Crystalloid Solutions Still Better than Colloid Solutions for Fluid Resuscitation

Abstract & Commentary

By Eric C. Walter, MD, MSc

Pulmonary and Critical Care Medicine, Northwest Permanente and Kaiser Sunnyside Medical Center, Portland

Dr. Walter reports no financial relationships relevant to this field of study.

This article originally appeared in the September 2012 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor Emeritus, Pulmonary and Critical Care Medicine, University of Washington, Seattle, and Dr. Thompson is Associate Professor of Medicine, University of Washington, Seattle. Drs. Pierson and Thompson report no financial relationships relevant to this field of study.

Synopsis: This blinded, randomized, controlled trial reports a higher risk of mortality, need for renal replacement therapy, and blood product transfusion in patients treated with the colloid solution hydroxyethyl starch compared to those treated with the crystalloid solution Ringer’s acetate.

Source: Perner A, et al; 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;367:124-134. Erratum: N Engl J Med 2012;367:481.

This blinded, randomized, multicenter trial compared the colloid solution low-molecular-weight hydroxyethyl starch (HES 130/0.42) with the crystalloid solution Ringer’s acetate for the treatment of severe sepsis. Patients 18 years of age or older diagnosed with severe sepsis (a defined focus of infection and at least two systemic inflammatory response syndrome criteria and at least one new organ failure) who needed fluid resuscitation were included. Patients were randomized in a 1:1 ratio, stratified by the presence or absence of shock, active hematologic cancer, and admission to a university or non-university hospital. Just over 1200 patients were screened, 407 were excluded, and 804 underwent randomization. Most patients were excluded for having received more than 1000 mL of synthetic colloid (37%) or having undergone renal replacement therapy (34%) prior to randomization. The median age was 66 years and 60% were male. At randomization, 84% of patients were in shock, 35% had acute kidney injury, and 61% were mechanically ventilated. Treatment groups were well balanced.

Patients judged to need fluid resuscitation by ICU clinicians were provided trial fluid up to a maximum of 33 mL/Kg of ideal body weight per day. This value was chosen to try to ensure that no patients received more HES than the manufacturer’s recommended daily dose of 50 mL/Kg. If additional fluid was required, unblinded Ringer’s acetate was used for all patients. Trial fluid was provided free of charge in identical bags prepared by the manufacturer. The manufacturer had no role in the protocol, trial conduct, data analysis, or reporting.

The composite primary outcome was either death or dependence on dialysis at 90 days and occurred more often in patients who received HES (51%) than in patients who received Ringer’s acetate ([43%] relative risk, 1.17; 95% confidence interval [CI] 1.01 to 1.36; P = 0.03]. Since only one patient in each group was dependent on dialysis at 90 days, the primary difference in outcome was due to higher mortality among patients given HES. Many secondary outcome measures were also worse among patients given HES. More patients required renal replacement therapy (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04) and blood transfusions (relative risk, 1.20; 95% CI, 1.07 to 1.36).


Strengths of this study include a large, heterogeneous patient population from both university and community hospitals in several countries with few exclusion criteria. Thus, the study is well generalizable. The trial was well blinded, minimizing bias. The authors had excellent follow-up with 798 of 804 patients contributing data at 90 days.

There seems to be an endless debate over the use of colloids and crystalloids for fluid resuscitation. Colloids are generally believed to raise oncotic pressure better than crystalloids, allowing for greater plasma volume expansion with less overall fluid requirements. For example, the natural colloid albumin may expand plasma volume 40% more than crystalloid. In the Saline vs Albumin Fluid Evaluation (SAFE) Study, a randomized controlled trial of albumin vs saline in an intensive care unit, patients given saline had a greater net fluid balance compared to those who received albumin.1 However, the plasma volume expansion properties may differ among colloid solutions. There were no significant differences in fluid volume balance between patients who received HES and Ringer’s Lactate in this study.

Those in favor of colloids argue that increased plasma volume expansion leads to a more rapidly improved blood pressure with less overall volume delivered. Despite these arguments, multiple trials have failed to show a benefit over crystalloids with respect to mortality. In the SAFE trial, 28-day mortality did not differ between the two groups. A recent Cochrane review of 66 randomized, controlled trials of various colloid solutions compared to crystalloids also found no difference in mortality.2 We now have evidence of increased mortality with the use of HES compared to Ringer’s acetate.

In summary, the use of HES compared to Ringer’s acetate was associated with increased mortality, need for renal replacement therapy, and blood product transfusion. These data, coupled with numerous previous studies and the increased expense of colloids, argue that crystalloids should be used preferentially for most patients requiring fluid resuscitation.


1. Finfer S, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350: 2247-2256.

2. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2012 Jun 13;6:CD000567.