Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care
Source: View publication →
In critically ill adults, fluid resuscitation with 6% hydroxyethyl starch did not improve 90-day survival compared to saline but significantly increased the risk of requiring renal-replacement therapy.
Key Findings
Study Design
Study Limitations
Clinical Significance
The CHEST trial definitively demonstrated that 6% HES 130/0.4 offers no mortality or clinically meaningful physiological advantage over inexpensive 0.9% saline for fluid resuscitation in critically ill adults, while exposing them to a significantly increased risk of severe acute kidney injury requiring renal replacement therapy. This landmark evidence, complementing the 6S trial in septic patients, effectively ended the routine use of synthetic starches in the ICU, shifting international standard practice toward the preferential use of crystalloids for acute volume expansion.
Historical Context
For decades, synthetic colloids such as hydroxyethyl starch (HES) were popular for fluid resuscitation in the ICU, driven by the belief that they expanded intravascular volume more efficiently and reduced total fluid requirements compared to crystalloids. While older, higher-molecular-weight starches were linked to acute kidney injury (e.g., in the 2008 VISEP trial), newer 'tetrastarches' (HES 130/0.4) were marketed as safe alternatives with minimal renal toxicity. The 2012 CHEST trial, published shortly after the 6S trial (which showed harm specifically in severe sepsis), provided definitive evidence across a broad, unselected medical-surgical ICU population that modern HES solutions offer no mortality benefit over saline and actively increase the risk of severe renal toxicity. These landmark findings prompted regulatory bodies worldwide, including the FDA and EMA, to issue strict black-box warnings or outright suspensions of HES use in critically ill patients.
Guided Discussion
High-yield insights from every perspective
What is the proposed pathophysiological mechanism by which hydroxyethyl starch (HES) induces acute kidney injury and increases the need for renal replacement therapy in critically ill patients?
Key Response
HES molecules are large macromolecules that are taken up by the proximal renal tubular epithelial cells via pinocytosis. Because they are resistant to lysosomal degradation, they accumulate intracellularly, leading to a condition known as osmotic nephrosis. This causes cellular swelling, vacuolization, interstitial inflammation, and luminal obstruction, ultimately manifesting as acute kidney injury (AKI).
Given the findings of the CHEST trial, how should a physician choose between crystalloids and colloids for initial fluid resuscitation in a patient presenting with hypovolemic shock, and what specific patient populations are most at risk of harm from synthetic colloids?
Key Response
The CHEST trial demonstrated that HES (a synthetic colloid) offers no mortality benefit over saline (a crystalloid) but significantly increases the risk of requiring renal replacement therapy. Therefore, crystalloids (like normal saline or balanced crystalloids) should be the first-line resuscitation fluid. Patients with sepsis or pre-existing renal dysfunction are at particularly high risk for HES-induced nephrotoxicity and coagulopathy, making synthetic colloids contraindicated in these groups.
The CHEST trial utilized 6% HES (130/0.4), a newer generation starch specifically developed to have a lower molecular weight and molar substitution ratio to mitigate renal toxicity. Why did this newer generation starch still fail to demonstrate a safety advantage in the ICU population, and how does this challenge the classic Starling principle of fluid resuscitation?
Key Response
Despite the lower molecular weight intended to improve clearance, critical illness alters endothelial glycocalyx integrity, causing capillary leak syndrome. This allows even these modified HES molecules to extravasate into the interstitium, nullifying their theoretical oncotic advantage. Furthermore, they still accumulate in renal tubules and the reticuloendothelial system. This invalidates the traditional reliance on colloids to maintain intravascular oncotic pressure during severe systemic inflammation, as the barrier is fundamentally compromised.
Reflecting on the evolution of fluid resuscitation, the CHEST trial was a pivotal moment that shifted ICU paradigms away from synthetic colloids. When teaching trainees about fluid stewardship, how can the results of this trial be used to reframe the concept of 'fluids as drugs' rather than benign volume expanders?
Key Response
The trial highlights that intravenous fluids possess distinct pharmacokinetic and pharmacodynamic properties with specific toxicity profiles. HES is not merely 'volume'; it is a pharmacological agent with tissue-specific toxicities (e.g., renal tubular accumulation, pruritus, coagulopathy). Teaching should frame fluid choice like choosing an antibiotic, requiring careful consideration of dose, duration, half-life, and specific organ toxicities, shifting the culture from 'filling the tank' to targeted, side-effect-aware prescription.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The CHEST trial used 90-day mortality as the primary endpoint but found a significant difference in the secondary endpoint of renal replacement therapy (RRT) utilization. From a methodological standpoint, how does the lack of standardized, objective criteria for initiating RRT across the 32 study sites introduce potential ascertainment bias, and how could future trial designs mitigate this?
Key Response
Since the decision to initiate RRT was at the discretion of treating clinicians rather than strictly protocolized, unblinding (accidental or inferred via recognized side effects like coagulopathy or pruritus) could influence a physician's threshold to start RRT. Future trial designs should utilize strictly protocolized, criteria-driven triggers for RRT initiation (e.g., specific KDIGO stage 3 criteria with defined refractory metabolic derangements) to ensure the endpoint is objectively measured and less susceptible to practice variation.
In reviewing the methodology of the CHEST trial, patients could receive substantial volumes of non-study fluids (like saline used as carrier fluids for medications). As an editor or peer reviewer, how would you evaluate the potential masking of the intervention effect caused by open-label fluid administration, and how does this affect the purity of the crystalloid versus colloid comparison?
Key Response
A critical reviewer would flag the total fluid balance and the volume of non-study crystalloids administered to the HES group. If the HES group received large volumes of saline as maintenance or carrier fluids, the trial essentially becomes a comparison of 'HES + Saline' versus 'Saline + Saline'. This dilution of the intervention could bias the primary mortality outcome towards the null, making it difficult to isolate the true effect size of the synthetic colloid alone, although the robust toxicity signal (RRT) despite this dilution makes the harm finding highly credible.
Following the publication of the CHEST trial and similar studies like the 6S trial, how did the Surviving Sepsis Campaign guidelines update their recommendations regarding the use of hydroxyethyl starches for fluid resuscitation in patients with sepsis or septic shock, and what is the GRADE classification of this evidence?
Key Response
Based on the high-quality evidence from the CHEST and 6S trials demonstrating increased rates of renal replacement therapy and no mortality benefit (and potential mortality harm in sepsis subgroups), the Surviving Sepsis Campaign updated their guidelines to issue a 'strong recommendation' against the use of hydroxyethyl starches (HES) for intravascular volume replacement in patients with sepsis or septic shock. The quality of evidence was graded as 'high', definitively establishing crystalloids as the standard of care for initial resuscitation.
Clinical Landscape
Noteworthy Related Trials
SAFE Trial
Tested
4% Albumin
Population
ICU patients requiring fluid resuscitation
Comparator
0.9% Sodium chloride (normal saline)
Endpoint
28-day all-cause mortality
6S Trial
Tested
6% Hydroxyethyl starch (HES) 130/0.42
Population
Patients with severe sepsis in the ICU
Comparator
Ringer's acetate
Endpoint
Death or end-stage kidney failure at 90 days
SMART Trial
Tested
Balanced crystalloids (Lactated Ringer's or Plasma-Lyte A)
Population
Critically ill adults admitted to the ICU
Comparator
0.9% Sodium chloride (normal saline)
Endpoint
Major Adverse Kidney Events within 30 days (MAKE30)
Tailored to your role
Want this tailored to you?
Add your specialty or training stage to get role-specific takeaways and more questions.
Personalize this analysis