Endpoints of Resuscitation for Circulatory Shock: When ... Slides.pdf · Endpoints of Resuscitation for Circulatory Shock: When Enough is Enough? ... Setting ED ICU ICU ICU Marik,

1

Endpoints of Resuscitation for Endpoints of Resuscitation for Circulatory Shock:Circulatory Shock:

When Enough is Enough?When Enough is Enough?Emanuel P. Rivers, MD, MPH, IOM

Vice Chairman and Research DirectorDepartments of Emergency Medicine and Surgery

Henry Ford HospitalDetroit, [email protected]

Supplemental oxygen ± endotracheal intubation and mechanical ventilation

Central venous and arterial catheterization

CVPCrystalloid

Colloid

<8 mm Hg

MAP

8-12 mm Hg

Vasopressor or Nitroglycerin<65 mm Hg

>90 mm Hg

ScvO2

=65 and =90 mm Hg

Goals achieved

=70%

Hospital admission

Yes

No

Sedation and/or paralysis

(if intubated)

Transfusion of red cells to hematocrit =30%

<70%

Dobutamine & Digoxin

<70%

=70%Intubation and Mechanical

Ventilation

2

Communication Avoids Misunderstanding and Prevents Problems

Increased Metabolic Demands: Fever, Tachypnea Hypovolemia,Vasodilation &

Myocardial Depression

Microvascular Alterations:Impaired Tissue Oxygen

Utilization

Inflammatory Mediators Produce Cardiovascular Insufficiency

Cytopathic Tissue Hypoxia

Fink, Crit Care Clin, 2002

3

The Purpose of Resuscitation “Perhaps Forgotten”

VO2

VO2

DO2Critical DO2

Delivery DependentGlob

al tis

sue

hypo

xia

Optimum region

Delivery Independent The Problem• Uniformity of terminology• Uniformity of goals• Under-resuscitation• Over-resuscitation• Multiple outcome

measures in clinical trials• How do we solve the

problem?

Endpoints and Tools

O2

ATP

Glucose

Substrates

Endpoints of Resuscitation

Lactate

Happy Cell

Base Deficit

(a-v)CO2

SvO2

pHi

DO2Mediators

Goal Directed Optimization of Cardiac Function

DO2- PaO2- Hemoglobin- Cardiac Output

Hemodynamic- Preload (CVP, PCWP)- Afterload (MAP, SVR)- Contractility (SV)- Heart Rate (BPM)- Shock Index (HR/SBP) - Coronary Perfusion Pressure

Microcirculation

VO2- Stress- Pain- Hyperthermia- Shivering- Work of breathing

4

Macro Endpoints

VO2

VO2

DO2Critical DO2

Delivery Dependent Delivery Independent

Global

tissu

e hyp

oxia

Optimum region

Physical ExamHeart Rate

Blood PressureShock IndexUrine OutputCVP/PCWP

O2

ATP

Glucose

Substrates Goal Directed


5

Effects of perfusion pressure on tissue perfusion in septic shock

• OBJECTIVE: To measure the effects of increasing MAP on systemic O2 metabolism and regional tissue perfusion in septic shock.

• DESIGN: Prospective study.

• SETTING: MICU and SICU patients in a tertiary care teaching hospital.

• PATIENTS: 10 patients with septic shock requiring pressoragents to maintain a MAP > 60 mm Hg after fluid resuscitation to a PAOP > 12 mm Hg.

LeDoux, Crit Care Med, 2000



43+/-13 mL/h (NS)49+/-18 mL/hrUrine Output

16+/-3 at 85 mm Hg (2.1+/-0.4 kPa) (NS)

13+/-3 mm Hg (1.7+/-0.4 kPa)

A-Gastric pCO2

3.0+/- 0.9 mEq/L (NS)3.1+/-0.9 mEq/LLactate

5.5+/- 0.6 L/min/m2 (p < 0.03) 4.7+/- 0.5 L/min/m2Cardiac Index

85 mmHg65 mmHg

• INTERVENTIONS: Norepinephrine was titrated to MAPsof 65, 75, and 85 mm Hg in 10 patients with septic shock.

6


CONCLUSIONS: – Increasing the MAP from 65 mm Hg to 85 mm Hg

with norepinephrine does not significantly affect• systemic oxygen metabolism• skin microcirculatory blood flow• urine output• splanchnic perfusion.


Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patientsCritical Care Medicine 1998;26:1646-1649

Todd Dorman, MD, FCCM; Michael J. Breslow, MD, FCCM; Pamela A. Lipsett, MD; Jeffrey M. Rosenberg, MD, PhD; Jeffrey R. Balser, MD, PhD; Yaniv Almog, MD; Brian A. Rosenfeld, MD, FCCM

• Radial artery pressure underestimates central pressure in hypotensive septic patients receiving high-dose vasopressor therapy.

