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      Accumulation of hydroxyethyl starch in human and animal tissues: a systematic review


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          To systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage.


          MEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation.


          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.


          Tissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00134-013-3156-9) contains supplementary material, which is available to authorized users.

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          Most cited references58

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          Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

          New England Journal of Medicine, 367(20), 1901-1911
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            Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes.

            Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells. The term refers to a nonspecific histopathologic finding rather than defining a specific entity. Osmotic nephrosis can be induced by many different compounds, such as sucrose, hydroxyethyl starch, dextrans, and contrast media. It has a broad clinical spectrum that includes acute kidney injury and chronic kidney failure in rare cases. This article discusses the pathological characteristics, pathogenesis, and various clinical entities of osmotic nephrosis.
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              Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function.

              Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation to replace intravascular volume, yet they have been increasingly associated with adverse effects on kidney function. This is an update of a Cochrane review first published in 2010. To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations. We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. The most recent search was completed on November 19, 2012. Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. All outcomes were analysed using relative risk (RR) and 95% confidence intervals (95% CI). Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random-effects model. This review included 42 studies (11,399 patients) including 19 studies from the original review (2010), as well as 23 new studies. Fifteen studies were excluded from the original review (nine retracted from publication due to concerns about integrity of data and six lacking individual patient creatinine data for the calculation of RIFLE criteria). Overall, there was a significant increase in the need for RRT in the HES treated individuals compared to individuals treated with other fluid therapies (RR 1.31, 95% CI 1.16 to 1.49; 19 studies, 9857 patients) and the number with author-defined kidney failure (RR 1.59, 95% CI 1.26 to 2.00; 15 studies, 1361 patients). The RR of AKI based on RIFLE-F (failure) criteria also showed an increased risk of AKI in individuals treated with HES products (RR 1.14, 95% CI 1.01 to 1.30; 15 studies, 8402 participants). The risk of meeting urine output and creatinine based RIFLE-R (risk) criteria for AKI was in contrast in favour of HES therapies (RR 0.95, 95% CI 0.91 to 0.99; 20 studies, 8769 patients). However, when RIFLE-R urine output based outcomes were excluded as per study protocol, the direction of AKI risk again favoured the other fluid type, with a non-significant RR of AKI in HES treated patients (RR 1.05, 95% CI 0.97 to 1.14; 8445 patients). A more robust effect was seen for the RIFLE-I (injury) outcome, with a RR of AKI of 1.22 (95% CI 1.08 to 1.37; 8338 patients). No differences between subgroups for the RRT and RIFLE-F based outcomes were seen between sepsis versus non-sepsis patients, high molecular weight (MW) and degree of substitution (DS) versus low MW and DS (≥ 200 kDa and > 0.4 DS versus 130 kDa and 0.4 DS) HES solutions, or high versus low dose treatments (i.e. ≥ 2 L versus < 2 L). There were differences identified between sepsis versus non-sepsis subgroups for the RIFLE-R and RIFLE-I based outcomes only, which may reflect the differing renal response to fluid resuscitation in pre-renal versus sepsis-associated AKI. Overall, methodological quality of the studies was good. The current evidence suggests that all HES products increase the risk in AKI and RRT in all patient populations and a safe volume of any HES solution has yet to be determined. In most clinical situations it is likely that these risks outweigh any benefits, and alternate volume replacement therapies should be used in place of HES products.

                Author and article information

                +39-471-908190 , +39-471-908303 , christian.wiedermann@asbz.it
                Intensive Care Med
                Intensive Care Med
                Intensive Care Medicine
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                21 November 2013
                21 November 2013
                : 40
                : 2
                : 160-170
                [1 ]GRID grid.413733.1, Department of Internal Medicine, , Central Hospital of Bolzano, ; Lorenz-Böhler-Street 5, 39100 Bolzano, Italy
                [2 ]GRID grid.5361.1, ISNI 0000000088532677, Division of Emergency and Intensive Care Medicine, Department of Internal Medicine, , Medical University of Innsbruck, ; Innsbruck, Austria
                © Springer-Verlag Berlin Heidelberg and ESICM 2013

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                Systematic Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg and ESICM 2014

                Emergency medicine & Trauma
                hydroxyethyl starch,hetastarch,storage,accumulation,uptake,deposit
                Emergency medicine & Trauma
                hydroxyethyl starch, hetastarch, storage, accumulation, uptake, deposit


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