Fluid resuscitation in septic shock

Anders Perner
Dept of Intensive Care, Rigshospitalet, University of Copenhagen
Scandinavian Critical Care Trials Group
www.ssai.info/research/SCCTG
Intensive Care Medicine
http://icmjournal.esicm.org/index.html
COIs - Research support from B Braun, Fresenius, CSL Behring
Honoraria from Ferring, LFB

University of
Copenhagen

Fluid resuscitation in septic shock

Triggers?
Which fluid?

How much?

Administer 30 ml/kg crystalloid for

hypotension or lactate > 4 mM

ICM 2013;39:165
CCM 2013;41:580

Hypotension a trigger for fluid

resuscitation in sepsis?
MAP > 65 associated to survival in septic
shock Varpula ICM 2005; 31: 1066

Goal-directed fluid therapy of patients

with hypotension or lactate > 4 mM

Rivers et al. NEJM 2001

Lactate > 4 mM as trigger for fluid in sepsis?

Rivers et al. NEJM 2001

Lower lactate trigger level?

SHOCK, Vol. 38, No. 1, pp. 4-10, 2012

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Lower lactate trigger level?

TRIAL

Fluid resuscitation in septic shock

Triggers?
Which fluid?

How much?

ICM 2013;39:165
CCM 2013;41:580

6S
TRIAL

6S
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Investigator-initiated & publicly-funded

6S
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Investigator-initiated & publicly-funded

High internal validity
Pre-publiced protocol and SAP
Five-flod blinding
100% follow-up

6S
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Investigator-initiated & publicly-funded

High internal validity
Pre-publiced protocol and SAP
Five-flod blinding
100% follow-up
High external validity
Pragmatic design
50% non-university hospitals
66% inclusion rate, simple inclusion and
few exclusion criteria

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Baseline characteristics
Group

Starch

Ringers

Numbers

398

400

Age

66 (56-75)

67 (56-76)

4 (1-13)

4 (1-13)

SAPS II

50 (40-60)

51 (39-62)

Acute kidney injury

36%

35%

Shock

84%

84%

Time from ICU admin to rando

Values are medians (IQRs) or numbers (%)

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Trial fluid
Starch

Ringers

Volume, ml

Volume, ml

Day 1 (14 h)

1500 (1000-1500)

1500 (1000-1550)

Day 2

1000 (300-1500)

1000 (500-1500)

Day 3

500 (0-1000)

425 (0-500)

Day 4

0 (0-500)

0 (0-500)

Day 5

0 (0-500)

0 (0-500)

3000 (1500-5000)

3000 (1800-5500)

Total (90 days)

Starch increased.

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Number needed to harm.

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ICM 2013; 39: 1936

Meta-analysis of HES130 vs. crystalloid/HA in sepsis

Mortality

RR 1.1 (1.0-1.2)

BMJ 2013; 346: f839

Starch increased.
Relative risk
increase
1.35
(1.01-1.80)

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RG Mller et al ESICM 2013

Meta-analysis of HES130 vs. crystalloid/HA in sepsis

Renal replacement therapy

RR 1.4 (1.1-1.7)

BMJ 2013; 346: f839

Bleeding outcomes

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ICM 2013, e-pub

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Time to bleeding

TRIAL

P=0.001

ICM 2013, e-pub

New data

The CRISTAL trial JAMA Oct. 2013

Open-label trial in 57 ICUs in 4 countries in a 9-year
period
ICU patients in shock
Randomisation by envelopes, fixed block size of 4
Any colloid (maily HES) vs. any crystalloid (maily
saline)

P<0.00000
P<0.001

Primary outcome

90-day mortality

The effect of bias on mortality in HES trials in

sepsis

Low risk of method. bias

RR 1.11 (1.01-1.23), p=0.03

High risk of method. bias

RR 0.49 (0.28-0.85), p=0.01

Test of heterogeneity
p=0.004

(BMJ 2013; 346: f839)

ICM 2013;39:165
CCM 2013;41:580

Shall we use albumin in sepsis?

HES comparator / Non-septic patient

Fraud?

