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The possibility of renal damage by hydroxyethyl starch has become the focus of intensive dispute based on the findings of published large trials. The aim of this narrative review is to analyze outcome reporting bias in the literature on volume resuscitation, focusing on selective outcome reporting in published randomized and observational trials with "modern" hydroxyethyl starch as therapeutic intervention. Three recent publications claimed to confirm renal safety of hydroxyethyl starch 130/0.4 for indications in severe sepsis, trauma, and critical illness, respectively. Selective outcome reporting was identified in these studies including underreporting of side effects and change of primary study outcomes. In conclusion, selective outcome reporting bias is identified in recent publications of clinical trials on volume resuscitation with HES.

Purpose: To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage., Methods: MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation., Results: Forty-eight studies were included: 37 human studies with a total of 635 patients and 11 animal studies. The most frequent indication for fluid infusion was surgery accounting for 282 patients (45.9%). HES localization in skin was shown by 17 studies, in kidney by 12, in liver by 8, and in bone marrow by 5. Additional sites of HES deposition were lymph nodes, spleen, lung, pancreas, intestine, muscle, trophoblast, and placental stroma. Among major organs the highest measured tissue concentration of HES was in the kidney. HES uptake into intracellular vacuoles was observed by 30 min after infusion. Storage was cumulative, increasing in proportion to dose, although in 15% of patients storage and associated symptoms were demonstrated at the lowest cumulative doses (0.4 g kg(-1)). Some HES deposits were extremely long-lasting, persisting for 8 years or more in skin and 10 years in kidney. Pruritus associated with HES storage was described in 17 studies and renal dysfunction in ten studies. In one included randomized trial, HES infusion produced osmotic nephrosis-like lesions indicative of HES storage (p = 0.01) and also increased the need for renal replacement therapy (odds ratio, 9.50; 95% confidence interval, 1.09-82.7; p = 0.02). The tissue distribution of HES was generally similar in animals and humans., Conclusions: Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

Background: Hydroxyethyl starch (HES) is in widespread clinical use for volume therapy with colloids. According to the most recent meta-analysis performed in 2010, published studies are of poor quality and report too few events to reliably estimate the benefits or risks of administering 6% HES 130/0.4. As results from new trials, reporting on a large number of events became available in 2011 and 2012, an updated meta-analysis was performed., Methods: Randomised controlled trials comparing the effects of 6% HES 130/0.4 with other colloid or crystalloid solutions were analysed for pooled effect size on mortality in eligible studies published up to 20 February 2012., Results: Overall, 13 studies reporting 1,131 participants met the inclusion criteria. The weight of evidence contributed by the two new trials was 51.3%. The pooled relative risk (RR) for mortality increased to 1.14 with a 95% confidence interval (CI) of 0.89 to 1.46. Publication bias favoring HES 130/0.4 was present (p = 0.038). Adjustment for the observed publication bias increased the RR for mortality to 1.25 (CI, 0.98 to 1.58; p = 0.069). No heterogeneity was found (I2, 0%; CI, 0% to 32%; p = 0.81)., Conclusions: Large-scale trials should help more precisely to determine the effect of HES 130/0.4 on mortality. In the interim, best current evidence suggests a trend toward higher mortality among HES 130/0.4 recipients.

