Publication

• Title: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis
• Acronym: 6S
• Year: 2012
• Journal published in: The New England Journal of Medicine
• Citation: Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134.

Context & Rationale

• Background

  • Hydroxyethyl starch (HES) solutions were widely used for intravascular volume resuscitation in sepsis and septic shock, partly driven by perceived haemodynamic efficiency (greater plasma volume expansion per infused millilitre than crystalloids).
  • Concerns existed about HES-associated acute kidney injury and coagulopathy; however, before 2012 there was ongoing debate about whether “newer” low–molecular weight, low–substitution starches (e.g., tetrastarch preparations) were safer than older products.
  • Severe sepsis RCT evidence with older starch formulations suggested clinically important harm, including increased renal failure and renal-replacement therapy (RRT), raising the question of whether any HES should be used in sepsis.¹
  • High-quality blinded evidence comparing a commonly used “modern” HES preparation against a balanced crystalloid, with patient-centred outcomes, was needed to resolve equipoise in routine ICU practice.
• Research Question/Hypothesis

  • In adults with severe sepsis requiring fluid resuscitation in ICU, does resuscitation with 6% HES 130/0.42 (balanced carrier solution) compared with Ringer’s acetate reduce death and/or dialysis dependence at 90 days?
• Why This Matters

  • Choice of resuscitation fluid is near-universal in septic shock; small relative effects can translate to large absolute population impact.
  • Renal injury, bleeding, and mortality are hard outcomes that determine long-term morbidity and resource utilisation; clarifying HES safety in sepsis is therefore high-stakes for ICU practice.
  • The trial tests whether physiological plausibility (volume expansion efficiency) translates into meaningful clinical benefit without unacceptable harm.

Design & Methods

• Research Question: Among adults with severe sepsis in ICU requiring fluid resuscitation, does 6% HES 130/0.42 versus Ringer’s acetate improve the 90-day composite of death or dialysis dependence?
• Study Type: Investigator-initiated, multicentre, randomised, parallel-group, double-blind trial conducted in Scandinavian ICUs (26 ICUs across Denmark, Finland, Iceland, Norway, and Sweden); stratified randomisation (shock at randomisation, haematological malignancy, and university vs non-university hospital).
• Population:
  • Adults (≥18 years) in ICU with severe sepsis within the previous 24 hours and judged by treating clinicians to require intravascular volume expansion.
  • Key exclusions included: receipt of >1000 mL synthetic colloid within 24 hours pre-randomisation; ongoing renal-replacement therapy at screening; and other protocolised exclusions (e.g., conditions where trial fluid use was considered inappropriate or unsafe).
• Intervention:
  • 6% hydroxyethyl starch 130/0.42 in a balanced electrolyte solution (HES 130/0.42) used as the trial fluid for intravascular volume resuscitation in ICU.
  • Maximum daily dose of trial fluid: 33 mL/kg ideal body weight; if additional volume expansion was required after reaching the cap, open-label Ringer’s acetate was used.
  • Trial fluid was stopped permanently in protocol-defined severe adverse reactions (e.g., severe bleeding, severe allergic reaction) or if renal-replacement therapy was initiated.
• Comparison:
  • Ringer’s acetate (balanced crystalloid) used as the trial fluid for intravascular volume resuscitation in ICU, with the same daily cap (33 mL/kg ideal body weight) to preserve blinding; open-label Ringer’s acetate permitted beyond the cap.
  • Other fluids (e.g., maintenance crystalloid, nutrition, medication diluents) and standard sepsis co-interventions were permitted according to local practice.
• Blinding: Double-blind (trial fluids supplied in identical masked packaging); clinicians, patients, investigators, and outcome assessors were blinded. This strengthens internal validity for objective outcomes (mortality) and reduces co-intervention bias.
• Statistics: Power calculation: a total of 800 patients were required to detect a 10% absolute reduction in the primary composite outcome (from 50% to 40%; assuming 45% mortality and 5% dialysis dependence) with 80% power at a two-sided 5% significance level; primary analysis was modified intention-to-treat (participants receiving at least one dose of trial fluid).
• Follow-Up Period: 90 days for the primary outcome (death or dialysis dependence at day 90); in-ICU secondary outcomes included organ failure metrics and adverse events during ICU stay.

Key Results

This trial was not stopped early. The planned enrolment target was reached.

