Molecular size and origin do not influence the harmful side effects of hydroxyethyl starch on human proximal tubule cells (HK-2) in vitro.

BACKGROUND: Recently, clinical trials revealed renal impairment induced by hydroxyethyl starch (HES) in septic patients. In prior studies, we managed to demonstrate that HES accumulated in renal proximal tubule cells (PTCs). The related pathomechanism has not yet been discovered. To validate our hypothesis that the HES molecule itself is harmful, regardless of its molecule size or origin, we conducted a comprehensive study to elucidate the influences of different HES preparations on PTC viability in vitro. METHODS: Cell viability of human PTC was measured with a cytotoxicity assay, quantifying the reduction of tetrazolium salt to colored formazan. Experiments were performed by assessing the influence of different carrier solutions of HES (balanced, nonbalanced, culture medium), different average molecular weights (70, 130, 200 kDa), different origins (potato or corn derived), and various durations of incubation (2-21 hours). Furthermore, HES 130/0.4 was fractionated by ultrafiltration, and the impact on cell viability of average single-size fractions with <3, 3 to 10, 10 to 30, 30 to 50, 50 to 100, and >100 kDa was investigated. We also tested the possible synergistic effects of inflammation induced by tumor necrosis factor-α. RESULTS: All tested HES solutions, regardless of origin or carrier matrix, decreased cell viability in an equivalent, dose-dependent manner. Coincubation with tumor necrosis factor-α did not reduce HES-induced reduction of cell viability. Minor differences were detected comparing 70, 130, and 200 kDa preparations. Analysis of fractionated HES revealed that each fraction decreased cell viability. Even small HES molecules (10-30 kDa) were significantly deleterious. CONCLUSIONS: For the first time, we were able to show that only the total mass of HES molecules applied is responsible for the harmful impact on renal PTC in vitro. Neither molecular size nor their origin showed any relevance.

Efeitos cardiovascular e metabólico da reposição volêmica com hidroxietilamido 130/0, 4 em felinos domésticos com hipovolemia induzida / Cardiovascular and metabolic effects of volemic expansion with hydroxyethyl starch 130/0, 4 in domestic cats with induced hypovolemia

O objetivo deste estudo foi comparar os efeitos da expansão volêmica produzida pelo hidroxietilamido 130/0,4 (HES 130/0,4) ou pelo sangue em gatas com hipovolemia induzida. Foram utilizadas 12 gatas adultas, sem raça definida (SRD), com peso médio de 2,85±0,28kg e hígidas. Os animais foram induzidos à anestesia geral com isofluorano a 5V por cento, intubados e conectados a um sistema sem reinalação de gases. Após a instrumentação, os animais foram mantidos sob anestesia com isoflurano em 1,3V por cento e mantidos em ventilação mecânica, ciclada a pressão. Em seguida, foi induzida a hipovolemia por meio da retirada de 30ml kg-1 de sangue da artéria femoral. Após 60 minutos da estabilização do paciente, os tratamentos foram iniciados. No grupo hidroxietilamido (GH, n=06), os animais receberam, como reposição volêmica, o hidroxietilamido 130/0,4 no mesmo volume de sangue retirado e, no grupo sangue (GS, n=06), os animais receberam o próprio sangue retirado, sendo considerado grupo controle. A pressão arterial sistólica, a diastólica e a média e a pressão venosa central aumentaram após a reposição volêmica em ambos os grupos. Observou-se, para o GH, aumento da PaCO2 no T15, no T30 e no T60. Houve redução do pH no T30 e no T45 e de íons Na+ no T90 para GH. A restauração das pressões arteriais com a administração de HES 130/0,4 foi similar ao grupo controle. A reposição volêmica com HES 130/0,4 produz aumento acentuado da PVC; e o uso do HES 130/0,4 em gatas submetidas à hipovolemia não produziu alterações clinicamente significativas no equilíbrio ácido-básico.

The aim of this study was to compare the volemic expansion effects produced by hydroxyethyl starch 130/0.4 (HES 130/0.4) or blood, in female cats with induced hypovolemia. Twelve healthy adult female cats, crossbreed and weighing an average of 2.85±0.28kg were used. They were induced into general anesthesia with isofluorane at 5V percent, intubated and connected to a non-rebreathing system. After instrumentation, the animals were maintained under anesthesia with isofluorane at 1.3V percent and maintained on pressure cycled mechanic ventilation. Afterwards, hypovolemia was induced by withdrawal of 30ml kg-1 of blood from the femoral artery. After 60 minutes of stabilization of the patient, the treatments were initiated. In the hydroxyethyl starch group (GH, n=06) the animals received hydroxyethyl starch 130/0.4 as volemic expansion at the same volume of blood withdrawed, in the blood group (GS, n=06) the animals received their own withdrawed blood, being considered the control group. The systolic, diastolic and mean arterial pressures and central venous pressure increased after volemic expansion in both groups. An increase of PaCO2 at T15, T30 and T60 in GH was observed. In addition, there was reduction of pH at T30 and T45 and Na+ ions at T90 in GH. The arterial pressure restoration with the use of HES 130/0.4 was similar to the control group; the volemic expansion with HES 130/0,4 produces accentuated increase of CVP; the use of HES 130/0,4 in female cats submitted to hypovolemia did not produce clinically significant alterations in acid-base equilibrium.

Initial administration of hydroxyethyl starch vs lactated Ringer after liver trauma in the pig.

