The New England Journal of Medicine JUNE 27, 2012

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

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

Bottom Line

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

Key Findings

1. At 90 days, the composite primary outcome (death or end-stage kidney failure) occurred in 51% of patients in the HES group compared to 43% in the Ringer's acetate group (relative risk, 1.17; 95% CI, 1.01 to 1.36; P=0.03).

2. Mortality at 90 days was significantly higher in the HES group (51%) than in the Ringer's acetate group (43%), with a relative risk of 1.17 (P=0.03).

3. Patients in the HES group required renal replacement therapy more frequently than those in the Ringer's acetate group (22% vs. 16%; relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04).

4. There was no significant difference in the occurrence of severe bleeding between the HES group (10%) and the Ringer's acetate group (6%).

Study Design

Design

RCT

Double-Blind

Sample

804

Patients

Duration

90 days

Median

Setting

Multicenter, Scandinavia

Population Adult patients with severe sepsis admitted to the intensive care unit.

Intervention Fluid resuscitation with 6% hydroxyethyl starch 130/0.42 up to 33 ml per kilogram of ideal body weight per day.

Comparator Fluid resuscitation with Ringer's acetate.

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

Study Limitations

• The study was performed in a specific clinical setting (Scandinavian ICUs), which might limit generalizability to other health care systems with different fluid resuscitation practices.

• Despite the randomization, the trial was designed to detect a 10% absolute difference, and while statistically significant findings were noted, the clinical interpretation is heavily influenced by the secondary and exploratory findings.

• The primary composite outcome was overwhelmingly driven by mortality rather than the intended focus on end-stage kidney failure (dialysis dependence).

Clinical Significance

The results of the 6S trial provided high-quality evidence that HES 130/0.42 is not a safe alternative to balanced crystalloids in patients with severe sepsis, leading to a significant increase in mortality and the need for renal replacement therapy. This trial was pivotal in shifting international fluid resuscitation guidelines away from the use of starch-based colloids in septic patients.

Historical Context

Before this trial, hydroxyethyl starch (HES) was widely used for rapid circulatory stabilization in septic shock under the assumption that lower molecular weight starches were safer than previous high-molecular-weight formulations. The 6S trial, along with subsequent meta-analyses and the concurrent CHEST trial, fundamentally challenged this assumption and led to global regulatory restrictions on the use of HES in critically ill populations.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the primary pathophysiological mechanism by which hydroxyethyl starch (HES) 130/0.42 is thought to cause acute kidney injury in septic patients, and how does this contrast with the clearance of crystalloids?

Key Response

Unlike crystalloids, which are filtered or distributed into the extracellular space, HES molecules are taken up by renal proximal tubular cells through pinocytosis. In the setting of sepsis-related inflammatory stress, this leads to 'osmotic nephrosis-like' lesions (cytoplasmic vacuolization). This accumulation impairs tubular function and increases the risk of requiring renal replacement therapy, as highlighted by the significantly higher RRT rates in the 6S trial starch group.

Resident

A patient with severe sepsis requires aggressive fluid resuscitation. Based on the 6S trial, compare the 90-day mortality and renal outcomes for HES 130/0.42 versus Ringer's acetate, and explain how this should influence your choice of fluid.

Key Response

The 6S trial demonstrated that HES 130/0.42 increased 90-day mortality (51% vs. 43%; p=0.03) and the need for renal replacement therapy (22% vs. 16%; p=0.04) compared to Ringer's acetate. Consequently, HES should be avoided in patients with severe sepsis, and balanced crystalloids like Ringer's acetate or lactate should be the preferred resuscitation fluids to avoid preventable harm.

Fellow

The 6S trial and the CHEST trial both evaluated 6% HES 130, yet reported different findings regarding mortality. Analyze the patient population and trial design differences that might explain why 6S found a mortality signal while CHEST did not.

