Sepsis and septic shockPractical hemodynamic consequences

Intensive Care Training ProgramRadboud University Medical Centre Nijmegen

Septic cardiomyopathy

• Present in > 50% and often masked by low vascular resistance - unmasked by NE

• Acute and reversible (in a few days)

• Accompanied by low filling pressures due to concomitant ↓ RV function and small increase in LV compliance

Veillard-Baron A. Ann Int Care 2011;1:6

Veillard-Baron A. Ann Int Care 2011;1:6

Veillard-Baron A. Ann Int Care 2011;1:6

RV dysfunction

Day 1 Day 2

Veillard-Baron A. Ann Int Care 2011;1:6

Septic cardiomyopathy

Veillard-Baron A. Ann Int Care 2011;1:6

Small increase in compliance

Veillard-Baron A. Ann Int Care 2011;1:6

Size of balloonis LV volume Highest mortality

Lowest mortality

Intermediate mortality

LVEF and CI in sepsis

Veillard-Baron A. Ann Int Care 2011;1:6

Excessive vasodilation

Increased endothelialpermeability

Venous pooling

Systolic myocardial dysfunction

Diastolic myocardial dysfunction

Mitochondrial dysfunctionMicrocirculatory shunting

Vasodilatation in SepsisSeptic shock with lactate acidosis

iNO synthase ↑

NO ↑

cGMP ↑

Vasopressin secretion ↑

Vasopressin stores ↓

Vasopressin plasma ↓

ATP ↓, H+ ↑, Lactate ↑ vascular smooth muscle

Open KATPOpen KCa

Cytoplasmic Calcium ↓

Phosphorylated myosin ↓

Vasodilatation

IFN-Υ ± IL-10 ↑

IDO activity ↑

Tryptophan ↓ & kynurenine ↑

Increased KT ratio plasma

Lymphocyte apoptosis ↑

Microvascular reactivity ↓

IL-6 ↑e NO ↓

Darcey CJ. PLOSone 2011;6:e21185

N = 80

Changsirivathanathamrong D. Crit Care Med 2011;39:2678-2683

INOTROPIC DOSE

IDO ACTIVITY

N = 16

Changsirivathanathamrong D. Crit Care Med 2011;39:2678-2683

Microcirculation

• Measured by Sidestream Darkfield Imaging or NIRS

• Decrease in capillary density with increased heterogeneous perfusion

• Evidence accumulating that changes in perfusion induce tissue hypoxia (in contrast to the adaptive theory)

De Backer D. Ann Intensive Care 2011;1:27

Microcirculation in sepsis

0

25

50

75

100

% perfused vessels % perfused capillaries % absent blood flow % intermittent blood flow

Control Acetylcholine

De Backer D. Am J Respir Crit Care Med 2002;166:98-104

Normal Sepsis

Nitroglycerin and microcirculation in sepsis

Boerma EC. Crit Care Med 2010;38:93-100

N = 70

Patients with severe sepsis/septic shock treated with EGDT

Boerma EC. Crit Care Med 2010;38:93-100

Mitochondrial dysfunction

XXX XXX

Sepsis ONOO- ↑↑

Peroxynitrite

PARP + Caspase activation

ApoptosisNecrosis

Treatment

• Volume loading

• Inotropic agents

• Increasing afterload with NE / vasopressin

• Vasodilator (experimental)

HES 130/0.4 versus NaCl 0.9% - CRYSTMAS• Prospective MC (N=24), DB RCT

• Age ≥ 18, severe sepsis

• Primary endpoint: amount of fluid for achieving hemodynamic stability

Guidet B. Crit Care 2012;16:R94

HES 130/0.4 versus NaCl 0.9% - CRYSTMAS• 88 vs 86 patients reached hemodynamic

stability (NS)

• Amount of fluid < with HES: 1379 ± 886 vs 1709 ± 1164 mL (p = 0.0185)

