1

Goal-directed resuscitation insepsis; a case-based

approach

Jorge A Guzman, MD, FCCM

Head, Section Critical Care Medicine

Respiratory Institute

Cleveland Clinic Foundation

The challenges to managing septicshock are to find the right

parameters to monitor and the end-points for adequate resuscitation

• The hemodynamic status of critically illpatients is complex

• Complicating co-morbidities

• Conflicting therapeutic goals(hemodynamic instability and ALI/ARDS)

2

Resp

on

se

Days After Injury

Pro

gre

ssiv

eO

rgan

Dysfu

ncti

on

Injury

1 3 10 14 21

Primary OrganDysfunction

Secondary OrganDysfunction

Sh

oc

k

Resu

scit

ati

on

Reco

very

Reco

very

SIRS

Early GoalDirectedTherapy

AppropriateAntibiotics

Management of shock

Glucose control

Ventilatory support

aPC

Earlyrecognition

Beal, AL. JAMA 1994 271;226-33.

Goal-directed resuscitation

Identify circulatory failureMAP < 65 mm Hg – Lactate > 2 mmol/L

Global macrocirculatory goals• MAP > 65 mm Hg• Adequate preload

• Adequate urine output

Microcirculatory goals• ScvO2 > 65-70%

• Lactate < 2 mmol/L• Base excess

• Microcirculation assessment• PCO2 gap

• NIRS• OPS

Tim

ing UPSTREAM

DOWNSTREAM

3

A 72 y/o male presented to the ED with increasing SOB, feverand cough. He has no significant PMH. His initial BP was 85/55mm Hg. Mechanical ventilation was started due to poorresponse to O2 supplementation via VM. He was resuscitatedwith 2 L on NS and sent to the MICU. An hour later his SBPremains in the 90s, he is making some urine, and he hasreceived 3.5 L of NS thus far

Physicians in the ICU continue

administering intravenous fluids

SSC guidelines for initial resuscitation

Central venous pressure 8-12 mm Hg

Mean arterial pressure (MAP) ≥65 mm Hg

Urine output ≥0.5 mL·kg-1·hr-1

Central venous (superior vena cava) or mixed venousoxygen saturation ≥70% or ≥65%, respectively (grade1C)

If ScvO2 or SvO2 of 70% or 65%, respectively, is notachieved with fluid resuscitation to the CVP target, thentransfusion of PRBC to achieve a Htc of ≥30% and/oradministration of a dobutamine infusion (up to amaximum of 20 μg·kg-1·min-1) be used to achieve thisgoal (grade 2C).

Crit Care Med 2008; 36:296-327

4

Central venous andarterial catherization

Sedation, paralysis (ifintubated), or both

Hospital admission

Crystalloid

Colloid

Vasoactive agents

Transfusion of red cellsuntil hematocrit 30%

Inotropic agents

CVP

Goalsachieved

ScvO2

< 8 mm Hg

8 - 12 mm Hg

65 and 90 mm Hg

70 mm Hg

No

Yes

< 65 mm Hg

> 90 mm Hg

< 70%

< 70%

70%

Supplemental oxygen ±endotracheal intubation and

mechanical ventilation

MAP

Engl J Med. 2001;345:1368-1377.

Volume resuscitation was sufficient

to restore ScvO2 of >70%

in 36% of all patients

In-hospital mortality

30.5

46.5

0

20

40

60

80

100

Protocol

Controls

28-day mortality

33

49

0

20

40

60

80

100

Protocol

Controls

60-day mortality

4457

0

20

40

60

80

100

Mortality (%)

Protocol

Controls

*

*

*

EGDT; administered treatments

*

Rivers E. NEJM 2001; 345:1368-1377

IV Fluids

5

3.5

0

2

4

6

8

10

12

6 hr pRx 7-72 hr pRx

IVflu

ids

(L)

EGDT

Controls

PRBC

0

20

40

60

80

100

6 hr pRx 7-72 hr pRx

Pa

tie

nts

(%)

EGDT

Controls 0

10

20

30

40

50

60

Press

ors0-

6

Press

ors7-

72

Dobuta

0-6

Dobuta

7-12

MV

0-6

MV

7-72

PAC

0-6

PAC

7-72

Pe

rce

nt

(%)

EGDT

Standard

*

*

9% of EGDT ptsgot nitroglycerin!

5

Normal BP may be misleading in sepsis

24

44

70

45

0

10

20

30

40

50

60

70

80

Initial ScvO2 Mortality (60 d)

Perc

en

t(%

)

EGDT (n = 25) Controls (n = 23)

Cryptic shock; patients with MAP > 100 mm Hg and serumlactate > 4 mmol/L

Donnino, M et al. Chest 2003;124,90S

*

Should lactate, procalcitonin, or other inflammatorymarkers be measured routinely?

Three hrs and 7L of fluids after ICU admission, his XR shows morecongestion. The CVP is 9 mm Hg and the patient remains of highFiO2 (80%), PEEP was increased to 10 cm H2O, and he is now onvasopressor support (norepinephrine 8 g/min). His Hb is 9.5 g/dLand his lactate remains elevated (4.4 mmol/L)

Is CVP still a goodpreload indicator for this

patient?

