"Colloids: What did we learn last year and what happened in the meantime?" 2nd Fluid Academy Day Antwerpen 2012 Rainer Gatz ICU physician Herlev Hospital Copenhagen, Denmark

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Swede n Denmark Ringer's“normal” saline

Rainer Gatz, Herlev, Denmark -november 2012 Bleck Scale of Evidence (BMJ 2000) Class 0: Things I believe Class 0a: Things I believe despite the available data Class 1: Randomised controlled clinical trials that agree with what I believe Class 2: Other prospectively collected data Class 3: Expert opinion Class 4: Randomised controlled clinical trials that don't agree with what I believe Class 5: What you believe that I don't. Thomas P Bleck Professor of Neurology, Neurosurgery, and Medicine, Northwestern University Feinberg School of Medicine 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Rainer Gatz, Herlev, Denmark -november 2012 my topics are: 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - the types of colloids - what we learnt last year - the state of the colloid-crystalloid debate - last year's trials on this subject - ongoing trials - recommendations for future use of starches - all within 15 minutes what we learnt last year - last year's trials on this subject

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Rainer Gatz, Herlev, Denmark -november 2012 What did we learn last year? in the eyes of the coagulation specialist “6% isooncotic hetastarch is better than gelatin”

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012 “colloids in general are not better than crystalloids in ICU patients “ “but seem to be better in severe sepsis, cardiac surgery and liver cirrhosis “

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012 What did we learn last year? “albumin is better for patients with liver disease“ “and seems to be beneficial in sepsis“

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012 What did we learn last year? “the last generation starches are perfectly acceptable and safe “

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012 “looking forward to small volume, hypertonic solutions with a colloid that is charged “

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012

an acknowledgement! this work has been done with much inspiration and information from the critical care mailing list ccm-l listowner David Crippen, Pittsburgh, USA 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" starches and their substitution degrees 0.7 Hetastarch 0.6 Hexastarch 0.5 Pentastarch 0.4 TetrastarchVoluven®0.42Tetraspan® derived from:maize potato gelatins - urea-linked gelatinHaemaccel® - succinylated gelatinGelofusin® albumin colloid types

Rainer Gatz, Herlev, Denmark -november 2012 colloid types 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" source: Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults Yunos et alii, JAMA 2012;308(15): SID (mEq/l) (without metabolisable anions)

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" colloid types albumin just a reminder: this is not a completely pure product, completely identical to the natural thing - produced by ethanol fractionation and chromatography - undergoes a virus inactivation process - contains impurities: protein aggregates and prekallikrein activator - contains additives: octanoate

ff Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" albumin - a 1953 tracer study Tracer Experiments With I181 Labeled Human Serum Albumin: Distribution And Degradation Studies Solomon A. Berson et alii, J Clin Invest., 1953, plasma vessel rich vessel poor 60%

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" albumin - a 1953 tracer study Tracer Experiments With I181 Labeled Human Serum Albumin: Distribution And Degradation Studies Solomon A. Berson et alii, J Clin Invest., 1953, "The apparent space of distribution in non-ascitic subjects averaged about 2.5 times the plasma volume. Two apparent rates of transfer between plasma and extravascular spaces with half times of approximately 3 and 24 hours, were observed."

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" albumin - transmembrane transport albondin Albondin-mediated capillary permeability to albumin Schnitzer JE, Oh P J Biol Chem 1994 Feb 25;269(8): "About 50% of albumin transport is dependent on binding to the endothelial cell surface glycoprotein, albondin. The remaining, binding- and concentration-independent transport could occur through intercellular junctions and/or fluidphase transport via vesicular transcytosis and/or transendothelial channels." albumin - transmembrane transportalbondin

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" albumin genetically determined analbuminaemia Analbuminemia: Three cases resulting from different point mutations in the albumin gene Proc. Nati. Acad. Sci. USA Vol. 91, pp , September 1994 Scott Watkins, Jeanne Madison, Monica Galliano, Lorenzo Minchiotti, and Frank W. Putnam "Analbuminemia was reported in a 39-yr-old Italian man.... Analysis by rocket electrophoresis gave a serum albumin value of 5 mg/dl. The subject did not exhibit edema and was essentially asymptomatic."

