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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. ATP synthesis. Relative speed. ATP consumption. 0. 0.25. 0.5. 0.75. 1.

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slide1

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

slide2

ATP synthesis

Relative speed

ATP consumption

0

0.25

0.5

0.75

1

Energy charge

slide3

+ 2 ATP

Glycolisis

Lactate - piruvate

Glucose

Krebs cycle

30 ATP

slide4

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

During glycolysis

slide5

succinate

NADH + H+

2Cyt c

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

slide6

Matrix

ATP SYNTHASE

ATP

ADP + Pi

3H+

Inner

membrane

H+

H+

H+

H+

H+

3H+

Inter-membrane space

slide7

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

slide8

Oxyconformers

Fresh water turtle

Hybernating frog

slide9

Oxyconformers

Metabolic shut down

Protein synthesis , half life 

Channel arrest ( ion motive ATPases)

Decrease electron transport and proton leaks

90 – 95% decrease of demand

slide11

Oxyregulators

Flow redistribution

Partial oxygen conformance (shut down)

Metabolic rearrangement (Pasteur)

slide12

Oxyregulators

Metabolic shut down

(Protein synthesis )

=

VO2/O2 dependency

Hours

Secondary mitochondrial damage

Apoptosis

Necrosis

slide14

Gene regulation

Krebs

enzymes

Glycolitic

enzymes

Metabolic re-arrangement

HFI - 1

slide15

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

slide16

Oxygen debt concept

Venous oxygen saturation

Lactate and acidosis

Venous/tissue PCO2

Markers of energy failure

slide17

After muscle exercise measured as increased VO2

VO2 (L/min)

Time

VO2 (L/min)

Hypothetical beseline

In ICU estimated as decreased VO2

Time

Oxygen debt

slide18

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 !!!

slide19

Physiological background

VO2(mL/min)

1

SatvO2= SataO2 -

*

Q (L/min)

Hb (gr/L) * 1.39

metabolism

1

-

SatvO2 =

Lung

*

hemodynamic

carrier

slide20

OH-

OH-

A-

A-

SID

BB

SID

BB

HCO3-

HCO3-

Positive charges

Negative charges

Negative charges

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

slide21

%

100

Alkalosis

Acidosis

80

60

40

20

0

< 20

> 60

20 - 25

25 - 30

30 - 35

35 - 40

40 - 45

45 - 50

50 - 55

55 - 60

H+ [nanomoles/liter]

Mortality at entry

721 critically ill

slide22

The importance of

mixed venous PCO2

slide23

CO2 content vs CO2 tension

CvCO2 = CaCO2 + VCO2/Q

CvO2 = CaO2 - VO2/Q

slide24

BE 0

BE -5

BE -10

BE -15

BE -20

80

60

40

CO2 content (mL%)

20

20

40

60

80

100

120

PCO2 (mmHg)

slide25

lemon

drops

+

CocaCola

CocaCola

PCO2

HCO-3

PCO2

+

HCO-3

Coca Cola effect

slide26

Low pH

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

Indeed…

Low SatvO2  may indicate or may not energy failure

All indicate energy failure

slide27

VO2

Lactate 

VO2

Lactate 

Energy failure

Volume test

VO2

Lactate 

Dobutamine test

BE - Lactate

VO2

Lactate 

Hemodynamic and mitochondrial failure

Hemodynamic failure

Pump failure

Pump failure or mitochondrial dysfunction

Mitochondrial dysfunction

slide28

Dobutamine test (stress test)

VO2

Reserve at limit

=

Lactate

VO2

=

Good reserve

Lactate

Absence of energy failure

slide29

1.0

Cardiac index group (156 events)

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

135

180

252 (129)

108 (13)

94 (4)

90 (3)

87

253 (133)

102 (8)

90 (4)

86 (3)

83

257 (133)

106 (16)

89 (4)

85 (1)

84

Probability of survival

Days after randomization

Patients at risk (N° of events)

Gattinoni L et al. N Engl J Med 333;1025-32, 1995

slide30

Early goal direct therapy

SvO2 70%

Control 49.2

Baseline SvO2

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

slide31

Shoemaker

Chest 1994

DO2

target

C

38%

T*

21%

C

67.3

CI

68.2

SVO2

69.7

Gattinoni

NEJM 1995

Rivers

NEJM 2001

C

70.7

48.4%

CI

72.1

48.6%

SVO2

71.7

52.1%

SVO2

49.2% 48.6%

SVO2

65.3% 70.3%

CT*

46.5 30.5

Preoperative

ER

ICU

Day 7

Day 2

slide32

% 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

slide33

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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