Choice of fluid in sepsis
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, LFP
University of
Copenhagen
ICM 2013;39:165
CCM 2013;41:580
6S
TRIAL
6S
TRIAL
Investigator-initiated & publicly-funded
6S
TRIAL
Investigator-initiated & publicly-funded
High internal validity
Pre-publiced protocol and SAP
Five-fold blinding
100% follow-up
6S
TRIAL
Investigator-initiated & publicly-funded
High internal validity
Pre-publiced protocol and SAP
Five-fold blinding
100% follow-up
High external validity
Pragmatic design
50% non-university hospitals
66% inclusion rate, simple inclusion and
few exclusion criteria
6S
Inclusion criteria
Adult patients in the ICU
AND
Fulfil severe sepsis criteria within 24 h
AND
Need for fluid resuscitation
TRIAL
6S
TRIAL
Intervention
6% HES 130/0.42 in Ringer’s acetate (Tetraspan)
or
Ringer’s acetate (Sterofundin)
Masked trial fluid up till 33 ml/IBW-kg/day
Trial fluid
#1
Trial fluid
#2
Trial fluid
#X
6S
TRIAL
Baseline characteristics
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%
Time from ICU admin to rando
Shock
84%
Values are medians (IQRs) or numbers (%)
84%
6S
TRIAL
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)
6S
TRIAL
Fluid volumes and balances
180 g HES
Starch increased….
6S
TRIAL
6S
TRIAL
Number needed to harm….
6S
TRIAL
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….
6S
TRIAL
Earlier use of RRT with starch
6S
TRIAL
ESICM 2013
6S
RRT and risk of death
TRIAL
NEJM 2012
6S
RRT and risk of death
TRIAL
NEJM 2012
Meta-analysis of HES130 vs. crystalloid/HA in sepsis
RRT
RR 1.4 (1.1-1.7)
BMJ 2013; 346: f839
Starch increased bleeding
6S
TRIAL
ICM 2013 39(12):2126
6S
Earlier bleeding with starch
TRIAL
P=0.001
ICM 2013 39(12):2126
Bleeding and risk of death
6S
TRIAL
ICM 2013 39(12):2126
6S
TRIAL
Reduced QoL at 1-year with starch
Starch
Ringer’s
SF-36
P value
Physical component
summary score
37 (29-48)
40 (32-51)
0.23
Mental component
summary score
45 (36-55)
53 (39-60)
0.01
Critical Care 2013; 17: R58
The 6S summary
Higest methodological standards
Tested starch in clinical practice
Included patients fairly early
Gave fluid volumes early and well within the
labelled dose
Biological plausibility – Cause-and-effect
6S
TRIAL
A ‘correct’ indication for starch?
Existing data do not support ‘correct’ indication
for starch
Haase et al. Critical Care 2013
A safe starch dose?
A safe starch dose?
Higher volume
Lower volume
Cochrane CD007594
CHEST: HES 130/0.4 vs saline in 7,000 general ICU patients
Increased use of RRT, RBCs and
SAEs with mean 500 ml of starch
Myburgh et al. NEJM 2012
Crystalloid to HES volume ratio in blinded trials
Ratio
CHEST
6S trial
NaCl vs 6% HES130
Ringer vs 6% HES130
CRYSTMAS NaCl vs 6% HES130
n=7000
n= 800
n= 196 1.0
1.2
1.1
New data
The CRISTAL trial JAMA Oct. 2013
• Open-label trial
• ICU patients in shock
• Randomisation by envelopes, fixed block size of 4
• Any colloid (maily HES) vs. any crystalloid (maily
saline)
Primary outcome
90-day mortality
The CRISTAL trial JAMA Oct. 2013
•High risk of bias in 3 domains
•Unblinded
•Uncertain allocation concealment
•Baseline imbalance
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<0.01
ICM 2013;39:165
CCM 2013;41:580
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
SAFE septic pts – outcome
Finfer S. ICM 2010
Multivariate analyses
Finfer S. 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
Until then.....................
crystalloids for sepsis
www.NEJM.org Sept 24th 2013
3
2
4
1
www.NEJM.org Sept 24th 2013
6S
TRISS
TRIAL
TRIAL
anders.perner@regionh.dk