Background: Intravenously infused hydroxyethyl starch (HES) can be found in urine, plasma and tissues. HES remaining in plasma and tissues is thought to increase the risk of clinical complications. HES solutions of lower molecular weight and substitution have been developed to increase urinary excretion and reduce plasma persistence. However, their effect on tissue uptake of HES has not been investigated in human subjects., Objective: Our objective was to test the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES., Data Sources: Computer searches were performed of MEDLINE; EMBASE; the Cochrane Library; meeting abstract databases in surgery, anaesthesiology and intensive care; ClinicalTrials.gov; and Google. Supplementary sources were reference lists and electronic tables of journal contents. No time period or language restrictions were imposed., Study Selection: Clinical studies were eligible for inclusion in the meta-analysis, if data were reported both for cumulative urinary excretion of HES over 24 hours after infusion and for plasma HES concentration at 24 hours., Data Extraction: Data were extracted on 24-hour urinary excretion of HES, 24-hour HES plasma concentration, plasma volume, HES molecular weight and substitution, study design, type and demographics of subjects, indication for fluid infusion, and HES infusion regimen. Tissue uptake of HES was computed as the difference between the infused dose and the sum of urinary excretion and residual plasma HES at 24 hours., Data Synthesis: Twenty-five clinical studies totalling 287 subjects were included. Tissue uptake of low-molecular-weight HES (≤200 kD) was 42.3% (95% confidence interval [CI] 39.6, 45.0) compared with 24.6% (CI 17.8, 31.4) for high-molecular-weight HES (p < 0.001). Similarly, tissue uptake of lower-substitution HES (≤0.5) was 42.4% (CI 39.5, 45.3) versus 26.6% (CI 19.6, 33.6) for higher-substitution HES (p < 0.001). Among the three most often investigated single HES solutions, tissue uptake of 130/0.4 (42.6%; CI 35.0, 50.2) and HES 200/0.5 (43.3%; CI 39.4, 47.2) closely coincided, whereas uptake of HES 450/0.7 (22.2%; CI 14.8, 29.6) was lower (p = 0.001 and p < 0.001, respectively)., Conclusions: This meta-analysis did not support the hypothesis that lower molecular weight and substitution decrease tissue uptake of HES. Further clinical studies of HES tissue uptake are needed.

Introduction: It has been hypothesized that hyperoncotic colloids might contribute to acute kidney injury (AKI). However, the validity of this hypothesis remains unclear., Methods: A meta-analysis was conducted of randomized controlled trials evaluating AKI after infusion of hyperoncotic albumin and hydroxyethyl starch (HES) solutions. Mortality was a secondary endpoint. Eligible trials were sought by multiple methods, and the pooled odds ratios (OR) for AKI and death and 95% confidence intervals (CI) were computed under a random effects model., Results: Eleven randomized trials with a total of 1220 patients were included: 7 evaluating hyperoncotic albumin and 4 hyperoncotic HES. Clinical indications were ascites, surgery, sepsis and spontaneous bacterial peritonitis. Hyperoncotic albumin decreased the odds of AKI by 76% (OR, 0.24; CI, 0.12-0.48; P < 0.0001), while hyperoncotic HES increased those odds by 92% (OR, 1.92; CI, 1.31-2.81; P = 0.0008). Parallel effects on mortality were observed, with hyperoncotic albumin reducing the odds of death by 48% (OR, 0.52; CI, 0.28-0.95; P = 0.035) and hyperoncotic HES raising those odds by 41% (OR, 1.41; CI, 1.01-1.96; P = 0.043)., Conclusions: This meta-analysis does not support the hypothesis that hyperoncotic colloid solutions per se injure the kidney. Renal effects appear instead to be colloid-specific, with albumin displaying renoprotection and HES showing nephrotoxicity.

Hydroxyethyl starch (HES) has come into widespread use for fluid management of acutely ill patients. Certain characteristic complications of HES, notably renal impairment, hemorrhage and pruritus, have been well documented with all types of HES solutions. The use of HES solutions with lower molecular weight and substitution has been claimed to minimize these safety risks. In particular, solutions of 200 kDa molecular weight and 0.5 substitution (HES 200/0.5) and of 130 kDa molecular weight and 0.4 substitution (HES 130/0.4) have been advocated for their superior safety profile. A critical appraisal of the available evidence does not provide reassurance that these or other HES solutions are risk free. Most evidence indicates the equivalence of HES 200/0.5 and HES 130/0.4 with respect to effectiveness for volume expansion. Since HES 130/0.4 is newer, its safety profile is less well characterized; however, it appears to share the same complication risks as those of HES 200/0.5. In randomized clinical trials employing sensitive markers, both HES 200/0.5 and HES 130/0.4 have been shown to impair renal function. Both coagulopathy and clinical bleeding have been documented after administration of either HES 200/0.5 or HES 130/0.4, and the magnitude of negative effects on hemostasis has been similar for these two HES solutions. Pruritus is a common side effect of all HES solutions, including HES 200/0.5 and HES 130/0.4, and can occur in diverse clinical settings in some cases after only small HES doses. Typically presenting as pruritic crises of delayed onset, this complication is often severe, protracted and refractory to treatment. An additional risk of HES infusion is the occurrence of potentially life-threatening anaphylactoid reactions, which are 4.5 times as frequent after HES as albumin exposure. Limiting the dose and duration of HES therapy may be helpful in lessening the risk of undesired side effects; at present however, reliance on particular HES solutions does not appear sufficient to ensure safety.