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

Energy charge

Rel

ativ

e sp

eed

0 0.25 0.5 0.75 1

ATP synthesis

ATP consumption

GlucoseGlucose

+ 2 ATP

Krebs cycle

30 ATP

Lactate - piruvateLactate - piruvate

Gly

colis

is

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

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

3H+

3H+

ADP + Pi

ATP

Matrix

Inter-membrane space

Inn

erm

embr

ane

H+ H+H+

H+

H+

ATP SYNTHASE

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

CatMan

Oxyregulators

Flow redistribution

Partial oxygen conformance (shut down)

Metabolic rearrangement (Pasteur)

Oxyregulators

Metabolic shut down(Protein synthesis )

=VO2/O2 dependency

Secondary mitochondrial damage

Necrosis Apoptosis

Hours

Bickler PE and Donohoe PH, J Exp Biol 205, 3579-3586 (2002)

Metabolic re-arrangement

HFI - 1

Glycoliticenzymes

Krebsenzymes

Gene regulation

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

Markers of energy failure

Venous/tissue PCO2

Lactate and acidosis

Venous oxygen saturation

Oxygen debt concept

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

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 !!!

=

Physiological background

SatvO2= SataO2 -VO2 (mL/min)

Q (L/min)

1

Hb (gr/L) * 1.39*

SatvO2 = metabolism

hemodynamic

1

carrier*Lung -

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

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

The importance of

mixed venous PCO2

CO2 content vs CO2 tension

CvCO2 = CaCO2 + VCO2/Q

CvO2 = CaO2 - VO2/Q

20 40 60 80 100 120

20

40

60

80BE 0BE -5BE -10BE -15BE -20

CO

2 con

ten

t (

mL

%)

PCO2 (mmHg)

Coca Cola effect

lemondrops+

Coc

aCol

a

PCO2+

HCO-3

Coc

aCol

a

PCO2

HCO-3

Indeed…

Low SatvO2 may indicate or may not energy failure

All indicate energy failure

• Low pH

• High lactate• Negative BE• Decreased SID• High PvCO2

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

Absence of energy failure

Reserve at limit

Good reserve

Dobutamine test (stress test)

VO2

Lactate=

VO2

Lactate=

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

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

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

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

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