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Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

ABSTRACT: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis.The 6S trial will randomize 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer's acetate or Ringer's acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%.The 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed.ClinicalTrials.gov: NCT00962156.

SUBMITTER: Perner A

PROVIDER: S-EPMC3040153 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

Perner Anders A Haase Nicolai N Wetterslev Jørn J Aneman Anders A Tenhunen Jyrki J Guttormsen Anne Berit AB Klemenzson Gudmundur G Pott Frank F Bødker Karen Doris KD Bådstøløkken Per Martin PM Bendtsen Asger A Søe-Jensen Peter P Tousi Hamid H Bestle Morten M Pawlowicz Malgorzata M Winding Robert R Bülow Hans-Henrik HH Kancir Claude C Steensen Morten M Nielsen Jonas J Fogh Bjarne B Madsen Kristian R KR Larsen Nils H NH Carlsson Marcela M Wiis Jørgen J Petersen John Asger JA Iversen Susanne S Schøidt Ole O Leivdal Siv S Berezowicz Pawel P Pettilä Ville V Ruokonen Esko E Klepstad Pål P Karlsson Sari S Kaukonen Maija M Rutanen Juha J Karason Sigurbergur S Kjældgaard Anne Lene AL Holst Lars Broksø LB Wernerman Jan J

Trials 20110127

<h4>Background</h4>By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis.<h4>Methods/design</h4>The 6S tria ...[more]

PMID: 21269526

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Project description:There are limited data on the efficacy of early fluid resuscitation with third-generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported.In this randomized, controlled, double-blind trial, 48 patients with severe burn injury were assigned to receive either lactated Ringer's solution plus 6% HES 130/0.4 in a ratio of 2:1 or lactated Ringer's solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality.Three-day totals of administered resuscitation fluid (medians) were 21,190 mL in the lactated Ringer's group and 19,535 mL in the HES group (HES: -1,213 mL; P?=?0.39). Creatinine levels from day 1 to 3 (HES: +0.4 ?mol/L; 95% confidence interval (CI) -18.7 to 19.5; P?=?0.97) and urinary outputs from day 1 to 3 (HES: -58 mL; 95% CI -400 to 283; P?=?0.90) were not different. Six patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P?=?0.95). Length of ICU stay (HES vs. lactated Ringer's: 28 vs. 24 days; P?=?0.80) and length of hospital stay (31 vs. 29 days; P?=?0.57) were similar. Twenty-eight-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P?=?0.95), and in-hospital mortality was 8 in the HES group vs. 5 patients in the lactated Ringer's group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P?=?0.31).There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to lactated Ringer's solution would lead to a volume-sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus lactated Ringer's solution could not be considered superior to lactated Ringer's solution alone.ClinicalTrials.gov NCT01012648.