6

What to monitor? Preload

• Preload is defined as the load before contraction of theventricle starts

• Static measures of preload– CVP/RAP – right ventricular preload

– PAOP – left ventricular preload

– EDV - usually by echo

• Dynamic measures of preload– Examine CV response to respiratory changes in pleural

pressure, mainly in ventilated patients

– Give a fluid bolus and see what changes- the classical fluidchallenge…

Static measures of preloadThere is NO correlation between blood volume and CVP

7

0

2

4

6

8

10

12

CVP

mm

Hg

Responders

Non responders

Intensive Care Med 2004; 30:1740Crit Care Med 2007; 35; 64

32/66 VLS (48%)500 mL HES27>15% SVISeptic shockMichard F (2003)

20 (53%)500 ml NS38>15% in ABF(Doppler)

Critically ill w/circulatory failure

Monnet X (2005)

20 (39%)4 ml/kg colloid x251>10% in SVICritically ill w/circulatory failure

Vallee F (2005)

9 (43%)1 L Ringer or 500mL HES

21>15% in COCritically ill w/circulatory failure

Heenan S (2006)

RespondersChallengeNDefinition ofResponders

Patients

4 (40%)25 mL/Kg ofRinger

10Increase in COSepsis w/circulatory failure

Swensen CH(2006)

21/35 VLS (60%)500-1000mL15>15% SVISepsisw/circulatory

failure

Tavernier B(1998)

16 (40%)500 mL HES40>15%Septic shockcirculatory failure

Michard F (2000)

13/22 VLS (59%)8 ml/kg HES20>15% CISeptic shockFessel M (2005)

10 (15%)PLR & 500 ml NS22>15% in ABF(Doppler)

Critically ill w/circulatory failure

Lafanechère A(2006)

Hofer CK (2005)

Preisman S(2005)

21 (60%)10 mL/kg (IBS) 6% HES

35>35% SVIAbdominalsurgery

32/70 VLS (46%)250 mL colloids18>15% SVCardiac surgery

50% of critically ill patients may be loaded with fluidsunnecessarily!

He

mo

dyn

am

icre

sp

on

seto

fluid

load

ing

8

Ann Surg 2003; 238:641

Fluid balance and outcomes

CCM- 2006;12:219

NEJM 2006; 354:2564

If CVP is not the answer, then what?

Arterial pressure variations during mechanical ventilation

Reverse pulsus paradoxus

Anesthesiology 2005; 103:419

9

Small scale-high speed

Large scale-slow speed

Quick bedside trick

• Drawbacks

– No spontaneous breathing efforts

– Need larger tidal volumes (> 8mL/kg)

– Arrhythmias

– Assure accurate line recording (avoid bubbles, kinks,clots, etc)

– Does not work in patients with cor pulmonale - RVF

– Caution in CHF

What to monitor?Dynamic measures of preload- Arterial pressure variations

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What to monitor?Dynamic measures of preload- Response to a fluid challenge

Preload

LV

Ou

tpu

t(S

V,

CO

)

Normal Contractility

Bolus

Decreased Contractility

Passive leg raising maneuver

What to monitor?Dynamic measures of preload-Passive Leg Raising

• Needs real time cardiovascular assessment (CO-CI)

• Ensure that there is a change in preload (CVP) before youcall it negative

• Not affected by spontaneous breathing and arrhythmias

• SCARCE OUTCOME DATA

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Five hours after ICU admission, MAP is 60 mm Hg on 30mcg/min of NE. His CVP is 10 mm Hg and no longer fluidresponsive. He remains mechanically ventilated requiringhigh FiO2 (0.6) and high PEEP and has minimal urine output.

ScvO2 is 62% and serum lactate is 4.2 mmol/L

Is it time to know his cardiac output?

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• Misuse of CO may worsen outcomes– Hayes et al. Elevation of Systemic Oxygen Delivery in the Treatment of

Critically Ill Patients. NEJM 1994;330:1717

• It would be of value if it guided therapies toimprove outcomes…

What to monitor?Stroke volume and cardiac output

CVP goals in Sepsis Trials

0

1

2

3

4

4 6 8 10 12 14 16 18

Trial CVP goal

Nu

mb

er

of

tria

ls

MAP goals in Sepsis Trials

0

1

2

3

4

60 65 70 75 80 85 90 95 100

Trial MAP goal

Nu

mb

er

of

tria

ls

CI goals in Sepsis Trials

0

1

2

3

4

2 3 4 5 6 7

Trial CI goal

Nu

mb

er

of

tria

ls

PAOP goals in Sepsis Trials

0

1

2

3

4

10 11 12 13 14 15 16 17 18

Trial PAOP goal

Nu

mb

er

of

tria

ls

Crit Care 2007; 11 R67

To Swan or not to Swan?