october2011EARSS, first results at ESICM january2012Simon et alii, two hit model of renal damage january2012Saw et alii, gelatin metaanalysis february 2012Muller et alii, HES and renal dysfunction march 2012Thomas-Rueddel et alii, gelatin metaanalysis may2012CRYSTMAS trial * june20126S trial june 2012BaSES trial, first results at ESA july2012PAL pilot study * august2012Bayer, colloids or crystalloids in shock reversal october2012CHEST trial october2012Albios study, first results at ESICM october2012Yunos et alii, chloride effect * results already communicated at last year's fluid academy day october2011EARSS, first results at ESICM january2012Simon et alii, two hit model of renal damage january2012Saw et alii, gelatin metaanalysis february 2012Muller et alii, HES and renal dysfunction march 2012Thomas-Rueddel et alii, gelatin metaanalysis may2012CRYSTMAS trial * june20126S trial june 2012BaSES trial, first results at ESA july2012PAL pilot study * august2012Bayer, colloids or crystalloids in shock reversal october2012CHEST trial october2012Albios study, first results at ESICM october2012Yunos et alii, chloride effect * results already communicated at last year's fluid academy day Rainer Gatz, Herlev, Denmark -november 2012 last year's developments - a timeline 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" october2011EARSS, first results at ESICM january2012Simon et alii, two hit model of renal damage january2012Saw et alii, gelatin metaanalysis february 2012Muller et alii, HES and renal dysfunction march 2012Thomas-Rueddel et alii, gelatin metaanalysis may2012CRYSTMAS trial * june20126S trial june 2012BaSES trial, first results at ESA july2012PAL pilot study * august2012Bayer, colloids or crystalloids in shock reversal october2012CHEST trial october2012Albios study, first results at ESICM october2012Yunos et alii, chloride effect * results already communicated at last year's fluid academy day

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" what DOES a clinician want to know? mortality morbidity renal injury and failure amount of bleeding amount of fluid needed for primary resuscitation cumulative fluid balance

The EARSS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" results as communciated at ESICM in Berlin, october 2011 NCT Early Albumin Resuscitation during Septic Shock Julien Charpentier, Jean Paul Mira, Hôpital Cochin, Paris

The EARSS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: prospective, multicentre, randomised, open clinical trial - eligible patients: septic shock of up to 6 hours duration - type of intervention: albumin versus 0.9% NaCl control group: 0.9% NaCl 100 ml /8h for 3 days albumin group:albumin 20% 20 g/8h for 3 days - primary outcome measure: 28 and 90 days mortality - secondary outcome measures: SOFA scores ICU and hospital length of stay incidence of renal failure and pulmonary oedema - type of trial: prospective, multicentre, randomised, open clinical trial - eligible patients: septic shock of up to 6 hours duration - type of intervention: albumin versus 0.9% NaCl control group: 0.9% NaCl 100 ml /8h for 3 days albumin group:albumin 20% 20 g/8h for 3 days - primary outcome measure: 28 and 90 days mortality - secondary outcome measures: SOFA scores ICU and hospital length of stay incidence of renal failure and pulmonary oedema

The EARSS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - number of patients included: 399 albumin group 393 control group - primary outcome results: 28 days mortality: albumin group:24.1% control group:26.3% P=0.43 subgroups: community acquired infection difference albumin versus control group P=0.29 nosocomial infection difference albumin versus control group P= days mortality albumin group:34.7% control group:35.1% P=0.94

The EARSS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results: ICU length of stay P=0.61 hospital length of stay P=0.45 incidence of renal failure oedema number with renal replacement therapy and creatinin levels virtually identical between both groups free of mechanical ventilation within 28 days:P=0.24

The EARSS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" quote from the presentation at ESICM Berlin "3 days hyperoncotic albumin administration is well tolerated"

Simon et alii, two hit model of renal damage Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Simon et alii, two hit model of renal damage Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: prospective randomised animal experiment - eligible patients: none, study done in 23 pigs - type of intervention: sham-treated group versus group with two-hit model combining haemorrhagic and septic shock - outcome measure: renal function and inflammatory response