• Key separation was by fluid composition (HES vs balanced crystalloid), not total trial fluid volume: 3000 (1500–5000) mL vs 3000 (1000–5000) mL; P=0.20.
• Renal and bleeding signals were directionally consistent with harm: RRT 22% vs 16% (RR 1.35; 95% CI 1.01 to 1.80; P=0.04); any bleeding 23% vs 15%; P=0.003.
• Pre-specified subgroup (primary outcome): shock at randomisation—yes: 179/336 vs 148/337 (RR 1.21; 95% CI 1.04 to 1.42); no: 23/62 vs 25/63 (RR 0.93; 95% CI 0.60 to 1.46); heterogeneity P=0.22.
• Pre-specified subgroup (primary outcome): acute kidney injury at randomisation—yes: 72/142 vs 63/140 (RR 1.13; 95% CI 0.88 to 1.44); no: 130/256 vs 110/260 (RR 1.20; 95% CI 1.00 to 1.45); heterogeneity P=0.60.

Internal Validity

• Randomisation and Allocation: Central randomisation with stratification (shock at randomisation, haematological malignancy, and university vs non-university hospital) supports allocation concealment and balance across key prognostic factors.
• Drop out or exclusions: 804 patients were randomised; 798 were included in the modified intention-to-treat population (required receipt of trial fluid); primary 90-day outcome ascertainment was complete for analysed participants.
• Performance/Detection Bias: Double-blinding and use of objective endpoints (mortality; dialysis dependence defined by receipt of RRT around day 90) reduce bias; clinician-driven initiation of RRT introduces potential variability for renal outcomes.
• Protocol Adherence: Daily trial-fluid cap exceeded in 28 participants in the HES group vs 41 in the Ringer’s acetate group (median excess 500 mL); synthetic colloids were administered after randomisation in 39 vs 38 participants, respectively (protocol deviations that may attenuate between-group separation).
• Baseline Characteristics: Groups were similar at baseline severity and organ failures (e.g., shock at randomisation 84% vs 84%; median SAPS II 50 vs 52; median SOFA 9 vs 9; kidney injury 36% vs 35%).
• Timing: Median time from ICU admission to randomisation was 3.7 (1.3–12.9) hours vs 4.0 (1.4–12.6) hours; 42% in each group had received synthetic colloids in the prior 24 hours (median 700 mL vs 500 mL among recipients), introducing pre-randomisation exposure that could dilute early treatment separation.
• Dose: Trial-fluid exposure was clinically meaningful but capped at 33 mL/kg ideal body weight/day; harm signals occurred despite this capped dosing, suggesting toxicity at doses consistent with routine ICU practice at the time.
• Separation of the Variable of Interest:
  • Trial fluid (median [IQR]): 3000 (1500–5000) mL vs 3000 (1000–5000) mL; P=0.20.
  • Total fluid balance (median [IQR]) during ICU stay: 5452 (1876–10518) mL vs 4616 (1271–9530) mL; P=0.17.
  • Early haemodynamic surrogates were similar: lactate at baseline 2.0 (1.3–3.5) vs 2.1 (1.4–3.7) mmol/L; 0–12 hours 2.2 (1.4–3.9) vs 2.2 (1.5–3.6) mmol/L; 12–24 hours 2.0 (1.3–3.3) vs 2.0 (1.4–2.8) mmol/L.
• Adjunctive therapy use: Blood product administration was higher with HES (median 1340 vs 1055 mL; P=0.003), consistent with differential bleeding risk and/or clinician response to perceived coagulopathy.
• Outcome Assessment: Mortality is objective; dialysis dependence and RRT use are clinically meaningful but may be influenced by local thresholds and practice variation in initiating RRT.
• Statistical Rigor: The trial met planned sample size, used pre-specified hypothesis testing at two-sided alpha 0.05, and analysed outcomes in a modified intention-to-treat framework with supportive analyses.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong, supported by double-blinding, objective primary outcome, and balanced baseline characteristics; the main threats are non-protocolised RRT initiation and pre-/post-randomisation colloid exposure that could attenuate treatment separation for renal endpoints.

External Validity

• Population Representativeness: Adults with severe sepsis treated in mixed Scandinavian ICUs with high illness severity and organ failure burden (84% with shock at randomisation; substantial respiratory and circulatory failure) are broadly representative of ICU sepsis populations in high-income settings.
• Applicability: Findings apply most directly to ICU-based resuscitation using HES 130/0.42 in a balanced carrier solution compared with a balanced crystalloid (Ringer’s acetate); extrapolation to early emergency department resuscitation, lower-risk perioperative populations, or non-sepsis indications should be cautious.
• Health-system considerations: The multicentre pragmatic design across diverse ICUs supports real-world relevance; however, local practice patterns (including thresholds for RRT) may differ internationally.

Conclusion on External Validity: Generalisability is good for adult ICU severe sepsis/septic shock populations in comparable health systems, but is more limited for earlier pre-ICU resuscitation phases and for populations excluded by protocol (e.g., those already receiving large-volume colloid or on established RRT).