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What to monitor?Stroke volume and cardiac output

Cardiacoutput

Electricimpedance/reactance

Arterial waveformanalysis-

Pulse contour(can also get SVV)

Lithium indicatordilution

Transpulmonarythermodiluton(can also getSVV-EVLW)

Indirect Fick

Partial CO 2

rebreathing

Transthoracic-transesophageal

Echocardiography

Thermodilution(PAC)

The future:Intensivists assessing LVF

using hand-held echo

• 6 hr of US training

• Blinded to the patient’s clinical condition

Severe failureMild-Moderate

71%69%Correct interpretation-Degree of LV failure

80%92%Correct interpretation

Abnormal LVFNormal LVF

Melamed R et al. Chest 2009; 135:1416

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Six hours after ICU admission, MAP is 62 mm Hg on22 mcg/min of NE and 5 mcg/min dobutamine. HisCVP is 12 mm Hg and no longer fluid responsive.He remains mechanically ventilated with an FiO2 of0.6. Lactate is 3.5 mmoL/L. Cardiac output obtainedby pulse contour is 6.0 L/min

Should we now focus on ScvO2 and/or lactates asend-points of resuscitation?

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Understanding ScvO2

92

92

72

71

9975

97

66

88

7578

The difference between ScvO2 and SvO2

changes in shock

ScvO2 > SvO2 by 5-8 %units

What to monitor?Central venous oxygen saturation

Oxygen Delivery

Oxyg

en

Co

nsu

mp

tio

nL

acta

teS

VO

2(S

cV

O2) VO2 (SvO2 - ScvO2)

Lactic acidosis

Critical OxygenDelivery Threshold

If Hb and SaO2 are

normal a lowScvO2/SvO2

reflects a LOWOUTPUT state

BUT IT DOES NOTTELL YOU THE REASON

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Since metabolic demands vary widelyin critically patients,

there is NO NORMAL CARDIAC

OUTPUT for critically ill patients

ScvO2 may help decide whetheradditional interventions are

necessary

Oxygen Delivery

Oxyg

en

Co

nsu

mp

tio

nL

acta

teS

VO

2(S

cV

O2)

A normal ScvO2 does not indicateadequate perfusion in sepsis

Treciak S et al. Critical Care 2008;9(suppl):S20

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Crit Care Med 1988; 16: 655-658

Low venous oxygen saturation wasinfrequent in a Dutch study

• Mean ScvO2 74.0 ± 10.2%; mean lactate 2.7 ±2.2 mmol/L. Mean CVP 9.8 ± 5.4 mm Hg. Only1% (of septic shock pts) had a ScvO2 < 50% van

Beest et al. Critical Care 2008; 12:R33

• Baseline ScvO2 in patients with septic shock (n79) was 71 ± 12.3 % Shapiro NI et al, Crit Care Med 2006;34:1025-32

Venous saturation was high amongpatients in the Multiple Urgent Sepsis

Therapies (MUST) protocol

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Dysoxia is present with normal or highScvO2 in septic ICU patients

Perel A, Intensive Care Med 2008; 34:S65Rivers EP, et al. Crit Care Med 2007; 35:2016-24

Severe GlobalTissue Hypoxia

Lactate >4 mmol/LScvO2 <70%

Moderate GlobalTissue Hypoxia

Lactate >2 mmol/LScvO2 <70%

Resolved GlobalTissue Hypoxia

Lactate<2 mmol/LScvO2 >70%

High lactates witha high ScvO2

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Am J Surg 1996;171:221

Ann Emerg Med 2005; 45:524-8

Hyperlactatemia; aerobic etiologyrelevant to sepsis

• Increased aerobic glycolysis bycatecholamine stimulated Na+-K+ ATPasehyperactivity (Lancet 2005; 365:871)

• Mitochondrial dysfunction (Lancet 2002; 360:219)

• Impaired pyruvate dehydrogenase activity(Shock 1996; 6:89)

• Sepsis-induced impaired lactate clearance(Am J Resp Crit Care Med 1998;157:1021)

Paradigm shiftHyperlactatemia due to tissue hypoxiamay be the exception and not the rule

May explain failed trials aimingat supranormal DO2

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• Failure to normalize lactate carried a 100% mortality• Clearing between 48-96 hrs had a 42.5% mortality• Patients clearing in <24 hr had a mortality of 4%

Am J Surg 2001; 182;481-5

Crit Care Med 2004; 32:1637-62

The selection of hemodynamic parameters tomonitor and end-points for resuscitation during

septic shock is rarely straightforward!

The complexity of critical illness and the presence oftherapeutic conflicts (heart vs. lungs) necessitates

monitoring of a combination of parameters

Preload&

Fluid responsiveness

Cardiac function

CO-SV- echo

ScvO2

Lactate

Hemodynamic management in shock

Macrocirculation Microcirculation

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• Protocol driven early aggressive goal-directedresuscitation improve the outcome of patients in septicshock IF INITIATED EARLY

• Monitoring techniques that couple measurement of COwith ventilatory variations of systolic arterial pressure,pulse pressure, and SV enhance the ability to predictfluid responsiveness in circulatory failure

• Agreeing on end-points for resuscitation is difficult, but acombination of macro and microcirculatory targetsseems likely to yield better results

In summary…