Choice of fluid in sepsis University of Copenhagen Anders Perner Dept of Intensive Care, Rigshospitalet, University of Copenhagen Scandinavian Critical.

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Choice of fluid in sepsis University of Copenhagen Anders Perner Dept of Intensive Care, Rigshospitalet, University of Copenhagen Scandinavian Critical Care Trials Group Intensive Care Medicine COIs - Research support from B Braun, Fresenius, CSL Behring Honoraria from Ferring, LFP

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

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 TRIAL

Inclusion criteria Adult patients in the ICU AND Fulfil severe sepsis criteria within 24 h AND Need for fluid resuscitation 6S TRIAL

6S TRIAL 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 Age66 (56-75)67 (56-76) Time from ICU admin to rando 4 (1-13) 4 (1-13) SAPS II50 (40-60)51 (39-62) Acute kidney injury36%35% Shock84%84% Values are medians (IQRs) or numbers (%) 6S TRIAL

Trial fluid StarchRingers Volume, ml Day 1 (14 h)1500 ( )1500 ( ) Day ( )1000 ( ) Day 3500 (0-1000)425 (0-500) Day 40 (0-500) Day 50 (0-500) Total (90 days)3000 ( )3000 ( ) 6S TRIAL

Fluid volumes and balances 6S TRIAL

180 g HES

Starch increased…. 6S TRIAL

Number needed to harm…. 13 6S TRIAL

6S TRIAL ICM 2013; 39: 1936

Meta-analysis of HES130 vs. crystalloid/HA in sepsis Mortality RR 1.1 ( ) BMJ 2013; 346: f839

Starch increased…. 6S TRIAL

ESICM S TRIAL Earlier use of RRT with starch

RRT and risk of death 6S TRIAL NEJM 2012

RRT and risk of death 6S TRIAL NEJM 2012

Meta-analysis of HES130 vs. crystalloid/HA in sepsis RRT RR 1.4 ( ) BMJ 2013; 346: f839

Starch increased bleeding 6S TRIAL ICM (12):2126

6S TRIAL P=0.001 Earlier bleeding with starch ICM (12):2126

Bleeding and risk of death 6S TRIAL ICM (12):2126

StarchRinger’s SF-36P 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 6S TRIAL Reduced QoL at 1-year with starch Critical Care 2013; 17: R58

The 6S summary 6S TRIAL 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?

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 CHESTNaCl vs 6% HES130 n= S trialRinger vs 6% HES130 n= CRYSTMAS NaCl vs 6% HES130 n= 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 ( ), p=0.03 Low risk of method. bias High risk of method. bias RR 0.49 ( ), p=0.01 Test of heterogeneity p<0.01

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

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

Shall we use albumin in sepsis?

Fraud? 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

Sept 24 th 2013

3241

6S TRIAL TRISS TRIAL