1025
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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