can “goal directed therapy” reduce mortality on the icu luciano gattinoni, md, frcp università...
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Can “goal directed therapy” reduce mortality on the ICU
Luciano Gattinoni, MD, FRCPUniversità di Milano Fondazione IRCCS- “Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena”Milan, Italy
2006, Paris
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Energy charge
Rel
ativ
e sp
eed
0 0.25 0.5 0.75 1
ATP synthesis
ATP consumption
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GlucoseGlucose
+ 2 ATP
Krebs cycle
30 ATP
Lactate - piruvateLactate - piruvate
Gly
colis
is
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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
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Matrix
Inter-membrane space
NADH + H+ NAD+
Q
QH2
succinate fumarate
Q
QH2
2H+2Cyt c
2H+
4H+
4H+
4H+
2H+
½O2 H2O
COMPLEX I COMPLEX II COMPLEX III COMPLEX IV
Inn
er
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3H+
3H+
ADP + Pi
ATP
Matrix
Inter-membrane space
Inn
erm
embr
ane
H+ H+H+
H+
H+
ATP SYNTHASE
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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
CatMan
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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
Secondary mitochondrial damage
Necrosis Apoptosis
Hours
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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
Glycoliticenzymes
Krebsenzymes
Gene regulation
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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
ApoptosisNecrosis
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Markers of energy failure
Venous/tissue PCO2
Lactate and acidosis
Venous oxygen saturation
Oxygen debt concept
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Oxygen debt
Time
VO
2 (L
/min
)
After muscle exercise measured as increased VO2
Time
VO
2 (L
/min
)
In ICU estimated as decreased VO2
Hypothetical beseline
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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
Long lasting Oxygen debt ???
Oxygen conformance is mandatory !!!
=
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Physiological background
SatvO2= SataO2 -VO2 (mL/min)
Q (L/min)
1
Hb (gr/L) * 1.39*
SatvO2 = metabolism
hemodynamic
1
carrier*Lung -
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Con
cen
trat
ion
s (m
Eq
/L)
0
20
40
60
80
100
120
140
160
Negative
charges
HCO3-
A-
OH-
Positive
charges Negative
charges
HCO3-
A-
OH-
SID
SID
BB
BB
SID = Actual SID – Reference SID
BE = Actual BB – Reference BB
SID = BE
SID approach
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Mortality at entry721 critically ill
< 2020 - 25
25 - 30
30 - 35
35 - 40
40 - 45
45 - 50
50 - 55
55 - 60
> 600
20
40
60
80
100%
H+ [nanomoles/liter]
Alkalosis Acidosis
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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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20 40 60 80 100 120
20
40
60
80BE 0BE -5BE -10BE -15BE -20
CO
2 con
ten
t (
mL
%)
PCO2 (mmHg)
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Coca Cola effect
lemondrops+
Coc
aCol
a
PCO2+
HCO-3
Coc
aCol
a
PCO2
HCO-3
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Indeed…
Low SatvO2 may indicate or may not energy failure
All indicate energy failure
• Low pH
• High lactate• Negative BE• Decreased SID• High PvCO2
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Energy failure
BE - Lactate
Pump failure or
mitochondrial dysfunction
Hemodynamic failure
Pump failure
Volume test
VO2 Lactate
Mitochondrial dysfunction
VO2 Lactate
Dobutamine test
VO2 Lactate
VO2 Lactate
Hemodynamic and mitochondrial failure
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Absence of energy failure
Reserve at limit
Good reserve
Dobutamine test (stress test)
VO2
Lactate=
VO2
Lactate=
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Pro
bab
ilit
y of
surv
ival
Days after randomization0 45 90 135 180
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
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 333;1025-32, 1995
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Early goal direct therapy SvO2 70%
Baseline SvO2 Control 49.2Treated 48.6
In hospital
28 days
60 days
Control therapyn° 133
Treatmentn° 130
P
Mortality
46.5% 30.5%
49.2%
56.9%
33.3%
44.3%
0.009
0.01
0.03
Rivers et al. N Engl J Med 2001; 345:1368-77
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Preoperative ER ICUDay 2 Day 7
ShoemakerChest 1994
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
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0-2020-40
40-6060-80
80-100
Mor
tali
ty (
%)
0
20
40
60
80
100
84 60 88 127 376Patients
% of time within the 70% SatvO2 target
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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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