• Cumulative volume over 4 days similar

• Time to reach HDS 11.8 ± 10.1 vs 14.3 ± 11.1 hours (NS)

• No differences in LOS, morbidity, mortalityGuidet B. Crit Care 2012;16:R94

HES 130/0.4 versus NaCl 0.9% - CRYSTMAS

0

10

20

30

40

Mortality 28D Mortality 90D ARF after screening

(%)

HES 130/0.4 NaCl 0.9%

NS NS

Guidet B. Crit Care 2012;16:R94

NS

Guidet B. Crit Care 2012;16:R94

HES 130/0.42 versus Ringer’s acetate

• Adult patients with severe sepsis

• MC (N = 26), blinded, stratified clinical trial

• HES 130/042 vs Ringer’s acetate

• Daily maximum dose 33 mL/kg IBW

• Primary outcome composite death/dialysis dependence at D90

Perner A. N Engl J Med 2012;367:124-134

HES 130/0.42 versus Ringer’s acetate

0

15

30

45

60

Death/DD Day 90 Death Day 90 Severe bleeding RRT

Ringer’s HES 130/04

P = 0.03 P = 0.03 P = 0.09 P = 0.04

No differences in total amount of fluid neededPerner A. N Engl J Med 2012;367:124-134

HES 130/0.4 versus Ringer’s acetate

Perner A. N Engl J Med 2012;.../...

Durairaj L. Chest 2008;133:252-263

35.4 - 65.2%

15% BJA 2012

Fluid therapy and microcirculation

Proportion perfused small vessels

Baseline Fluids

Early septic shock

Late septic shock Ospina-Tascon G. Intensive Care Med 2010;36:949-955

Despite similar changes in CI

Lactate driven therapy

0

10

20

30

40

50

33,9

43,5

Mor

talit

y (%

)

Control Lactate driven

N = 348P = 0.067

Admission lactate ≥ 3 mmol/lGoal: lactate ↓ ≥ 20% in 2 hrs

• After correction for risk factors mortality lower in lactate group (HR 0.61, p = 0.006)

• Duration MV ↓, duration ICU stay ↓, lower SOFA score

Jansen TC. Am J Respir Crit Care Med 2010, 182:752-761

Patient with septic shock

Hypotension - Lactate ↑ - Low UP

Observation

Inadequate vital organ perfusion

Inference

Cardiac output must be low

Inference

Rapid fluid bolus resuscitation

Consequence

“Therapy is necessary and life-saving and better than moderate fluid therapy + early vasopressors”

Often repeated

Hilton AK. Crit Care 2012;16:302

SmvO2

Cardiac Output = VO2

CaO2 - CmvO2

Fick Equation

CaO2 = (Hb (mmol/l) × 2.16 × SaO2) + (0.003 × PaO2 (mm Hg))

CmvO2 = (Hb (mmol/l) × 2.16 × SmvO2) + (0.003 × PmvO2 (mm Hg))

The amount of dissolved oxygen in plasma is negligible

Normally ScvO2<SmvO2 due to the higher oxygen extraction of the brain

Oxygen extraction in the heart almost maximal

Oxygen extraction in the kidneys is minimal

Low cardiac output may decrease perfusion of the GI tract, lowering oxygen saturation in the VCI and changing the relationship between ScvO2 - SmvO2

General remarks

• SmvO2 is a surrogate for cardiac output only if Hb, SaO2 and VO2 remain constant

• If SaO2 is low, the difference between A-V saturation is a better surrogate for cardiac output

• The relation between cardiac output and SmvO2 is non-lineair (next slide)

50% 70%

Mixed Venous Oxygen Saturation (%)

Car

diac

Inde

x (%

of n

orm

al)

