Concerns over use of hydroxyethyl starch solutions.
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ABSTRACT:
SUBMITTER: Hartog CS
PROVIDER: S-EPMC4707718 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
Publications
Concerns over use of hydroxyethyl starch solutions.
Hartog Christiane S CS Natanson Charles C Sun Junfeng J Klein Harvey G HG Reinhart Konrad K
BMJ (Clinical research ed.) 20141110
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Project description:Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-34.Hydroxyethyl starch (HES) is widely used for fluid resuscitation in ICUs, but its safety and efficacy have not been established in patients with severe sepsis.To assess the effects of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end-stage kidney failure in patients with severe sepsis.Multicenter, parallel-group, blinded, randomized clinical trial, in patients with severe sepsis.Patients with severe sepsis admitted to the ICU received fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal body weight per day.Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal replacement therapy compared with those receiving Ringer's acetate.
| S-EPMC3672539 | biostudies-other
Project description:It is heavily debated whether or not treatment with hydroxyethyl starch 130/0.4 contributes to the development of acute kidney failure in patients with severe sepsis. In the previous issue of Critical Care, Muller and colleagues report no association between initial resuscitation with hydroxyethyl starch 130/0.4 and renal impairment in a cohort of septic patients. Can we then consider hydroxyethyl starch 130/0.4 a safe intervention? The answer is no - observational data should be interpreted with caution and should mainly be used to identify risks, while safety must be assessed in randomised clinical trials. With these factors in mind, Muller's data associate the use of vasopressors with poor outcome, underlining the need for further randomised clinical trials to assess the potential harmful effects of common interventions in the critically ill.
| S-EPMC3681340 | biostudies-other
Project description:Cis-platinum has been widely used as a first-line chemotherapy agent in clinics for more than 40 years. Although considerable efforts have been expended for developing platinum-based nano drug delivery systems (NDDS) to resolve the problems of low water solubility, short half-life, and severe side effects of cis-platinum, it remains challenging to apply these nanoplatforms to cancer treatments in clinics on account of the issues related to safety, complex fabrication procedures, and limited cellular uptake. Herein, we constructed a novel cis-platinum delivery system with hydroxyethyl starch (HES), which is a semisynthetic polysaccharide that has been used worldwide as colloidal plasma volume expanders (PVE) in clinics for several decades. By combining TEM, AFM, and DLS, we have found that HES particles are colloidal nanoparticles in solution, with diameters ranging from 15 to 40 nm as a function of molecular weight. We further revealed that HES adopted a hyperbranched colloidal structure with rather compact conformation. These results demonstrate that HES is a promising nanocarrier to deliver drug molecules. Taking advantage of the poly-hydroxyl sites of HES, we constructed a novel HES-based cis-platinum delivery nanoplatform. HES was directly conjugated with cis-platinum prodrug via an ester bond and decorated with an active targeting molecule, lactobionic acid (LA), contributing toward higher in vitro antitumor activity against hepatoma carcinoma cells as compared to cis-platinum. These results have significant implications for the clinically used plasma volume expander-HES and shed light on the clinical translation of HES-based nano drug delivery systems.
| S-EPMC9473228 | biostudies-literature
Project description:IntroductionFluid administration in critically ill patients may affect acid-base balance. However, the effect of the fluid type used for resuscitation on acid-base balance remains controversial.MethodsWe studied the effect of fluid resuscitation of normal saline and the colloids gelatine 4%, hydroxyethyl starch (HES) 6%, and albumin 5% on acid-base balance in 115 clinically hypovolemic critically ill patients during a 90 minute filling pressure-guided fluid challenge by a post-hoc analysis of a prospective randomized clinical trial.ResultsAbout 1700 mL was infused per patient in the saline and 1500 mL in each of the colloid groups (P<0.001). Overall, fluid loading slightly decreased pH (P<0.001) and there was no intergroup difference. This mildly metabolic acidifying effect was caused by a small increase in chloride concentration and decrease in strong ion difference in the saline- and HES-, and an increase in (uncorrected) anion gap in gelatine- and albumin-loaded patients, independent of lactate concentrations.ConclusionIn clinically hypovolemic, critically ill patients, fluid resuscitation by only 1500-1700 mL of normal saline, gelatine, HES or albumin, resulted in a small decrease in pH, irrespective of the type of fluid used. Therefore, a progressive metabolic acidosis, even with increased anion gap, should not be erroneously attributed to insufficient fluid resuscitation.Trial registrationISRCTN Registry ISRCTN19023197.