Project description:ObjectiveTo assess the effects of fluid therapy with hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin on mortality, kidney injury, bleeding, and serious adverse events in patients with sepsis.DesignSystematic review with meta-analyses and trial sequential analyses of randomised clinical trials.Data sourcesCochrane Library, Medline, Embase, Biosis Previews, Science Citation Index Expanded, CINAHL, Current Controlled Trials, Clinicaltrials.gov, and Centerwatch to September 2012; hand search of reference lists and other systematic reviews; contact with authors and relevant pharmaceutical companies.Study selectionEligible trials were randomised clinical trials comparing hydroxyethyl starch 130/0.38-0.45 with either crystalloid or human albumin in patients with sepsis. Published and unpublished trials were included irrespective of language and predefined outcomes.Data extractionTwo reviewers independently assessed studies for inclusion and extracted data on methods, interventions, outcomes, and risk of bias. Risk ratios and mean differences with 95% confidence intervals were estimated with fixed and random effects models.ResultsNine trials that randomised 3456 patients with sepsis were included. Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin did not affect the relative risk of death (1.04, 95% confidence interval 0.89 to 1.22, 3414 patients, eight trials), but in the predefined analysis of trials with low risk of bias the relative risk of death was 1.11 (1.00 to 1.23, trial sequential analysis (TSA) adjusted 95% confidence interval 0.95 to 1.29, 3016 patients, four trials). In the hydroxyethyl starch group, renal replacement therapy was used more (1.36, 1.08 to 1.72, TSA adjusted 1.03 to 1.80, 1311 patients, five trials), and the relative risk of acute kidney injury was 1.18 (0.99 to 1.40, TSA adjusted 0.90 to 1.54, 994 patients, four trials). More patients in the hydroxyethyl starch group were transfused with red blood cells (1.29, 1.13 to 1.48, TSA adjusted 1.10 to 1.51, 973 patients, three trials), and more patients had serious adverse events (1.30, 1.02 to 1.67, TSA adjusted 0.93 to 1.83, 1069 patients, four trials). The transfused volume of red blood cells did not differ between the groups (mean difference 65 mL, 95% confidence interval -20 to 149 mL, three trials).ConclusionIn conventional meta-analyses including recent trial data, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin increased the use of renal replacement therapy and transfusion with red blood cells, and resulted in more serious adverse events in patients with sepsis. It seems unlikely that hydroxyethyl starch 130/0.38-0.45 provides overall clinical benefit for patients with sepsis.

Project description:Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-34.Hydroxyethyl starch (HES) is widely used for fluid resuscitation in ICUs, but its safety and efficacy have not been established in patients with severe sepsis.To assess the effects of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end-stage kidney failure in patients with severe sepsis.Multicenter, parallel-group, blinded, randomized clinical trial, in patients with severe sepsis.Patients with severe sepsis admitted to the ICU received fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal body weight per day.Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal replacement therapy compared with those receiving Ringer's acetate.

Project description:Whether third-generation hydroxyethyl starch solutions provoke kidney injury or haemostatic abnormalities in patients having cardiac surgery remains unclear. We tested the hypotheses that intra-operative administration of a third-generation starch does not worsen postoperative kidney function or haemostasis in cardiac surgical patients compared with human albumin 5%. This triple-blind, non-inferiority, clinical trial randomly allocated patients aged 40-85 who underwent elective aortic valve replacement, with or without coronary artery bypass grafting, to plasma volume replacement with 6% starch 130/0.4 vs. 5% human albumin. Our primary outcome was postoperative urinary neutrophil gelatinase-associated lipocalin concentrations, a sensitive and early marker of postoperative kidney injury. Secondarily, we evaluated urinary interleukin-18; acute kidney injury using creatinine RIFLE criteria, coagulation measures, platelet count and function. Non-inferiority (delta 15%) was assessed with correction for multiple comparisons. We enrolled 141 patients (69 starch, 72 albumin) as planned. Results of the primary analysis demonstrated that postoperative urine neutrophil gelatinase-associated lipocalin (median (IQR [range])) was slightly lower with hydroxyethyl starch (5 (1-68 [0-996]) ng.ml-1 ) vs. albumin (5 (2-74 [0-1604]) ng.ml-1 ), although not non-inferior [ratio of geometric means (95%CI) 0.91 (0.57, 1.44); p = 0.15] due to higher than expected variability. Urine interleukin-18 concentrations were reduced, but interleukin-18 and kidney injury were again not non-inferior. Of 11 individual coagulation measures, platelet count and function, nine were non-inferior to albumin. Two remaining measures, thromboelastographic R value and arachidonic acid-induced platelet aggregation, were clinically similar but with wide confidence intervals. Starch administration during cardiac surgery produced similar observed effects on postoperative kidney function, coagulation, platelet count and platelet function compared with albumin, though greater than expected variability and wide confidence intervals precluded the conclusion of non-inferiority. Long-term mortality and kidney function appeared similar between starch and albumin.

Dataset Information

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

Publications

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

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