Strengths & Limitations

• Strengths:
  • Large, multicentre, double-blind randomised design in routine ICU practice.
  • Clinically meaningful 90-day primary endpoint and high completeness of follow-up for the analysed population.
  • Comparator was a balanced crystalloid, reducing confounding by chloride load and aligning with contemporary crystalloid practice in many ICUs.
  • Pragmatic delivery increases applicability to real-world decision-making around fluid resuscitation.
• Limitations:
  • Modified intention-to-treat analysis (required receipt of trial fluid) slightly departs from strict intention-to-treat, although exclusions were few.
  • Initiation of RRT was not protocolised and may vary by centre, potentially affecting renal outcomes; mortality signal is less vulnerable to this concern.
  • Primary composite outcome was dominated by mortality because dialysis dependence at day 90 was rare (1 participant per group), which may reduce interpretability of the composite as “death or end-stage kidney failure”.
  • Substantial pre-randomisation exposure to synthetic colloids (42% in each group) could dilute early separation in exposure and bias towards the null for some harm signals.

Interpretation & Why It Matters

• Clinical implication

  In ICU patients with severe sepsis, HES 130/0.42 increased 90-day mortality and need for RRT compared with Ringer’s acetate (death at 90 days: 51% vs 43%; RR 1.17; 95% CI 1.01 to 1.36; P=0.03; RRT: 22% vs 16%; RR 1.35; 95% CI 1.01 to 1.80; P=0.04), supporting avoidance of HES for sepsis resuscitation.
• Plausible harm pathways

  Observed signals were consistent with renal toxicity and coagulopathy: any bleeding 23% vs 15% (P=0.003) and higher blood product use 1340 vs 1055 mL (P=0.003), alongside renal injury outcomes favouring balanced crystalloid.
• Trialists’ lesson for fluid research

  Haemodynamic surrogates did not distinguish groups in the first 24 hours (e.g., lactate 0–12 hours 2.2 vs 2.2 mmol/L), yet hard outcomes diverged, underscoring why fluid trials must prioritise patient-centred outcomes over presumed “efficiency” or short-term physiological targets.

Controversies & Subsequent Evidence

• Published correspondence challenged aspects of physiological framing and trial conduct (including monitoring strategy and interpretation of renal endpoints); the exchange emphasised that pragmatic, blinded evaluation of hard outcomes was prioritised over haemodynamic optimisation protocols.²
• Renal outcomes were debated because RRT initiation thresholds were not standardised; however, the mortality signal (objective, blinded) and concordant RRT signal strengthened the inference of harm.
• Subsequent large ICU RCT evidence in a broader critically ill population (CHEST) also demonstrated increased renal-replacement therapy with HES and no mortality benefit, supporting that the 6S findings were not isolated to one health system or one protocol.³
• Meta-analyses incorporating 6S, CHEST and other RCTs reported increased risk of mortality and acute kidney injury with HES compared with crystalloids, reinforcing the consistency of the harm signal across trials and settings.⁴⁵
• Contemporary sepsis guidelines recommend crystalloids as first-line resuscitation fluids and recommend against hydroxyethyl starch in sepsis/septic shock, reflecting the balance of evidence on harm and lack of benefit.⁶

Summary

• 6S was a large, double-blind, multicentre ICU RCT comparing 6% HES 130/0.42 with Ringer’s acetate in adults with severe sepsis.
• The primary 90-day composite occurred in 202/398 (51%) vs 173/400 (43%) (RR 1.17; 95% CI 1.01 to 1.36; P=0.03).
• 90-day mortality was higher with HES (201/398 [51%] vs 172/400 [43%]; RR 1.17; 95% CI 1.01 to 1.36; P=0.03).
• Renal-replacement therapy use was higher with HES (87/398 [22%] vs 65/400 [16%]; RR 1.35; 95% CI 1.01 to 1.80; P=0.04), with supporting post-hoc signals for renal injury.
• Trial fluid volumes were similar (3000 vs 3000 mL; P=0.20), supporting that harm was related to the starch solution rather than differential volume delivery.

Overall Takeaway

6S is a landmark ICU sepsis fluid trial because it provided blinded, patient-centred evidence that a commonly used “modern” HES preparation (130/0.42) caused harm compared with a balanced crystalloid. Its concordance with subsequent RCTs and meta-analyses shifted practice and guideline recommendations away from HES in sepsis, reinforcing crystalloids as default resuscitation fluids.

Bibliography

• 1Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139. Link
• 2Magder S, von Heymann C, Sander M, Spies CD, et al. Protocols, Physiology, and Trials of Hydroxyethyl Starch. N Engl J Med. 2012;367(13):1265-1267. Link
• 3Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911. Link
• 4Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309(7):678-688. Link
• 5Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;4:CD000567. Link
• 6Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. Link