Key Response

The 6S trial focused specifically on severe sepsis (a population with high capillary leak and renal vulnerability), whereas CHEST included a broad ICU population. Additionally, the 6S trial used HES 130/0.42 in Ringer's acetate, while CHEST used HES 130/0.40 in saline. The higher baseline risk of death in the 6S cohort (over 40% vs. roughly 18% in CHEST) likely made it easier to detect a significant difference in mortality caused by the potential toxic effects of starch accumulation.

Attending

The 6S trial was pivotal in shifting the 'colloid vs. crystalloid' debate. How did this study specifically refute the industry claim that 'modern' low-molecular-weight starches (like 130/0.42) solved the safety issues seen with older-generation starches like HES 200/0.5?

Key Response

Prior to 6S, it was argued that newer HES formulations with lower molecular weights and lower molar substitutions were safer because they were cleared more rapidly. The 6S trial provided definitive evidence that even these 'modern' starches carry a significant risk of death and renal failure in septic patients. This ended the routine use of HES in most intensive care settings and redirected the focus of teaching toward the safety of balanced crystalloids.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In the 6S trial, the investigators used a 90-day mortality endpoint rather than the more common 28-day endpoint. Critique the statistical and clinical implications of this choice in the context of evaluating a drug with potential cumulative tissue toxicity.

Key Response

A 90-day endpoint is superior for capturing the long-term sequelae of renal replacement therapy and the delayed clearance of starch from the reticuloendothelial system. While it increases the risk of 'noise' from non-study related events, for a substance like HES that accumulates in tissues, a 28-day window may be too short to see the full impact of drug-induced organ dysfunction on survival, potentially leading to a type II error.

Journal Editor

As a reviewer for the NEJM, what specific threats to internal validity would you flag regarding the blinding and fluid administration protocols in the 6S trial, given that HES and Ringer's acetate have different physical properties (e.g., viscosity and foam)?

Key Response

A tough reviewer would question if the investigators were truly blinded, as HES bags can look or behave differently when shaken or infused. The trial addressed this by using identical-looking opaque over-bags. Furthermore, the reviewer would check for a 'volume effect'—if the starch group received significantly less fluid due to its higher oncotic pressure, could the outcomes be biased by differences in total volume? The 6S trial reported similar median volumes in the first 24 hours, mitigating this concern.

Guideline Committee

How does the evidence from the 6S trial specifically align with or contradict current Surviving Sepsis Campaign (SSC) recommendations regarding the use of colloids, and what level of evidence does this trial provide?

Key Response

The 6S trial provides Level 1A evidence for harm. Current SSC guidelines (e.g., 2021 update) issue a 'strong recommendation' against using hydroxyethyl starches for fluid resuscitation in patients with sepsis or septic shock. This is a direct result of the 6S and CHEST trials, which demonstrated increased mortality and RRT. The guidelines now favor crystalloids as the first-line choice, with albumin only suggested as a second-line adjunct when large volumes of crystalloid are needed.

Clinical Landscape

Noteworthy Related Trials

2008

VISEP Trial

n = 537 · JAMA

Tested

10% pentastarch

Population

Patients with severe sepsis

Comparator

Modified Ringer's lactate

Endpoint

28-day and 90-day mortality

Key result: The study was stopped early for safety, showing that resuscitation with hydroxyethyl starch was associated with increased risk of acute renal failure.

2012

CHEST Trial

n = 7,000 · NEJM

Tested

6% hydroxyethyl starch (HES 130/0.4)

Population

ICU patients

Comparator

Saline

Endpoint

90-day mortality

Key result: There was no significant difference in 90-day mortality between the HES and saline groups, though the HES group required more renal-replacement therapy.

2015

SPLIT Trial

n = 2,278 · JAMA

Tested

Balanced crystalloids

Population

ICU patients

Comparator

0.9% saline

Endpoint

Acute kidney injury

Key result: There was no difference in the proportion of patients who developed acute kidney injury between the balanced crystalloid and saline groups.

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