Kids

HES comparator / Non-septic patient

Delaney et al CCM 2010

SAFE Albumin vs. Saline

Septic pts outcome

Finfer S et al. ICM 2010

Multivariate analyses

Finfer S et al. ICM 2010

Shall we use albumin in sepsis?

Probably not

Coming trial results

EARSS - 20% HA vs saline in septic shock

ALBIOS - 20% HA vs saline in severe sepsis

www.NEJM.org Sept 24th 2013

www.NEJM.org Sept 24th 2013

Fluid resuscitation in septic shock

Triggers?
Which fluid?

How much?

How much fluid in sepsis?

Continued as long as hemodynamics

improve
ICM 2013;39:165
CCM 2013;41:580

Improved survival by resuscitation guided

by MAP, CVP

and

ScvO2

More fluid given

AJRCCM 2010

AJRCCM 2010

Fluid balance associated to mortality

Boyd et al, CCM 2011

Secondary analysis of the VASST cohort
793 septic shock patients; highly selected
13% inclusion rate

Fluid balance associated to mortality

+3L
+1L
+5L

+8L

Boyd et al, CCM 2011

Fluid volume not associated to mortality

Smith & Perner, Crit Care 2012

Prospective, multicenter cohort of 163

consecutive, unselected patients with septic
shock in 6 ICUs
Pts divided in higher and lower fluid volume
groups by the median fluid volume
Subgroup analysis of pts with 3 days of
shock

Characteristics dependent on fluid volume after the 1. and 3. day

SAPS II

SOFA
score

Lactate
mmol/l

ScvO2
%

Pressor
dose

Dialysis

Death
day 90

After the 1. day of shock, n=164

>4.0 L

54 (19)

11 (4)

3.4 (3.3)*

70 (14)

0.25 (0.3)

39%

46%

<4.0 L

54 (22)

11 (4)

2.0 (1.6)

73 (14)

0.18 (0.2)

39%

55%

After the 3. day of shock, n=95

>7.5 L

53 (21)

10 (5)

2.6 (1.7)*

74 (14)

0.16 (0.1)

38%

40%**

<7.5 L

55 (13)

10 (4)

1.9 (1.8)

74 (11)

0.15 (0.1)

33%

62%

Characteristics dependent on fluid volume after the 1. and 3. day

SAPS II

SOFA
score

Lactate
mmol/l

ScvO2
%

Pressor
dose

Dialysis

Death
day 90

After the 1. day of shock, n=164

>4.0 L

54 (19)

11 (4)

3.4 (3.3)*

70 (14)

0.25 (0.3)

39%

46%

<4.0 L

54 (22)

11 (4)

2.0 (1.6)

73 (14)

0.18 (0.2)

39%

55%

After the 3. day of shock, n=95

>7.5 L

53 (21)

10 (5)

2.6 (1.7)*

74 (14)

0.16 (0.1)

38%

40%**

<7.5 L

55 (13)

10 (4)

1.9 (1.8)

74 (11)

0.15 (0.1)

33%

62%

The cohort studies on fluid volumes

in septic shock show..
Differing results
Depend on population, disease severity,
timing, design: Fluid balance vs volume?
Inherent problems with confounding by
indication, time-dependency, repeated
exposure and competing risks

We give alot of non-resus fluids

Day 1

6S

SAFE

HES

Ringer

Albumin

Saline

Trial fluid

1.9

2.1

1.3

1.7

Other fluids

2.2

2.0

1.7

1.8

Total, L

4.1

4.1

3.0

3.5

Ratio

0.46

0.51

0.43

0.49

Fluid resuscitation in septic shock

Hypotension or high lactate (4 mM)

Give crystalloids
Avoid HES
Albumin?
Ensure hemodynamic improvement ScvO2 and lactate clearence
Watch cummulative fluid balance
Limit non-resuscitation fluids

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TRISS
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anders.perner@regionh.dk

Fluid balance associated to mortality

Murphy et al, Chest 2009

Retrospective, two-center cohort in US of
212 pts with septic shock AND ALI
Results complex

Fluid balance associated to mortality

Murphy et al, Chest 2009