• The higher mean femoral arterial pressures:– immediate reduction in

norepinephrine infusions in 11 of the 14 patients.

• Clinical management, based on radial pressures, may lead to excessive vasopressor administration.

7

8

Low Dose to High DoseVasopressor

No Vasopressorto High DoseVasopressor

0

20

40

60

No Vasopressor

No Vasopressorto Low DoseVasopressor

Mor

talit

y (%

)

20%

37%

58%54%

0

10

20

30

40

50

60

0-6 hours 6-72 hours 0-72 hours% R

ecei

ving

Vas

opre

ssor

s

15%

No Corticosteroids

9

O2

ATP

Glucose




An ICU Therapy Forever Changed

• A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy

10

Stop An International Crisis

• Transfusions do make a difference in shock or global tissue hypoxia states.

• Conservative management during the convalescent phase.

Abuse to the clinician after giving blood

Hemodilution After Volume

15

20

25

30

35

40

Baseline 3 hours 6 hours 7-72 hours

ControlTreatment

**

*

0

2

4

6

8

10

12

14

0-6 hours 6-72 hours 0-72 hours

ControlTreatment

339.49

447.13

0

50100150200

250300350400450

500

0-72 hours

No difference in blood transfused over 72 hours

between groups

3.6 Liters More Fluid

60 ml

108 ml

11

Transfusion Decisions Depend on the Clinical Sate

DO 2crit

VO2

Lactate

Delivery IndependentVO2

Delivery DependentVO 2

SVO 2

OER

DO 2

VO2

Lactate

SVO2

OER

Hemodynamic Phases of Sepsis

SVO2

OER

Lactate

• Even SvO2 is a combination of various tissue beds.

• The coronary circulation is at the highest risks.

12


DO 2crit

VO2

Lactate


Delivery DependentVO 2

SVO 2

OER

DO 2

VO2

Lactate

SVO2

OER

Hemodynamic Phases of Sepsis

SVO2

OER

Lactate


DO 2crit

VO2

Lactate


Delivery DependentVO2

SVO 2

OER

DO 2

VO2

Lactate

SVO 2

OER

Dietrich, Critical Care, Med, 2000

Marik, JAMA, 2000

Herbert, NEJM, 2001

Vincent, JAMA, 2002

13

Transfusion Studies

3.4--------1.7 – 1.9Cardiac Index

Resuscitated--------5.3 - 6.1CVP (mmHg)

69.5--------48.6 - 49.2SvO 2 (%)

2.6----1.8±1.8 -1.8±2.16.9 - 7.7Lactate (mM/L)

9.910.1-12.2*8.2-8.211.3 – 11.4Hemoglobin

49.653-5957-5862-67Age

Up to 48 hoursOver 2 weeks24 hours<1Time (hours)

ICUICUICUEDSetting

Marik, JAMA, 1993Vincent,

JAMA, 2002Hebert, NEJM, 1999EGDT, NEJM,

2002

Transfusion Studies

Excluding dialysis patients, patients likely to die in 24

hours and patients in established septic shock

(systolic blood pressure <90 mmHg).

20-23%16-13%100%In shock or global tissue

hypoxia?

Decreased pHi18.5 -10% ICU22 -17% 28 day22.2 vs. 28.1% (0.05) 56-30.5%

Mortality

And Endpoints

----16.5-13.520.9±7.3- 21.3±8.120.4±7.4 -21.4±6.9APACHE

Marik, JAMA, 1993Vincent,

JAMA, 2002Hebert, NEJM, 1999EGDT, NEJM,

2002

14

O2

ATP

Glucose





250 ml/min

25%

1000 ml/min

SvO2 = 65-75%20 volume %

5 liters/min.

15

70-75%

VO2

• Stress• Pain• Hyperthermia• Shivering• Work of breathing

DO2

• PaO2• Hgb• Cardiac Output

- +

ScvO2 SvO2

Using Metabolic Endpoints

SvO2

16

Lactate and Outcome

(Mizock, Dis Mon, 1989) (Weil, Circulation, 1970)

(Abramson and Scalea, J Trauma, 1993)

13.6193>48 hrs

77.862124-48 hrs

100027<24 hrs

%SurvivalNonsurvivorsSurvivorsClearance

0

1

2

3

4

5

6

0 8 16 24 36 48

Time (hrs)

Lac

tate

(mM

/L)

Survivors Non-survivors

N = 76

17

Crit Care Med 2004 Vol. 32, No. 8

• No clearance• <0 mM/L/hr

• Intermediate clearance• 0-1 mM/L/hr

• High clearance• >1 mM/L/hr

∆ Lactate (ED Admission - ED Discharge)ED Length of Stay (hrs)

