Commentary

Fluid resuscitation is the cornerstone of treatment for patients with hypovolemia due to severe sepsis [1]. Colloids are used as they are thought to remain in the intravascular space longer, achieve faster circulatory stabilization [2], and require less amount of fluid for resuscitation compared with crystalloids [3]. Hydroxyethyl starches (HESs) are synthetic colloids composed of amylopectin obtained from maize or potato starch and vary in their molecular weight, hydroxyethyl moieties, and in the ratio of C2 to C6 substitutions [4].

Results of clinical trials comparing resuscitation with colloids and crystalloids have been conflicting. Compared to modified Ringer's lactate solution, resuscitation with HES 200/0.5 has been associated with increased risk of acute kidney injury (AKI) and requirement of renal replacement therapy [5]. Another recent study (CRYSTMAS) found that resuscitation with low molecular weight HES 130/0.4 was associated with less time to hemodynamic stabilization and no difference in AKI, renal replacement therapy, and mortality compared to resuscitation with 0.9% saline [2]. However, this study was underpowered to detect differences in mortality and establish safety of low molecular weight HES [6].

In this trial, Perner and colleagues [7] elegantly demonstrate that patients with severe sepsis who received fluid resuscitation with HES 130/0.42 had increased mortality, increased risk of renal replacement therapy, a trend for increased bleeding, and increased blood product transfusion when compared to resuscitation with Ringers acetate. Interestingly, the study did not find that patients who received colloids require less amount of fluid when compared to crystalloids. Strengths of the study include being well-designed and adequately powered with broad inclusion criteria and low risk of bias due to double-blinding and the multicenter nature of the trial. Importantly, the study measured patient-centered long-term clinical outcomes, such us 90-day mortality and renal replacement therapy. Since Ringers acetate was a vehicle for HES in the intervention arm and was also the fluid in the control arm, it allows one to examine the causal effect of HES on outcomes.

The few limitations of the study include a lack of a control for co-interventions and protocol violation. Of 69 patients with protocol violation, 28 patients in the HES group and 41 patients in the Ringers acetate group received trial fluid at doses higher than the maximum specified in the protocol. Moreover, the criteria for initiation of renal replacement therapy were not pre-specified in the study protocol, and the determination of requirement of fluid for resuscitation was based on clinician judgment rather than more objective hemodynamic parameters.

Several important points related to the mechanisms of harmful effects of HES deserve further consideration. First, the study showed that resuscitation with HES was associated with increased risk of AKI requiring renal replacement therapy compared to resuscitation with Ringer's acetate (22% versus 16%, P = 0.04). This study adds to the growing body of literature that suggests that HES, independent of the molecular weight or molar substitution, increases the risk of AKI in an at-risk population [8]. Although not well understood, potential mechanisms by which HES might cause AKI include increased uptake of the starch into the proximal renal epithelial cells inducing 'osmotic nephrosis-like lesions', tubular obstruction caused by the production of hyperviscous urine, and renal interstitial inflammation [9].

Second, more patients receiving HES compared to Ringers acetate received blood product transfusions (relative risk, 1.20; 95% confidence interval (CI), 1.07 to1.36; P = 0.002) with higher volumes (cumulative median blood product volume, HES versus Ringers acetate, 1,340 versus 1,055 ml; P = 0.003). Multiple studies have demonstrated that HES molecules were associated with platelet dysfunction, interact with the coagulation cascade, and decrease factor VIII and von Willebrand factor levels [4] and fibrin polymerization [10]. Importantly, increased bleeding tendency has also been observed with use of low molecular weight starches [11].

Maize-derived and potato-derived HESs (as used in the study by Perner and colleagues) have structural differences due to differences in the percentage of amylopectin (98% versus 75%) and C2/C6 substitution ratio (9:1 versus 6:1) [4]. However, there is conflicting evidence regarding whether this structural difference has a clinical impact. For instance, while molecular studies demonstrate biochemical differences between these two starches [12], ex vivo studies show no difference in bleeding effects [10]. These findings suggest that the risk of AKI and increased bleeding diathesis associated with HES is a class effect of starches rather than its molecular weight or molar substitution [8].

Another recent large (n = 7,000) clinical trial (CHEST) found no difference in 90-day mortality between HES 130/0.40 and 0.9% saline in a heterogeneous group of critically ill patients [13]. However, the need for renal replacement therapy was higher among patients who received HES (7.0% versus 5.8%; relative risk, 1.21; 95% CI, 1.00 to 1.45; P = 0.04) compared to saline. Moreover, patients in the CHEST trial were less severely ill than patients in the study by Perner and colleagues, and in the subgroup analysis of patients with severe sepsis, there was a trend towards increased AKI and mortality in those who received HES.

More recently, when taking into consideration the absence of significant clinical benefit and the potential harmful effect of starches based on the above studies, the 2013 surviving sepsis campaign [14] recommended against using any HES in patients with severe sepsis. Another recently completed large (n = 3,000) clinical trial (CRYSTAL) [15] comparing crystalloids and colloids will provide additional insight into HES fluid resuscitation on clinical outcomes.

Recommendation

Fluid resuscitation with HES 130/0.4 increases risk of AKI requiring renal replacement therapy and mortality in patients with severe sepsis. Given evidence of harm and lack of significant clinical benefit, HES 130/0.4 should not be used for fluid resuscitation for critically ill patients with severe sepsis.