creatinine clearance, ml/min, 12 hours after sepsis: Ringer's acetate:76 ± 23 6% HES 130/0.42 in acetate:97 ± 15 10% HES 200/0.5:13 ± 14 (significant) 4% gelatin in acetate:38 ± 8 (significant) sham treated:98 ± 48 Simon et alii, two hit model of renal damage Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" fluid balance, ml/kg BW, 12 hours after sepsis: 335 ± 94 in the Ringer's treated group versus 70 to 150 in the other groups (P< 0.05) creatinine clearance, ml/min, 12 hours after sepsis: Ringer's acetate:76 ± 23 6% HES 130/0.42 in acetate:97 ± 15 10% HES 200/0.5:13 ± 14 (significant) 4% gelatin in acetate:38 ± 8 (significant) sham treated:98 ± 48 histology, acute tubular necrosis score: Ringer's acetate:0.8 ± 0.3 6% HES 130/0.42 in acetate:1.8 ± % HES 200/0.5:2.2 ± 0.4 (significant) 4% gelatin in acetate:2.6 ± 0.5 (significant) sham treated:0.3 ± 0.6 histology, acute tubular necrosis score: Ringer's acetate:0.8 ± 0.3 6% HES 130/0.42 in acetate:1.8 ± % HES 200/0.5:2.2 ± 0.4 (significant) 4% gelatin in acetate:2.6 ± 0.5 (significant) sham treated:0.3 ± 0.6

Saw et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Saw et alii, gelatin metaanalysis

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: meta-analysis (studies using randomisation, no cross-over, with comparison of gelatin use to that of crystalloids or other colloids including isotonic albumin, but not other blood products) - eligible patients: patients in perioperative and critical care settings 30 randomised controlled trials involving 2709 patients, primary endpoint available in 14 studies with 1788 patients - primary outcome measure: hospital mortality, alternatively 28-day mortality - secondary outcome measures: incidence of acute renal failure total blood loss during study periods volume of blood transfused incidence of allergic reactions hospital length of stay - type of trial: meta-analysis (studies using randomisation, no cross-over, with comparison of gelatin use to that of crystalloids or other colloids including isotonic albumin, but not other blood products) - eligible patients: patients in perioperative and critical care settings 30 randomised controlled trials involving 2709 patients, primary endpoint available in 14 studies with 1788 patients - primary outcome measure: hospital mortality, alternatively 28-day mortality - secondary outcome measures: incidence of acute renal failure total blood loss during study periods volume of blood transfused incidence of allergic reactions hospital length of stay

Saw et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome result: - risk of mortality: gelatin versus all other types of fluids: (odds ratio 1.03, 95% confidence interval 0.80 to 1.32) not significantly different

Saw et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results: - amount of blood lossed: 19 studies with 1252 patients report this no significant differences - amount of blood transfused: 11 studies with 796 patients report this - gelatin versus all other types of fluids no significant differences - gelatin versus crystalloids weighted-mean-difference 180 ml 95% CI 8 to 354 ml - significant - incidence of acute renal failure: 5 studies with 431 patients report this no significant differences in the subgroup of gelatin versus HES treatment there were fewer cases of acute renal failure in the gelatin group, but the comparison was mainly with HES 200

Saw et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - concerns / comments: "The quality of the published studies on gelatin solutions was also unsatisfactory, with no study having both adequate allocation concealment and double-blinding."

Thomas-Rueddel et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Thomas-Rueddel et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" 40 RCTs published between 1976 and 2010 patients receiving gelatin for resuscitation in comparison to albumin or crystalloids 3275 patients included

Thomas-Rueddel et alii, gelatin metaanalysis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" "No study was adequately powered to investigate the frequency of patient-important outcomes." "Despite over 60 years of clinical practice, the safety and efficacy of gelatin cannot be reliably assessed in at least some settings in which it is currently used."

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Muller et alii, Fluid management and risk factors for renal dysfunction

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: observational multicenter study in 15 Southern French ICUs, two periods - eligible patients: patients without a history of renal failure and treated for severe sepsis and septic shock surviving after 24 hours - type of intervention: intervention based on the Surviving Sepsis Campaign in the second period - primary outcome measure: factors associated with renal dysfunction and renal replacement therapy - number of patients included: 388

Muller et alii, Fluid management and risk factors for renal dysfunction Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome results: factors independently associated with renal dysfunction: - male gender - increase in SAPS II scores - being a surgical patient - no decrease in SOFA scores during the first 24 hours - being treated during the interventional period of the study factors independently associated with renal replacement therapy: - need for vasopressors - baseline value of plasma creatinine - secondary outcome results: mortality rate in patients with renal dysfunction versus in those without renal dysfunction (48% versus 24%, P < 0.01) mortality rate in patients requiring RRT 52% versus 26% in those not requiring RRT (P < 0.01)

Muller et alii, Fluid management and risk factors for renal dysfunction Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Use of colloids 315 of 388 patients received colloids association with renal dysfunction (no versus yes): 185 (78%) versus 101 (86%)P=0.07 association with renal replacement therapy (no versus yes): 241 (81%) versus 74 (82%)P=0.82 “Despite being used in more than 80% of patients with severe sepsis and/or septic shock, the administration of HES 130/0.4 in the first 24 hours of management was not associated with the occurrence of renal dysfunction.”

