The New England Journal of Medicine July 12, 2012

Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe Sepsis

Anders Perner, Nicolai Haase, Anne B. Guttormsen et al.

Bottom Line

In patients with severe sepsis, fluid resuscitation with 6% hydroxyethyl starch (HES) 130/0.42 resulted in an increased risk of 90-day mortality and a higher need for renal-replacement therapy compared with Ringer's acetate.

Key Findings

1. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk [RR] 1.17; 95% CI 1.01 to 1.36; P=0.03).

2. End-stage kidney failure (dependence on dialysis) was extremely rare and identical between groups, occurring in exactly 1 patient in each arm at 90 days.

3. The HES group had a significantly higher requirement for renal-replacement therapy during the 90-day period: 87 patients (22%) vs. 65 patients (16%) in the Ringer's group (RR 1.35; 95% CI 1.01 to 1.80; P=0.04).

4. Severe bleeding occurred more frequently in the HES group (38 patients [10%]) than in the Ringer's acetate group (25 patients [6%]), though this difference did not reach statistical significance (RR 1.52; 95% CI 0.94 to 2.48; P=0.09).

Study Design

Design

RCT

Double-Blind

Sample

798

Patients

Duration

90 days

Median

Setting

Multicenter, Scandinavia

Population Adult intensive care unit (ICU) patients who fulfilled criteria for severe sepsis within the previous 24 hours.

Intervention Fluid resuscitation with up to 33 mL per kilogram of ideal body weight per day of 6% hydroxyethyl starch (HES) 130/0.42 (Tetraspan).

Comparator Fluid resuscitation with up to 33 mL per kilogram of ideal body weight per day of Ringer's acetate.

Outcome A composite of death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.

Study Limitations

• Patients with pre-existing severe renal failure or severe bleeding were excluded, which limits the generalizability of the findings to those presenting with severe baseline complications.

• The maximum allowed fluid dose in the trial was 33 mL/kg of ideal body weight per day; patients requiring massive volume resuscitation beyond this limit were given open-label crystalloids, which could dilute the observed treatment effect.

• Despite rigorous blinding, distinct physiological responses to HES or crystalloids, as well as distinct adverse effects (such as bleeding or acute kidney injury), might have inadvertently unblinded the clinical teams.

Clinical Significance

The 6S trial provided definitive, practice-changing evidence that newer-generation hydroxyethyl starches are actively harmful in severe sepsis, causing higher mortality and driving acute kidney injury requiring dialysis. This landmark trial fundamentally shifted ICU fluid resuscitation practices globally. Following 6S and the contemporaneous CHEST trial, international guidelines (like the Surviving Sepsis Campaign) strongly recommended against using HES in septic patients, and global regulatory bodies (EMA, FDA) issued black box warnings and market suspensions for HES products in critically ill patients.

Historical Context

For decades, synthetic colloids like HES were favored in many European and international ICUs based on the physiological rationale that they expanded intravascular volume more effectively than crystalloids, requiring less fluid and theoretically reducing tissue edema. While older, high-molecular-weight starches were known to cause renal failure (demonstrated by the VISEP trial), the newer formulation (HES 130/0.42) was heavily marketed as a safer alternative without nephrotoxic effects. The 6S trial debunked this assumption, proving that the risk of renal toxicity, coagulopathy, and death persisted even with modern HES products in the context of sepsis.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pathophysiological mechanism by which hydroxyethyl starch (HES) contributes to acute kidney injury in patients with severe sepsis, leading to the increased need for renal-replacement therapy observed in this trial?

Key Response

HES molecules can accumulate in the reticuloendothelial system and renal proximal tubule cells, causing osmotic nephrosis. In sepsis, where renal perfusion may already be compromised and endothelial permeability is altered, this accumulation exacerbates tubular injury, accelerating acute kidney injury.

Resident

Given the findings of the 6S trial, how should your initial choice of resuscitation fluid change when managing a patient presenting to the ED with septic shock, and what are the clinical alternatives to HES?

Key Response

The trial definitively shows harm (increased mortality and RRT) with HES. Residents must recognize that crystalloids like Ringer's acetate or Lactated Ringer's are the preferred first-line fluids for sepsis resuscitation, avoiding synthetic colloids entirely due to toxicity.

