Effects of Hydroxyethylstarch on Renal Function in Severe Sepsis

Abstract & Commentary

Synopsis: The use of hydroxyethylstarch as a plasma-volume expander may increase the risk of acute renal failure in patients with severe sepsis or septic shock.

Source: Schortgen F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study. Lancet. 2001;357: 911-916.

Volume expansion is the mainstay of hemodynamic resuscitation. Primary choices for volume expanders are crystalloids or colloids. Whether crystalloids or colloids are preferable and whether one colloid is better than the others have been debated for a long time. Most studies have examined intermediate outcomes (such as hemodynamic responses) but no clinically relevant end points (such as mortality or tissue injury). A common practice is to use crystalloids for maintenance fluid therapy and colloids when fluid boluses are required to acutely increase the vascular volume. However, colloids have significant toxicities that must be considered when using them.

The study of Schortgen and colleagues raises the question of whether hydroxyethylstarches (HES) can impair renal function in critically ill patients, based on previous data showing that the use of HES in a selected population of brain-dead kidney donors was associated with immediate impairment of renal function in the transplant recipients.1

Schortgen et al carried out a multicenter, randomized study assessing the frequency of acute renal failure (ARF) in patients with sepsis or septic shock treated with HES or gelatin. The study took place between April 1998, and September 1999, in the ICUs of 3 French hospitals. Adults were eligible if they had severe sepsis or septic shock at admission or at any time during the stay in the ICU and were deemed by the physician to require fluid loading. Reasons for exclusion were: pregnancy, history of allergy to HES or gelatin; severe acute or chronic renal dysfunction; and previous administration of HES or mannitol. Eligible patients were randomized as soon as they met the study criteria for severe sepsis or septic shock requiring fluid loading. Patients assigned HES treatment received a 6% solution of HES of molecular weight 200 kDa and degree of substitution between 0.60 and 0.66 (33 mL/kg during the first day and 20 mL/kg daily thereafter). Patients assigned gelatin received 3% fluid-modified gelatin of molecular weight 35 kDa (with no dose limitation). The primary end point was ARF (defined as a 2-fold increase in serum creatinine from baseline or need for renal replacement therapy) during the ICU stay.

Of 328 patients screened, 129 were eligible and consented to take part in the study (HES 65, gelatin 64). The study groups were similar at admission to the ICU and at study inclusion. ARF developed after admission in 27 (42%) out of 65 in the HES group and 15 (23%) of 64 in the gelatin group (P = 0.028). Serum creatinine was 225 mmol/L vs. 169 mmol/L (P = 0.04). The frequency of oliguria was also higher in the HES group. However, similar numbers of patients required renal-replacement therapy in the 2 groups. Mortality and length of stay in the ICU were also similar in the 2 study groups. In a multivariate analysis, risk factors for ARF were mechanical ventilation and use of HES.

Comment by Francisco Baigorri, MD

A postal survey in Germany suggested that no "standard" exists for volume replacement in the critically ill.2 The kind of volume therapy used differs widely among the different ICUs. There are no clinical trials demonstrating the superiority of either form of fluid. Two recently published systematic reviews of randomized trials showed that resuscitation with colloids was associated with similar or even increased mortality.3,4 The benefits of colloids are that similar hemodynamic responses can be achieved with smaller volumes and the effects last longer, but colloids have significant toxicities (such as hypersensitivity reactions and coagulopathies). These adverse effects seemed to be less common with HES, such as hetastarch and pentastarch. Moreover, some studies suggested that these colloids might reduce abnormally increased microvascular permeability.5 However, the study of Schortgen et al prompts the thought that the use of HES should be avoided in patients at risk of ARF.

A combination of extreme ischemia and osmotic-nephrosis-like lesions has been pointed out as an explanation for the impairment of the renal function associated with the use of HES. The clinical relevance of the findings in the study of Schortgen et al, without an increased requirement of renal-replacement therapy, ICU mortality, or length of stay may be questionable, but we must consider carefully the potential implications. Most critically ill patients requiring fluid loading are at risk of multiple organ failure. Of course, further studies are needed to determine the exact problem. Meanwhile, fluid administration will continue to be individualized to each patient.4

References

1. Cittanova ML, et al. Lancet. 1996;348:1620-1622.

2. Boldt J, et al. Intensive Care Med. 1998;24:147-151.

3. Schierthout G, Roberts I. BMJ. 1998;316:961-964.

4. Choi P, et al. Crit Care Med. 1999;27:200-210.

5. Zikria BA, et al. Crit Care Med. 1989;17:1306-1309.