Choice of fluid in sepsis

University ofCopenhagen

Anders Perner

Dept of Intensive Care, Rigshospitalet, University of Copenhagen

Scandinavian Critical Care Trials Groupwww.ssai.info/research/SCCTG

Intensive Care Medicinehttp://icmjournal.esicm.org/index.html

COIs - Research support from B Braun, Fresenius, CSL Behring Honoraria from Ferring, LFP

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

6STRIAL

Investigator-initiated & publicly-funded

6STRIAL

Investigator-initiated & publicly-funded

High internal validityPre-publiced protocol and SAPFive-fold blinding100% follow-up

6STRIAL

Investigator-initiated & publicly-funded

High internal validityPre-publiced protocol and SAPFive-fold blinding100% follow-up

High external validityPragmatic design50% non-university hospitals66% inclusion rate, simple inclusion and

few exclusion criteria

6STRIAL

Inclusion criteria

Adult patients in the ICUAND

Fulfil severe sepsis criteria within 24 hAND

Need for fluid resuscitation

6STRIAL

6STRIAL

Trial fluid# 1

Trial fluid# 2

Trial fluid# X

Masked trial fluid up till 33 ml/IBW-kg/day

Intervention

6% HES 130/0.42 in Ringer’s acetate (Tetraspan)

or

Ringer’s acetate (Sterofundin)

Baseline characteristics

StarchRingers

Numbers 398 400

Age 66 (56-75) 67 (56-76)

Time from ICU admin to rando 4 (1-13) 4 (1-13)

SAPS II 50 (40-60) 51 (39-62)

Acute kidney injury 36% 35%

Shock 84% 84%Values are medians (IQRs) or numbers (%)

6STRIAL

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)

Total (90 days) 3000 (1500-5000) 3000 (1800-5500)

6STRIAL

Fluid volumes and balances6STRIAL

180 g HES

Starch increased….6STRIAL

Number needed to harm….

136STRIAL

6STRIAL

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….6STRIAL

ESICM 2013

6STRIALEarlier use of RRT with starch

RRT and risk of death6STRIAL

NEJM 2012

RRT and risk of death6STRIAL

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 bleeding6STRIAL

ICM 2013 39(12):2126

6STRIAL

P=0.001

Earlier bleeding with starch

ICM 2013 39(12):2126

Bleeding and risk of death6STRIAL

ICM 2013 39(12):2126

  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

6STRIAL

Reduced QoL at 1-year with starch

Critical Care 2013; 17: R58

The 6S summary6STRIAL

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

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?

Lower volume

Higher 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

Ratio

CHEST NaCl vs 6% HES130 n=7000 1.26S trial Ringer vs 6% HES130 n= 800 1.1CRYSTMAS NaCl vs 6% HES130 n= 196 1.0

Crystalloid to HES volume ratio in blinded trials

New data

• Open-label trial

• ICU patients in shock

• Randomisation by envelopes, fixed block size of 4

• Any colloid (maily HES) vs. any crystalloid (maily saline)

The CRISTAL trial JAMA Oct. 2013

Primary outcome

90-day mortality

•High risk of bias in 3 domains

•Unblinded

•Uncertain allocation concealment

•Baseline imbalance

The CRISTAL trial JAMA Oct. 2013

The effect of bias on mortality in HES trials in sepsis

RR 1.11 (1.01-1.23), p=0.03

Low risk of method. bias

High risk of method. bias

RR 0.49 (0.28-0.85), p=0.01

Test of heterogeneity p<0.01

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

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

Shall we use albumin in sepsis?

Fraud?

HES comparator / Non-septic patient

HES comparator / Non-septic patient

Kids

SAFE septic pts – outcome

Finfer S. ICM 2010

Multivariate analyses

Finfer S. ICM 2010

Coming trial results…

EARSS - 20% HA vs saline in septic shock

ALBIOS - 20% HA vs saline in severe sepsis

Shall we use albumin in sepsis?

Probably not

Until then.....................crystalloids for sepsis

www.NEJM.org Sept 24th 2013

www.NEJM.org Sept 24th 2013

3 2 4 1

anders.perner@regionh.dk

6S TRIAL

TRISS TRIAL