The CRYSTMAS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

The CRYSTMAS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: randomised, prospective, multicenter, active-controlled, double- blind - eligible patients: patients with severe sepsis requiring fluid resuscitation in several French and German ICUs - type of intervention: HES 6% (130/0.4) (Voluven®) versus NaCl 0.9% to haemodynamic stability - primary outcome measure: amount of fluid to achieve haemodynamic stability - type of trial: randomised, prospective, multicenter, active-controlled, double- blind - eligible patients: patients with severe sepsis requiring fluid resuscitation in several French and German ICUs - type of intervention: HES 6% (130/0.4) (Voluven®) versus NaCl 0.9% to haemodynamic stability - primary outcome measure: amount of fluid to achieve haemodynamic stability

The CRYSTMAS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome measures: time to achieve haemodynamic stability ICU and hospital length of stay mortality total quantity of study drug infused over four consecutive days area under the curve of SOFA score acute renal failure - number of patients included: 196 randomised, 174 (88 / 86) with complete datasets - secondary outcome measures: time to achieve haemodynamic stability ICU and hospital length of stay mortality total quantity of study drug infused over four consecutive days area under the curve of SOFA score acute renal failure - number of patients included: 196 randomised, 174 (88 / 86) with complete datasets

The CRYSTMAS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome results: amount of fluid to achieve haemodynamic stability - HES 1400 ± 890ml - NaCl 0.9% 1700 ±1200ml (mean difference = 331 ±1033ml, 95% CI 21 to 640ml, P = 0.02) ==> ratio crystalloid to colloid needed to achieve the same haemodynamic goals: 1.21 SAFE trial:1.4, VISEP 1.6 (day 1), FIRST trial primary outcome results: amount of fluid to achieve haemodynamic stability - HES 1400 ± 890ml - NaCl 0.9% 1700 ±1200ml (mean difference = 331 ±1033ml, 95% CI 21 to 640ml, P = 0.02)

The CRYSTMAS study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results: time to achieve haemodynamic stability: - HES 11.8 ±10.1 hours - NaCl 0.9% 14.3 ±11.1 hours (difference not significant) acute renal failure 24 (25%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454) no difference between AKIN and RIFLE criteria no significant difference in ICU and hospital length of stay, total quantity of study drug infused over four consecutive days or area under the curve of SOFA score no difference in mortality, coagulation, transfusion requirement, incidence of infections or pruritus up to 90 days after treatment initiation

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Scandinavian Starch for Severe Sepsis / Septic Shock NEnglJMed 2012; 367: /0.42

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: investigator-initiated, multicenter, parallel-group, blinded trial, randomised, in Denmark, Norway, Finland, and Iceland - eligible patients: patients with severe sepsis - type of intervention: fluid resuscitation in the ICU with either 6% HES 130/0.42 or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day - primary outcome measure: was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization The 6S study - type of trial: investigator-initiated, multicenter, parallel-group, blinded trial, randomised, in Denmark, Norway, Finland, and Iceland - eligible patients: patients with severe sepsis - type of intervention: fluid resuscitation in the ICU with either 6% HES 130/0.42 or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day - primary outcome measure: was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome measures: death at 28 days death at the time of the latest follow-up assessment severe bleeding while the patient was in the ICU severe allergic reactions SOFA score at day 5 after randomization the development of acute kidney injury doubling of the plasma creatinine level in the ICU acidosis (arterial pH <7.35) in the ICU percentage of days alive without renal-replacement therapy days alive without mechanical ventilation days alive out of the hospital in the 90 days after randomization