0

2

4

6

8

10

12

14

Lactate (mM/L)

No Clearance HighClearance

ED Admission ED Discharge

14

16

84

N = 114


∆ Lactate (ED Admission - ED Discharge)ED Length of Stay (hrs)

-30-20-10

01020304050607080

Lactate Clearance

%

1 2 3 4

N = 243

Quartiles of Lactate Clearance

18

Early Lactate Clearance

0 12 24 36 48 60 7263

4

5

6

7

8

9

10

11 No ClearanceIntermediate ClearanceHigh Clearance

Time (hr) p<0.05

MO

DS

50

23

12

05

101520253035404550

Mor

talit

y (%

)

No Clearance IntermediateClearance

HighClearance

1 2 3 40

1

2

3

4

5

6

7

8

9

10

Lactate Clearance Quartiles

Cas

pase

-3 (n

g/m

L)

% Lactate Clearance Quartiles andmean Biomarker Levels over 72 Hours

19

1 2 3 40

1

2

3

4

5

6

7

8

9

10

Cas

pas

e-3

(ng

/mL

)

1 2 3 40

10

20

30

40

50

60

70

80

90

100

110

120

Tu

mo

r n

ecro

sis

fact

or

α (p

g/m

L)% Lactate Clearance Quartiles

and mean Biomarker Levels over 72 Hours

1 2 3 40

100

200

300

400

500

600

700

800

900

1000

Lactate Clearance Gropus

IL-8

(pg/

mL)

O2

ATP

Glucose




Microcirculation



20

The oxygen consumption-delivery relationship

Global Tissue Hypoxia

Resuscitated

Delivery Dependent -Under-Resuscitated

Delivery Independent

(cytopathic tissue hypoxia)

Microcirculatory Dysfunction

21

• Orthogonal polarization spectral (OPS) imaging allows visualisation of the microcirculation.

• Assessing microcirculatory flow in septic-shock patients who had a MAP > 60 mm Hg and CVP > 12 mm Hg.

• The infusion of 0.5 mg of nitroglycerin resulted in a marked increase in microvascular flow on OPS imaging.

• Improved recruitment of the microcirculation could be a new resuscitation endpoint in septic shock.

Lancet 2002

Vascular occlusion and vasopressor use

Ischemia and

Cellular Hypoxia

Micro-Circulatory Defects

22

Increasing O2 ConsumptionBihari, NEJM, 1987

30-minute infusion of a vasodilator, prostacyclin(5 ng/kg/min in 27 critically ill patients

with acute respiratory failure and measured: O2 delivery and uptake to tissuesExtraction ratio (uptake/delivery)

• In the patients who died:– O2 extraction ratio rose – VO2 did not change.

• In the survivors:– O2 extraction ratio fell– VO2 increased.

Increasing O2 ConsumptionBihari, NEJM, 1987

Conclusion: (an underappreciated endpoint)

– Substantial O2 debt or cryptic shock in patients who subsequently die.

– Inadequate tissue oxygenation may be difficult to recognize

– Important mechanism in the development of irreversible multiple organ failure.

23

Oxygen Debt: To Pay or Not to Pay

Direct Association of Decreased VO2 Increased Mortality

• Cardiac arrest (Rivers, Chest, 1994)

• Trauma (Moore, J of Trauma, 1992)

• Sepsis (Tuchschmidt, Chest, 1991)

• Acute myocardial infarction (Rady, Chest, 1993)

• Heart transplantation (Mancini, J Clin Monit, 1991)

• Liver transplantation (Chest, 1992)

• ARDS (Appel, Chest, 1992)

24

O2

ATP

Glucose

Substrates


Lactate

Happy Cell

Base Deficit

(a-v)CO2

SvO2

pHi

DO2Mediators

Goal Directed



Microcirculation


Metabolic Endpoints of Resuscitation

VO2

VO2

DO2Critical DO2

Delivery Dependent Delivery Independent

Global

tissu

e hyp

oxia

ScvO2

(a-v)pCO2

Gastric Tonometry

Sublingual Cap.Base Deficit

Lactate

Pulmonary Artery Catheter in the ICU

O2 extraction Optimum region

25

(a-v) pCO2 Gradient < 5 mmHg

• PaCO2↓ but PvCO2↑ in circulatory failure and low flow states

(Mecher, Crit Care Med, 1990)

• Inverse relationship between CI and (a-v) pCO2

(Ducey, Crit Care Med, 1992), (Durkin, J Crit Care, 1993)(Rackow, Crit Care Med, 1994), (Teboul, Crit Care Med,

