KDIGO Clinical Practice Guideline for Acute Kidney Injury
Hydroxyethylstarch vs. Saline

Hydroxyethylstarch vs. Saline

Hydroxyethylstarch (HES) is a widely used, relatively inexpensive alternative to human albumin for correcting hypovolemia. Different HES preparations are available that vary with regard to concentration, mean molecular weight (MW), molar substitution, and substitution of hydroxyethyl for hydroxyl groups. The mean MW of the different HES preparations ranges between 70 000 and 670 000 Da. The colloid osmotic pressure effect is strongly dependent upon the concentration of colloid in the solution; e.g., 6% HES is iso-oncotic, whereas 10% HES is hyperoncotic. The number of hydroxyethyl groups per glucose molecule is specified by the molar substitution, ranging between 0.4 (tetrastarch) and 0.7 (heptastarch). Accordingly, HES solutions with a molar substitution of 0.5 or 0.6 are referred to as ‘‘pentastarch’’ or ‘‘hexastarch’’, respectively. More recently, tetrastarches (HES 130/0.4 and HES 130/0.42) have also been introduced.⁸⁷ High molecular substitution starch may impair coagulation by reducing the concentration of factor VIII: VIIIc and von Willebrand factor. Platelet activity may also be affected by blockade of the platelet fibrinogen receptor glycoprotein IIb/IIIa. Smaller starch molecules and those with less molecular substitution produce negligible coagulation defects.⁸⁸

Aside from these negative effects on coagulation, development of renal dysfunction has been a concern associated with the use of mainly hypertonic HES. Hypertonic HES may induce a pathological entity known as ‘‘osmotic nephrosis’’ with potential impairment of renal function.⁸⁹ It has even been recommended that ‘‘HES should be avoided in ICUs and during the perioperative period’’ (for a summary of this controversy, see de Saint-Aurin et al.⁹⁰ and Vincent⁹¹).

The first major randomized trial in patients with sepsis compared HES 200/0.60 to 0.66 with gelatin and showed a greater incidence of AKI in the HES group, but no effect on survival.⁹² Criticisms of this study include a higher baseline SCr level in the HES group, small sample size, and short follow-up duration of 34 days. In the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study,⁹³ patients with severe sepsis were randomly assigned to receive a hypertonic (10%) solution of low MW HES (HES 200/0.5), or an isotonic modified Ringer’s lactate solution. Patients in the HES group received a median cumulative dose of 70.4 ml per kilogram of body weight. The mortality was not significantly different, although showing a trend toward greater mortality at 90 days. However, the hypertonic HES group had a significantly higher rate of AKI (34.9% vs. 22.8%) and more days on which RRT was required (Suppl Table 1). Also, this study has been criticized for: i) using a hyperoncotic colloid solution with potentially harmful renal effects as shown in experimental research;⁹⁴ ii) markedly exceeding the pharmaceutically recommended daily dose limit for 10% HES 200/0.5 by more than 10% in >38% of patients; and iii) pre-existing renal dysfunction in 10% of study patients, which represents a contra-indication for infusion of 10% HES 200/0.5.⁹⁵ Posthoc analyses of the VISEP study showed the cumulative dose of HES to be a significant independent predictor for both mortality and RRT at 90 days. The median cumulative dose of HES in the VISEP Study was 70 ml/kg compared to 31 ml/kg in the study by Schortgen et al.⁹²

A systematic review of RCTs on the use of HES for fluid management in patients with sepsis totaling 1062 patients, including 537 patients from the VISEP study, showed an almost two-fold increased risk of AKI with HES compared to crystalloids.⁹⁶ Given these limitations, the results of these studies should be interpreted with caution. Furthermore, a large, prospective observational study found that HES infusion of any type (median volume 555 ml/d; intraquartile range 500–1000) did not represent an independent risk factor for renal impairment.⁹⁷; however, recently in a large cohort of critically ill patients (approximately 8000 subjects), infusion of 10% HES 200/0.5 instead of HES 130/0.4 appeared to be an independent risk factor for RRT.⁸⁷ Finally, a recent comprehensive Cochrane review⁹⁸ concluded that there is no evidence from RCTs that resuscitation with colloids, instead of crystalloids, reduces the risk of death in patients with trauma, burns, or following surgery.

The mechanisms of colloid-induced renal injury are incompletely understood, but may involve both direct molecular effects and effects of elevated oncotic pressure.⁹⁹ These concerns have led to the widespread adoption of lower MW starches as iso-oncotic solution, as resuscitation fluids. Theoretically, such solutions may have lower nephrotoxicity; however, as yet, no appropriately powered prospective randomized studies have reported the clinical benefit and safety of such solutions in comparison with crystalloids. A recent study by Magder et al. compared 10% 250/0.45 HES to isotonic saline in 262 patients who underwent cardiac surgery.¹⁰⁰ These investigators tested whether fewer patients required catecholamines the morning after cardiac surgery (a chief determinant of ICU discharge) with HES compared to saline, and found indeed this was the case (10.9% vs. 28.8%; P¼0.001). Importantly, the study found no evidence of nephrotoxicity: no difference in the daily creatinine, development of AKI by RIFLE criteria during hospital stay (16% in both groups), or need for RRT (1% in each group). Importantly, patients in the saline group received nearly 60% more volume for fluid resuscitation in the ICU compared to HES (887 vs. 1397 ml; P < 0.0001). While overall volumes were small, advocates for colloid resuscitation will note that this is exactly the reason colloids are preferred for patients requiring large-volume resuscitation.

The tonicity of colloid preparations may also vary by agent. A recent meta-analysis¹⁰¹ described 11 randomized trials with a total of 1220 patients: seven evaluating hyperoncotic albumin and four evaluating hyperoncotic starch. Hyperoncotic albumin decreased the odds of AKI by 76% while hyperoncotic starch increased those odds by 92% (odds ratio [OR] 1.92; CI 1.31–2.81; P = 0.0008). Parallel effects on mortality were observed. This meta-analysis concluded that the renal effects of hyperoncotic colloid solutions appear to be colloid-specific, with albumin displaying renoprotection and hyperoncotic starch showing nephrotoxicity. A 7000-patient study comparing 6% HES 130/0.4 in saline with saline alone was scheduled to begin in Australia and New Zealand in 2010. This study will provide further high-quality data to help guide clinical practice.¹⁰²

Thus, the use of isotonic saline as the standard of care for intravascular volume expansion to prevent or treat AKI is based upon the lack of clear evidence that colloids are superior for this purpose, along with some evidence that specific colloids may cause AKI, in addition to higher costs. It is acknowledged that colloids may be chosen in some patients to aid in reaching resuscitation goals, or to avoid excessive fluid administration in patients requiring large volume resuscitation, or in specific patient subsets (e.g., a cirrhotic patient with spontaneous peritonitis, or in burns). Similarly, although hypotonic or hypertonic crystalloids may be used in specific clinical scenarios, the choice of crystalloid with altered tonicity is generally dictated by goals other than intravascular volume expansion (e.g., hypernatremia or hyponatremia). One of the concerns with isotonic saline is that this solution contains 154 mmol/l chloride and that administration in large volumes will result in relative or absolute hyperchloremia (for a review, see Kaplan et al.¹⁰³). Although direct proof of harm arising from saline-induced hyperchloremia is lacking, buffered salt solutions approximate physiological chloride concentrations and their administration is less likely to cause acid-base disturbances. Whether use of buffered solutions results in better outcomes is, however, uncertain.