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - planned subgroup analyses: patients with shock at the time of randomisation patients with acute kidney injury at the time of randomisation - type of analysis: modified intention-to-treat - statistical power: 800 patients needed for the study to have 80% power to show an absolute between-group difference of 10 percentage points in the primary outcome measure and a 5% rate of dependence on dialysis at 90 days - number of patients included: 804 patients underwent randomisation, 798 were included - planned subgroup analyses: patients with shock at the time of randomisation patients with acute kidney injury at the time of randomisation - type of analysis: modified intention-to-treat - statistical power: 800 patients needed for the study to have 80% power to show an absolute between-group difference of 10 percentage points in the primary outcome measure and a 5% rate of dependence on dialysis at 90 days - number of patients included: 804 patients underwent randomisation, 798 were included

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" “Trial fluid (6% HES 130/0.42 in Ringer's acetate (Tetraspan 6%®, B. Braun) or Ringer's acetate (Sterofundin ISO®, B. Braun)” SID (without metabolisable anions) 29 mEq/l

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome result: - death at 90 days: - HES 130/0.4: 201 of 398 patients (51%) - Ringer's acetate: 172 of 400 patients (43%) relative risk, % confidence interval (CI), 1.01 to 1.36; P = 0.03

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results - renal-replacement therapy: - HES 130/0.4: 87 patients (22%) - Ringer's acetate: 65 patients (16%) (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04) - severe bleeding: - HES 130/0.4: 38 patients (10%) - Ringer's acetate: 25 patients (6%) (relative risk, 1.52; 95% CI, 0.94 to 2.48; P = 0.09) - secondary outcome results - renal-replacement therapy: - HES 130/0.4: 87 patients (22%) - Ringer's acetate: 65 patients (16%) (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04) - severe bleeding: - HES 130/0.4: 38 patients (10%) - Ringer's acetate: 25 patients (6%) (relative risk, 1.52; 95% CI, 0.94 to 2.48; P = 0.09)

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" relative risks with 95% confidence intervals (CIs) for the primary outcome of death or dependence on dialysis at day 90, among all patients and in the two predefined subgroups

Fluid Therapy before and after Randomisation The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The 6S study source:

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" source: Fresenius share prices

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

The 6S study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" source:

Basel Starch Evaluation in Sepsis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: double-blind, randomised, controlled monocentric study - eligible patients: 240 consecutive patients with sepsis, severe sepsis and septic shock - type of intervention: volume therapy with Ringer's lactate and saline or HES 130/0.4 in the first five days of intensive care treatment

Basel Starch Evaluation in Sepsis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome measure: intensive care length of stay hospital length of stay mortality kidney function

Basel Starch Evaluation in Sepsis Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: single centre, prospective before and after study comparing three different treatment periods (not randomised, sequential groups) - eligible patients: consecutive patients with severe sepsis - type of intervention: fluid therapy directed at preset haemodynamic goals with - HES (predominantly 6% hydroxyethyl starch 130/0.4) in the first period - 4% gelatin in the second period - only crystalloids in the third period

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome measures: time to shock reversal (serum lactate <2.2 mmol/l and discontinuation of vasopressor use) required fluid volumes in patients with septic shock - secondary outcome measures: acute kidney injury (defined by RIFLE criteria) new need for renal replacement therapy ICU length of stay - number of patients included: hydroxyethyl starch: 360 gelatin: 352 only crystalloids: 334

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome results: all groups showed similar time to shock reversal more fluid was needed over the first 4 days in the crystalloid group: fluid ratio1.4:1 crystalloids to HES 1.1:1 crystalloids to gelatin

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome results: Total fluids day 1 to 4, in ml/kg: - HES205 ( ) (versus crystalloid P<0.01) - gelatin224 ( ) - crystalloid239 ( ) after day 5, fluid balance was more negative in the crystalloid group Total fluids day during ICU stay, in ml/kg: - HES790 ( ) (versus crystalloid P<0.001) - gelatin631 ( ) (versus crystalloid P<0.001) - crystalloid406 ( )

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results: intensive care unit length of stay (in days): - HES18 (8 - 30) (versus crystalloid P<0.001) - gelatin13 (6 - 24) (versus crystalloid P<0.001) - crystalloid10 (4 - 18) Acute kidney injury by RIFLE (number and %): - HES254 (71) (versus crystalloid P<0.001) - gelatin238 (68) (versus crystalloid P=0.014) - crystalloid195 (58)

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - secondary outcome results: no significant differences for: - ICU or hospital mortality - mean and maximum SOFA scores - hospital length of stay