1998)

• ↑(a-v) pCO2 increases mortality(Bakker, Chest, 1992)

PcvCO2 PmvCO2

PaCO2

(a-v) pCO2 and Cardiac Index

(Cuschieri, Rivers and Donnino, Int Care Med, 2005)

0 2 4 6 8 100

2

4

6

8

10

(a-mv)pCO2 (mmHg)

CI p

ac(L

/min

/m2 )

0 2 4 6 8 100

2

4

6

8

10

(a-cv)pCO2 (mmHg)

CI p

ac(L

/min

/m2

)

ln(CI) = 1.942 - 0.18(a-mv)pCO2

r2 = 0.87ln(CI) = 1.884 - 0.173(a-cv)pCO2

r2 = 0.90

Mixed venous Central venous

N = 83

26

Sublingual CapnometryWeil, Crit Care Med 1999; 27:1225-1229.

26205N

>2.5 < 2.5Lactate (mM/L)

81 +/- 2453 +/- 845.2 +/- 0.7PSL CO2 mm Hg

physical signs of circulatory shock

without clinical signs of shock

healthy volunteers

When PSL CO (2) > 70 mm Hg, its positive predictive value for the presence of physical signs of circulatory shock was 1.00.

When it was <70 mm Hg, it predicted survival with a predictive value of 0.93.

3412N

(r2 = .84; p < .001)Correlation with

lactate

58 + 11 93 + 27Initial PSL CO2

mm Hg

SurvivorsDied from shock

27

Base Deficit

• Amount of base required to titrate 1L blood to normal pH.

• Indicator of volume deficit.

• Guide to resuscitation in trauma patient.(Davis, J Trauma, 1988)

• Affected by administration of bicarbonate, temp, ETOH, heparin.

Can I use Base Deficit or Anion Gap?

>10

7.0 to 9.9

4.0 to 6.9

Lactate Range mmol/L

0%

8.3%

11.1%

Serum HCO3>22 and A.G. <15

Wira and Rivers, Crit Care Med, 2005

28

Crit Care Med, 2007

Severe Global Tissue Hypoxia:Lactate > 4 mmole/liter

and ScvO2 < 70%)

Moderate Global Tissue Hypoxia:Lactate < 4 and >2 mmole/liter

and ScvO2 < 70%

Resuscitated:Lactate < 2 mmole /liter

and ScvO2 > 70%

29

0 12 24 36 48 60 723 60

200

400

600

800

1000

1200

1400

Hours after the start of treatment

Il-8

(pg/

dL)

0 12 24 36 48 60 723 60

100

200

300

400

500


IL-8

mur

ine

(pg/

mL)

EGDTStandard Therapy

Lactate > 4 mM/L and ScvO2 <70%

Lactate > 2 and < 4 mM/L and ScvO2 <70%

Lactate < 2 mM/L and ScvO2 > 70%

Chest, 2005

0 12 24 36 48 60 723 60

25

50

75

100


TN

F-α

(pg

/mL)

0 12 24 36 48 60 723 60

25

50

75

100

125

150

175

200


TNF-

α (

pg/m

L)

0 12 24 36 48 60 723 60

1

2

3

4

5


Cas

pase

-3 (

ng/m

L)

0 12 24 36 48 60 723 60

1

2

3

4

5

6

7

8

9

10


Cas

pase

-3 (

ng/m

L)

Tumor Necrosis Factor

Caspase-3

30

0 12 24 36 48 60 723 60

2500

5000

7500

10000

12500

15000 EGDTControl


IL-1

ra (p

g/m

L)

0 12 24 36 48 60 723 60

2500

5000

7500

10000

12500

15000

17500

20000 Lactate>4 and ScvO2<70%Lactate>2 and ScvO 2<70%Lactate<2 and ScvO2>70%


IL-1

ra (ng

/mL)

0 12 24 36 48 60 723 60

100

200

300

400

500


ICA

M-1

(ng

/mL)

0 12 24 36 48 60 723 60

100

200

300

400

500

600


ICA

M-1

(ng

/mL)

Intracellular Adhesion Molecule

IL-1 receptor Antagonist

31

32

Optimization Trials“A Closer Look”

Mortality

(Boyd, New Horiz, 1996)

Early

Late

(Kern, Crit Care Med, 2002)

33

O2

ATP

Glucose

Substrates


Lactate

Happy Cell

Base Deficit

(a-v)CO2

SvO2

pHi

DO2Mediators

Goal Directed



Microcirculation


Documents

Endpoints of Resuscitation for Circulatory Shock: When ... Slides.pdf · Endpoints of Resuscitation for Circulatory Shock: When Enough is Enough? ... Setting ED ICU ICU ICU Marik,