Choice of fluid in sepsis University of Copenhagen Anders Perner Dept of Intensive Care, Rigshospitalet, University of Copenhagen Scandinavian Critical Care Trials GroupIntensive Care MedicineCOIs - 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 Ringers acetate (Tetraspan) or Ringers 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 StarchRingers 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