Bayer et alii, colloids or crystalloids in shock reversal Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" concerns / comments: 24,326 surgical ICU patients were screened, 23,280 patients met exclusion criteria, including a total of 1,046 patients with severe sepsis or septic shock exclusion criteria - < 18 years - solid organ transplantation - renal failure requiring haemodialysis before ICU - extracorporeal membrane oxygenation - serum creatinine values missing at admission - admission during the 1 month wash-out period between changes in resuscitative fluid regimens

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study N Engl J Med, October 2012 DOI: /NEJMoa nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Stephen Streat on ccm-l, : (intensivist, Auckland, New Zealand) The protocol was published in ICM in January This was a 7000-patient trial which finished recruitment on 23rd January on schedule. It was done in 18 months, at an average recruitment rate of 75 patients per week. There was only a 2.9% loss to follow-up, mainly due to withdrawal of consent, and an 11% protocol violation rate. The study involved the administration of 4 million mls of fluids in bags of fluid! Tertiary outcomes (health economics etc.) will be analysed in Then they plan to follow-up practice with 'CHEST-TRIPS' in Rainer Gatz, Herlev, Denmark -november 2012 Stephen Streat on ccm-l, : (intensivist, Auckland, New Zealand) The protocol was published in ICM in January This was a 7000-patient trial which finished recruitment on 23rd January on schedule. It was done in 18 months, at an average recruitment rate of 75 patients per week. There was only a 2.9% loss to follow-up, mainly due to withdrawal of consent, and an 11% protocol violation rate. The study involved the administration of 4 million mls of fluids in bags of fluid! Tertiary outcomes (health economics etc.) will be analysed in Then they plan to follow-up practice with 'CHEST-TRIPS' in The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?"

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: prospective, multicentre, concealed, randomised controlled trial - eligible patients: 7000 patients planned to be recruited from 32 intensive care unit throughout Australia and New Zealand all pts admitted to the ICU and needing fluids, according to the treating physician, no strict treatment protocol - type of intervention: 6% HES (130/0.4) versus 0.9% sodium chloride for intravascular volume resuscitation in the Intensive Care Unit - type of trial: prospective, multicentre, concealed, randomised controlled trial - eligible patients: 7000 patients planned to be recruited from 32 intensive care unit throughout Australia and New Zealand all pts admitted to the ICU and needing fluids, according to the treating physician, no strict treatment protocol - type of intervention: 6% HES (130/0.4) versus 0.9% sodium chloride for intravascular volume resuscitation in the Intensive Care Unit

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome measure: 90-day all-cause mortality - secondary outcome measures: mortality in predefined subgroups incident renal failure (RIFLE criteria) Sequential Organ Failure Assessment (SOFA) score use of renal replacement therapy other organ failures (measured using SOFA) ICU mortality hospital mortality length of ICU stay quality of life assessment measured using EQ5D score in patients with traumatic brain injury, functional outcome measured using the Glasgow Outcome Score - primary outcome measure: 90-day all-cause mortality - secondary outcome measures: mortality in predefined subgroups incident renal failure (RIFLE criteria) Sequential Organ Failure Assessment (SOFA) score use of renal replacement therapy other organ failures (measured using SOFA) ICU mortality hospital mortality length of ICU stay quality of life assessment measured using EQ5D score in patients with traumatic brain injury, functional outcome measured using the Glasgow Outcome Score

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - planned subgroup analyses: patients admitted for trauma with traumatic brain injury patients admitted for trauma without traumatic brain injury patients with severe sepsis patients with pre-existing chronic renal failure in the absence of oliguria or anuria - type of analysis: intention-to-treat - statistical power: 90% power to detect an absolute difference of ≥3.5% in mortality 90% power to detect a relative risk increase of renal failure by number of patients included: 7000

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study primary outcome result 90-day all-cause mortality: - HES group:597 of 3315 (18.0%) - saline group:566 of 3336 (17.0%) (relative risk in the HES group, % confidence interval, 0.96 to 1.18; P=0.26

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study primary outcome results

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study secondary outcome results

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study secondary outcome results

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" The CHEST study source: supplement at