| S-EPMC5381890 | biostudies-literature
Project description:At present, effective anticancer therapy remains one of the most challenging tasks facing the scientific community. A major limitation to most conventional low-molecular weight anticancer chemotherapeutics is their unfavourable uptake by healthy tissue, fast metabolism and lack of tumour cell selectivity. One way to solve this problem is the application of hybrid nanoparticles containing widely known therapeutic substances. This study was performed with the aim of investigating the potential of use hydroxyethyl starch (HES) as a high-molecular weight carrier for anticancer drug (methotrexate, MTX). HES-MTX conjugates were characterized in terms of MTX content, hydrodynamic size, zeta potential, and drug release kinetics. In vitro biological characteristics were determined using different cancer cell lines. The antitumor effect in vivo was tested in NOD/SCID mice subcutaneously inoculated with MV-4-11 human leukaemia cells and CDF1 mice intraperitoneally inoculated with P388 murine leukaemia cells. The in vivo experiments revealed the considerably higher antitumor efficacy of HES-MTX conjugates in comparison to unconjugated drug. The results presented in this article demonstrate that the application of HES as an anticancer drug carrier can improve the treatment efficacy and have significant implications for the future design and implementation of drug-carrier conjugates. The study should help create new opportunities in the design of HES-based innovative drug-carrier conjugates.
| S-EPMC4186415 | biostudies-literature
Project description:While hydroxyethyl starch (HES) solutions are not recommended any longer in critically ill patients, data on efficacy and safety during surgery are still limited.In a randomized controlled trial 63 patients were assigned to receive 10% HES (130/0.42), 6% HES (130/0.42), or crystalloid within a goal-directed hemodynamic algorithm during pancreatic surgery. The primary endpoints were intraoperative volume of HES and time until fully on oral diet.The trial was terminated early upon recommendation of an independent data monitoring committee due to futility for efficacy at a planned interim analysis. The intraoperative volume of HES was not different between 10% and 6% HES group (2000 [1500; 2250] vs 2250 [1750; 3000] mL, P=.059). However, considering an inhomogeneity of patient's body weight between HES groups, there was a significant difference in intraoperative volume of HES between 10% and 6% group after adjusting for patient's body weight (24.0 [21.6; 28.3] vs 33.3 [28.2; 46.2] mL kg BW, P?=?.002). Patients in the HES groups required less additional fluid after dose limit than those in the crystalloid group, resulting in lower intraoperative net balances. The time until fully on oral diet was not different between all study groups. Applying KDIGO oliguria criterion, patients receiving 10% HES had more AKI compared to patients receiving crystalloids (86.7 vs 45.0%, P?=?.010), whereas those receiving 6% HES and crystalloids did not differ (58.8 vs 45.0%, P?=?.253). Further explorative analyses using a gray-zone approach indicated that patients receiving 6% HES below 18.8 mL kg will not experience AKI with near certainty.After adjusting for patient's body weight, patients receiving 6% HES required more volume of HES than patients receiving 10% HES. The relation of 140% represents very well the volume effect of a hyperoncotic 10% HES solution. Nonetheless, both HES solutions were similarly effective in reducing intraoperative fluid administration compared with crystalloid, but this did not result into differences in gastrointestinal outcomes. Patients receiving 10% HES showed an increased rate of AKI, whereas those receiving 6% HES and crystalloid did not differ. However, 6% HES should not be applied beyond 18 mL kg during surgery.
| S-EPMC5944526 | biostudies-literature
Project description:Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. Atomic force microscopy was used to demonstrate a pH-dependent assembly of CQ-HES into well-defined nanoparticles. In vitro studies in multiple PC cell lines showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration and invasion of PC cells when compared with HCQ. The enhanced inhibitory actions of CQ-HES compared to HCQ appeared to arise in part from the increased inhibition of ERK and Akt phosphorylation. We found no significant HCQ release from CQ-HES, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Due to its promising ability to block cancer cell invasion and the ability to form nanoparticles, CQ-HES has the potential as a drug delivery platform suitable for future development with chemotherapeutics to establish novel antimetastatic treatments.
| S-EPMC5996760 | biostudies-literature
Project description:Intestinal permeation enhancers (PEs) are key components in ∼12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo- and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.
| S-EPMC4910835 | biostudies-literature
Project description:After a safety review of hydroxyethyl starch (HES) solutions in 2013, restrictions on the use of HES were introduced in the European Union (EU) to reduce the risk of kidney injury and death in certain patient populations. Similar restrictions were introduced by the Food and Drug Administration in the United States and other countries. In October 2017, a second safety review of HES solutions was triggered by the European pharmacovigilance authorities based on a request by the Swedish Medical Products Agency to completely suspend HES. After several meetings and repeated evaluations, the recommendation to ban HES was ultimately not endorsed by the responsible committee; however, there was a vote for more restricted access to the drug and rigorous monitoring of policy adherence. This review delineates developments in the European pharmacovigilance risk assessment of HES solutions between 2013 and 2018. In addition, the divergent experts' opinions and the controversy surrounding this official assessment are described. As the new decisions might influence the availability of HES products for veterinary patients, potential alternatives to HES solutions, such as albumin solutions and gelatin, are briefly discussed.
| S-EPMC6345713 | biostudies-literature
Project description:PurposeTo systematically review clinical and preclinical data on hydroxyethyl starch (HES) tissue storage.MethodsMEDLINE (PubMed) was searched and abstracts were screened using defined criteria to identify articles containing original data on HES tissue accumulation.ResultsForty-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.ConclusionsTissue storage of HES is widespread, rapid, cumulative, frequently long-lasting, and potentially harmful.
| S-EPMC7728635 | biostudies-literature