The Pharmacokinetics and Tolerability of an Intravenous Infusion of the New Hydroxyethyl Starch 130/0.4 (6%, 500 mL) in Mild-to-Severe Renal Impairment

Clinical Research, Fresenius Kabi, 61346 Bad Homburg, Germany.
Anesthesia & Analgesia (Impact Factor: 3.47). 09/2002; 95(3):544-51, table of contents. DOI: 10.1097/00000539-200209000-00007
Source: PubMed


Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven®; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CLcr) to severe renal impairment (mean CLcr: 50.6 mL·min-1. 1.73 m-2), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72-96 h. CLcr had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC0-inf) clearly depended on renal function comparing subjects with CLcr <50 with those with CLcr ≥50 (ratio 1.73). Peak concentration (Cmax, 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CLcr ≥30, 59% of the drug could be retrieved in urine, versus 51% at CLcr 15-<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Predose amylase concentrations inversely correlated with baseline CLcr. Residual HES plasma concentrations after 24 h were small in all subjects (≤0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation.

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    • "However, as reported by our group, older-generation HES such as the hyperoncotic HES 200/0.6 (10%) might be associated with a higher incidence of renal failure and higher overall mortality in severe burn injury [12]. One explanation could be related to the fact that only about 33% to 66% of the administered hyperoncotic HES is excreted in the urine in the first 24 hours after infusion [18]. Thus, the remaining HES molecules, which are still in high concentration, may circulate for a long time and a substantial proportion might accumulate in various tissues, including kidney. "
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    ABSTRACT: There are limited data on the efficacy of early fluid resuscitation with third generation hydroxyethyl starch (HES 130) in burn injury. Adverse effects of HES on survival and organ function have been reported. In this randomized, controlled, double-blind trial 48 patients with severe burn injury were assigned to receive either Lactated Ringer's solution plus 6% HES 130/0.4 in a ratio of 2:1 or Lactated Ringer's solution with no colloid supplement for the first 72 hours. Primary outcome parameter was the group difference of administered total fluid from intensive care unit (ICU) admission up to day 3. Secondary outcomes included kidney and lung injury and failure, length of stay, and mortality. 3 days total of administered resuscitation fluid (medians) was 21,190 ml in the Lactated Ringer's group and 19,535 ml in the HES group (HES: -1,213 ml; P = 0.39). Creatinine levels day 1 to 3 (HES: +0.4 mumol/l; 95% CI -18.7 to 19.5; P = 0.97) and urinary output day 1 to 3 (HES: -58 ml; 95% CI -400 to 284; P = 0.90) were not different. 6 patients in each group developed acute respiratory distress syndrome (ARDS) (risk ratio 0.96; 95% CI 0.35 to 2.64; P = 0.95). Length of ICU stay (HES vs. Lactated Ringer's: 28 vs. 24 days; P = 0.80) and length of hospital stay (31 vs. 29 days; P = 0.57) were similar. 28-day mortality was 4 patients in each group (risk ratio 0.96; 95% CI 0.27 to 4.45; P = 0.95), in-hospital mortality was 8 in the HES group vs. 5 patients in the Lactated Ringer's group (hazard ratio 1.86; 95% CI 0.56 to 6.19; P = 0.31). There was no evidence that early fluid resuscitation with balanced HES 130/0.4 (6%) in addition to Lactated Ringer's solution would lead to a volume sparing effect in severe burn injury. Together with the findings that early renal function, incidence of ARDS, length of stay, and mortality were not negatively influenced by HES in this setting, balanced HES 130/0.4 (6%) plus Lactated Ringer's solution could not be considered superior to Lactated Ringer's solution alone.Trial registration: NCT01012648.
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    • "In this view, the above described results of this study might also be explained by prevention of I/R-induced renal cell injury in APC-treated rats and protective effects of APC on cellular integrity and tight junction structure [44,45]. There is some evidence that traditional HES solutions can impair renal function and should be used with caution in patients with renal insufficiency [46]. In contrast, the latest generation of HES with low molecular weight and low degree of substitution (such as HES 130/0.4) is suggested to have minimal influence on renal function and coagulation. "
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    ABSTRACT: We aimed to test whether continuous recombinant human activated protein C (APC) administration would be able to protect renal oxygenation and function during endotoxemia in order to provide more insight into the role of coagulation and inflammation in the development of septic acute kidney injury. In anesthetized, mechanically ventilated Wistar rats, endotoxemia was induced by lipopolysaccharide administration (10 mg/kg i.v. over 30 min). One hour later, the rats received fluid resuscitation with 0 (LPS + FR group; n = 8), 10 (APC10 group; n = 8), or 100 (APC100 group; n = 8) μg/kg/h APC for 2 h. Renal microvascular oxygenation in the cortex and medulla were measured using phosphorimetry, and renal creatinine clearance rate and sodium reabsorption were measured as indicators of renal function. Statistical significance of differences between groups was tested using two-way ANOVA with Bonferroni post hoc tests. APC did not have notable effects on systemic and renal hemodynamic and oxygenation variables or creatinine clearance. The changes in renal microvascular oxygenation in both the cortex (r = 0.66; p < 0.001) and medulla (r = 0.80; p < 0.001) were correlated to renal sodium reabsorption. Renal sodium reabsorption is closely correlated to renal microvascular oxygenation during endotoxemia. In this study, fluid resuscitation and APC supplementation were not significantly effective in protecting renal microvascular oxygenation and renal function. The specific mechanisms responsible for these effects of APC warrant further study.
    Full-text · Article · Dec 2013
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    • "Patients with severe underlying kidney failure were excluded from the present study. However, importantly, in a pharmacokinetic study in which 500 ml 6% HES 130/0.4 was administered to each of 19 patients with pre-existing renal insufficiency of variable degree, the maximum plasma concentration of starch and its terminal half-life were not affected by renal insufficiency [24]. "
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    ABSTRACT: Inadequate initial treatment and delayed hemodynamic stabilization (HDS) may be associated with increased risk of death in severe sepsis patients. In order to compare the hemodynamic efficacy and safety of 6% HES 130/0.4 and NaCl 0.9% for HDS in patients with severe sepsis, we designed a prospective, multicenter, active-controlled, double-blind, randomized study in intensive care units. 174 out of 196 patients reached HDS (88 and 86 patients for HES and NaCl, respectively). Significantly less HES was used to reach HDS vs. NaCl (1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group (mean difference = -331± 1,033, 95% CI -640 to -21, P = 0.0185). Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl, respectively. Total quantity of study drug infused over four consecutive days, ICU and hospital LOS, and area under the curve of SOFA score were comparable. Acute renal failure occurred in 24 (24.5%) and 19 (20%) patients for HES and NaCl, respectively (P = 0.454). There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality, coagulation, or pruritus up to 90 days after treatment initiation. Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups.
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