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" controversy on ccm-l! Ho-hum - elderly patients in first world ICUs don't differ whether treated with crystalloid or colloid. Still want to know how to apply this to a 25 year old with a 3 day old perf appendix or in a 25 year old who blows up like a Michelin Man on Ringer's but maintains normal body weight (and most other parameters) on starch (or gelatin back in the day). Eric intensivist, Durban, South Africa De: Eric Hodgson Para: International Critical Care Medicine Group

Rainer Gatz, Herlev, Denmark -november 2012 The CHEST study 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" controversy on ccm-l! I see such patients and don't use HES and they don't bloat.You are overtreating with crystalloids in that case. 1 liter of HES cannot miraculously make a patient less bloaty. Prasanna thoracic surgeon, Bangalore, India answer by Prasanna, ccm-l, : De: Prasanna Simha Para: International Critical Care Medicine Group

The Albios study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Efficacy of Albumin Administration for Volume Replacement in Patients With Severe Sepsis or Septic Shock the ALBumin Italian Outcome Sepsis (ALBIOS) Study

The Albios study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - type of trial: interventional, randomised, open label - eligible patients: severely septic and septic shock patients admitted to ICU - type of intervention: albumin to plasma level of >=30g/l versus crystalloid infusion, to predefined haemodynamic goals according to the early-goal directed therapy (infusion of other colloids was not allowed) - type of trial: interventional, randomised, open label - eligible patients: severely septic and septic shock patients admitted to ICU - type of intervention: albumin to plasma level of >=30g/l versus crystalloid infusion, to predefined haemodynamic goals according to the early-goal directed therapy (infusion of other colloids was not allowed)

The Albios study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome measures: 28-day, 90-day survival - secondary outcome measures: number and severity of organ dysfunction (as recorded by the SOFA score) hospital and intensive care unit (ICU) length of stay - number of patients included: 1815 patients, interim analysis of DSMB advised to continue after 1300 patients 908 in the albumin, 907 in the crystalloid group - primary outcome measures: 28-day, 90-day survival - secondary outcome measures: number and severity of organ dysfunction (as recorded by the SOFA score) hospital and intensive care unit (ICU) length of stay - number of patients included: 1815 patients, interim analysis of DSMB advised to continue after 1300 patients 908 in the albumin, 907 in the crystalloid group

The Albios study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" - primary outcome results: (no final results yet; only results till hospital discharge) mortality at hospital discharge: - 36% for the albumin group, 37% for the crystalloid group (no significant difference) - secondary outcome measures: not available yet

The Albios study Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" comment on ccm-l, Septic shock has a trend to low mortality with albumin (p=0.056). We will have to wait for final results. Murillo Santucci Cesar de Assunção São Paulo, Brasil

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" JAMA 2012;308(15):

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" “Conclusion: The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT.” 0.7 l of gelatin per patient in the control period, no artificial colloids administered during the intervention period 154 / 120 possible confounders: succinylated gelatin (as used in this study) contains Na / Cl 154 / 120 mmol/l, is thus naturally "balanced"

Rainer Gatz, Herlev, Denmark -november 2012 open studies 2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" CRISTAL study Efficacy and Safety of Colloids Versus Crystalloids for Fluid Resuscitation in Critically Ill Patients NCT BaSES trial Basel Starch Evaluation in Sepsis NCT RASP trial Lactated Ringer Versus Albumin in Early Sepsis Therapy NCT Efficacy and Safety of Colloids Versus Crystalloids for Fluid Resuscitation in Critically Ill Patients NCT and many, many more....

2nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" Rainer Gatz, Herlev, Denmark -november 2012 Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients Konrad Reinhart, Anders Perner, Charles L. Sprung, Roman Jaeschke, Frederique Schortgen, A. B. Johan Groeneveld, Richard Beale and Christiane S. Hartog Intensive Care Medicine Volume 38, Number 3 (2012), We recommend not to use HES with molecular weight >=200 kDa and/or degree of substitution >0.4 in patients with severe sepsis or risk of acute kidney injury and suggest not to use 6% HES 130/0.4 or gelatin in these populations. We recommend not to use colloids in patients with head injury and not to administer gelatins and HES in organ donors. We suggest not to use hyperoncotic solutions for fluid resuscitation. We conclude and recommend that any new colloid should be introduced into clinical practice only after its patient-important safety parameters are established.

Rainer Gatz, Herlev, Denmark -november nd Fluid Academy Day Antwerpen 2012 "Colloids: What did we learn last year and what happened in the meantime?" my two conflicts of interest