Fellow

How do the findings of the 6S trial compare with the CHEST trial regarding the use of HES in critically ill patients, and how does the specific molecular weight and substitution ratio of HES 130/0.42 theoretically affect its safety profile compared to older starches?

Key Response

The CHEST trial also found increased RRT need with HES in a broader ICU population, though mortality was not significantly different, whereas 6S focused specifically on severe sepsis and found increased mortality. HES 130/0.42 was designed to have a lower molecular weight and substitution ratio to facilitate faster clearance and reduce tissue accumulation compared to older starches, yet both 6S and CHEST proved it still causes significant harm.

Attending

Before the 6S trial, colloids were often favored for their theoretical ability to expand intravascular volume more efficiently than crystalloids. How do you use the results of the 6S trial to teach trainees about the fallacy of surrogate endpoints when they conflict with patient-centered outcomes?

Key Response

The 6S trial is a classic example of how physiological rationale (colloids stay in the vessel longer) fails in the face of complex pathophysiology (endothelial glycocalyx degradation in sepsis causing capillary leak, plus direct HES nephrotoxicity). It highlights the necessity of large RCTs measuring hard outcomes like mortality rather than relying on surrogate hemodynamic markers.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The 6S trial utilized a pragmatic, multicenter, blinded design. How should investigators handle the competing risk of death when analyzing the time-to-event data for the need for renal-replacement therapy, and why is this statistical consideration critical in sepsis trials?

Key Response

In critical care trials, death is a significant competing risk for secondary morbidities like the initiation of RRT. The analysis requires understanding that standard Kaplan-Meier estimates could overestimate the incidence of RRT if death is not treated as a competing risk using models like Fine-Gray, ensuring the nephrotoxic signal of HES is accurately quantified.

Journal Editor

A critical reviewer might scrutinize the fluid management protocols outside of the blinded study fluid interventions. How could variations in co-interventions, such as the use of open-label fluids, vasopressors, and specific indications for initiating RRT across the 26 different ICUs, introduce bias or dilute the treatment effect in this trial?

Key Response

While the trial was blinded, lack of strict protocols for non-study fluid administration or standardized triggers for RRT initiation across various Scandinavian ICUs could introduce practice misalignment. A seasoned editor would evaluate whether these pragmatic elements introduce noise that could skew the primary outcome or if the randomization successfully balanced these unmeasured variables.

Guideline Committee

Based on the findings of the 6S trial alongside other major trials like CHEST, what precise modifications were necessitated in the Surviving Sepsis Campaign guidelines regarding fluid resuscitation, and what is the GRADE strength of this recommendation?

Key Response

The 6S trial provided high-quality evidence that directly led the Surviving Sepsis Campaign to issue a strong recommendation against the use of hydroxyethyl starches for intravascular volume replacement in patients with sepsis or septic shock. This shifted the paradigm globally, upgrading crystalloids to the undisputed first-line therapy with a strong recommendation based on high quality of evidence.

Clinical Landscape

Noteworthy Related Trials

2004

SAFE Trial

n = 6,997 · NEJM

Tested

4% Albumin (colloid)

Population

Intensive care unit patients requiring fluid resuscitation

Comparator

0.9% Sodium chloride (crystalloid)

Endpoint

28-day all-cause mortality

Key result: Albumin and saline resulted in similar 28-day mortality rates and similar rates of new organ failure across the general ICU population.

2008

VISEP Trial

n = 537 · NEJM

Tested

10% Hydroxyethyl starch (200/0.5)

Population

Patients with severe sepsis or septic shock

Comparator

Modified Ringer's lactate

Endpoint

28-day mortality and rate of organ failure

Key result: HES therapy was associated with significantly higher rates of acute renal failure and more days receiving renal replacement therapy.

2012

CHEST Trial

n = 7,000 · NEJM

Tested

6% Hydroxyethyl starch (130/0.4)

Population

Patients admitted to the ICU requiring fluid resuscitation

Comparator

0.9% Sodium chloride

Endpoint

90-day mortality

Key result: There was no significant difference in 90-day mortality, but HES patients were more likely to require renal-replacement therapy.

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