Initial lactate clearance and mortality

0

20

40

60

80

100

In-Hosptal mortality

%

Lactate clearance Lactate non-clearance

N = 166

N = 38N = 128

Non-clearance is decrease in lactate < 10%

Lactate Non-

clearance

Lactate clearance

ScvO2 < 70% 3 20 23

ScvO2 ≥ 70% 11 114 125

14 134 148

P = 0.457

No relation between ScvO2 > 70 and lactate clearance

Arnold RC. Shock 2009;32:35-39

ScvO2 and cardiac output in sepsis

Perner A. Acta Anaesthesiol Scand 2010;54:98-102

Arterial waveform derived variables

10,3 0,4 0,5 0,6 0,7 0,8 0,9

CVP

GEDVI

LVEDAI

SVV

SPV

PPV

AUC

29 full-text articles685 patients

Marik PE. Crit Care Med 2009;37:2642-2647

P < 0.001

P < 0.001

PPV SPV

SVV

Lansdorp B. BJA 2012: Epub ahead of print

Predictive value of PLR test

10,6

Semirecumbent starting

Supine starting

Arrhythmias

Sinus rhythm

Partial support

Controlled ventilation

PLR-cPP

PLR-cCO

Area Under Curve

0,80

P < 0.001

9 full-text articles353 patients

Cavallaro F. Intensive Care Med 2010;36:1475-1483

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-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20

CVP (mm Hg)

Increase in CVP

Venous ReturnCardiac Output

(l/min)

PEEP increase

Increase in CVP

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1

2

3

4

5

6

-6 -4 -2 0 2 4 6 8 10 12 14 16 18 20

CVP (mm Hg)

Venous ReturnCardiac Output

(l/min)

Dopamine or Norepi in patients with shock

0

5

10

15

20

25

30

Arrhythmic events

NorepenephrineDopamine

%

De Backer D. N Engl J Med 2010;362:779-789

0

5

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15

20

25

Arrhythmias A. fib VT VF0,51,0

11,012,4

1,22,4

20,5

24,1

Dopa NE

*%

De Backer D. N Engl J Med 2010;362;779-789

Dopamine or Norepi in patients with shock

De Backer D. N Engl J Med 2010;362:779-789

Norepinephrine and preload

Before After

CI (l/min/m2) 3.2 ± 1.0 3.6 ± 1.1

GEDVI (ml/m2) 694 ± 148 742 ± 168

Septic shockN = 105

Decreased SVV from13 ± 6 to 9 ± 5%

Only patients with a low EF (< 45%) and an increasein MAP > 75 mm Hg had no increase in CI

Hamzaoui O. Crit Care 2010;14:R142

Vasodilatory shock - N = 21

NE 0.20 ± 0.18μg/kg/min.

NE 0.29 ± 0.18μg/kg/min.

NE 0.42 ± 0.31μg/kg/min.

Nygren A. Acta Anaesthesiol Scand 2010;54:814-820

Levosimendan and myocardial depression

Enrolment

ScreeningLVEF > 45%

48 hours

Dobu (5 μg/kg/min) +Norepinephrine (MAP 70)

Start

ScreeningLVEF < 45%

EchoHemodynamics

Gastric perfusion

24 hours

Levosimendan (0.2) ordobutamine (5 μg/kg/min)

Stop

EchoHemodynamics

Gastric perfusion

Morelli A. Intensive Care Med 2005;31:638-644

N = 28

Levosimendan and myocardial depression

Morelli A. Intensive Care Med 2005;31:638-644

LevosimendanLevosimendan DobutamineDobutamine

Baseline 24 h Baseline 24 h

EDVI (ml/m2) 75.8 ± 23.8 66.2 ± 24.6 ** 84.2 ± 25.1 82.9 ± 26.4

ESVI (ml/m2) 46.7 ± 21.9 36.9 ± 19.4 ** 52.4 ± 25.8 50.5 ± 25.3

LVEF (%) 37.1 ± 3.0 45.4 ± 8.4 ** 37.3 ± 2.6 40.8 ± 11.3

20

35

50

SVI LVSWI SVI LVSWI

Before After

Levosimendan Dobutamine

** **