BACKGROUND: This study tested the circulatory effectiveness of post-trauma administration of a large intravascular volume expander, hydroxyethyl starch 130/0.4 (HES), vs standard lactated Ringer's solution (RL). METHODS: Liver injury was inflicted in 14 pigs [31 (4) kg; mean (sd)] and treatment simulated an acute pre-hospital event: after a standard first-respond delay (7 min), volume administration was provided in three phases to simulate increasing intravascular access. In the first two phases, the fluid was administered either by HES or by RL and, during the last phase, all animals received HES to stabilize the intravascular volume. RESULTS: The liver trauma severed an equal number of 1-3 mm diameter blood vessels [1.4 (0.6)] and after 7 min, the blood loss was 184 (127) ml and mean arterial pressure had decreased by 19 (13) mm Hg (P<0.01). The intravascular volume expansion effect was 115 (25)% for HES and 76 (21)% for RL (P<0.05), yet oxygen uptake was maintained in zero of seven vs three of seven pigs and the survival was three of seven vs seven of seven, respectively (P<0.05). In these animals, the initial administration of HES provoked uncontrolled bleeding, whereas the administration of RL was associated with attenuated bleeding: total blood loss 2455 (1919) vs 311 (208) ml, respectively (P<0.01), reflecting that bleeding ceased in six of the pigs administered RL. CONCLUSIONS: After injury, the intravascular volume expanding effect of HES was larger than that for RL. However, initial administration of HES provoked uncontrolled haemorrhage, suggesting that prioritizing intravascular volume expansion did not result in stabilization of the circulation after haemorrhage.

Hydroxyethyl starch-induced pruritus relieved by a combination of menthol and camphor.

Hydroxyethyl starch is a key component of many colloid volume expanders used in hypovolemic shock and otologic disease. Pruritus is a common side effect. Histopathology reveals multiple cytoplasmic vacuoles in dermal macrophages, endothelial cells, and perineural cells with electron-dense foreign material within the said vacuoles. Although classically refractory to treatment with corticosteroids and antihistamines, some benefit has been achieved with capsaicin, ultraviolet light therapy, and oral naltrexone. We present a case responsive to menthol and camphor and discuss the possible therapeutic mechanism.

Evaluation of a new hydroxyethyl starch solution (HES 130/0.4) in patients undergoing preoperative autologous blood donation.

STUDY OBJECTIVE: To compare the tolerance and efficacy of the new hydroxyethyl starch (HES) 130/0.4 with a current HES solution (HES 200/0.5) in patients undergoing preoperative autologous blood donation as a model of surgical blood loss. HES 130/0.4 is expected to be a plasma substitute as efficacious as current HES solutions while offering such advantages as more complete renal elimination and reduced tissue storage. DESIGN: Controlled, randomized, double-blind, phase II clinical trial. SETTING: 1500-bed university hospital. PATIENTS: 60 ASA physical status II and III patients scheduled for elective cardiac and noncardiac surgery, and meeting selection criteria for autologous blood donors. INTERVENTIONS: Collection of 500 mL of blood with simultaneous intravenous (IV) infusion of 500 mL of either HES 130/0.4 or HES 200/0.5 (mean molecular weight 130 kD and 200 kD, degree of substitution 0.4 and 0.5, respectively). MEASUREMENTS: Noninvasive measurements of heart rate and arterial blood pressure were obtained every 5 minutes until 1 hour after blood donation and infusion of the study drugs; laboratory studies (complete blood counts, electrolytes, markers of renal and liver function) were performed; and follow-up assessment of adverse events was undertaken by questionnaire 24 hours after blood donation and infusion of the study drugs. MAIN RESULTS: Both hemodynamics and laboratory test results did not differ significantly between the groups at any time. Hemodynamics remained stable in each group, and no adverse event was observed in any patient until one hour after blood donation and infusion of the study drugs. Adverse events elicited by postphlebotomy questionnaire were mild and probably unrelated to HES infusion. CONCLUSIONS: Intravenous infusion of 500 mL of the new HES 130/0.4 was tolerated well and maintained cardiovascular stability in patients undergoing preoperative autologous blood donation. HES 130/0.4 proved equivalent to HES 200/0.5 in every measured respect. Its pharmacokinetic profile may render HES 130/0.4 an attractive alternative to current HES solutions.

Lactated Ringer's solution versus hydroxyethyl starch for volume replacement in autologous blood donors with cardiovascular disease: a controlled, randomized trial.

BACKGROUND AND OBJECTIVES: The study was designed to evaluate whether volume replacement following blood donation can prevent arterial hypotension in autologous blood donors with cardiovascular disease. MATERIALS AND METHODS: One hundred nineteen autologous blood donors with known cardiovascular disease were randomly allocated to receive, following withdrawal of 500 ml of blood, either no infusion (control group) or a 25 ml/min intravenous infusion of either 1,500 ml of lactated Ringer's solution (LRS) or 500 ml of 6% hydroxyethyl starch (HES). Starting before phlebotomy, arterial blood pressure was measured oscillometrically every 5 min until 90 min after donation. RESULTS: Group means showed little difference between the groups in blood pressure throughout the monitoring period. The proportion of patients who at least once had a > or = 20% decrease from baseline in systolic blood pressure was 3-5 times greater in the control group than in the LRS and the HES group (50 vs. 10 and 15%, respectively; p < 0.001 on chi 2 analysis for a 2 x 3 table). Systolic hypertensive episodes (> or = 20% increase over baseline) were observed more frequently in the LRS group than in the control and the HES group (41 vs. 10 and 18%, respectively; p = 0.003). CONCLUSION: Both LRS and HES, administered at a volume ratio to blood loss of 3:1 and 1:1, respectively, significantly reduced the incidence of systolic hypotensive episodes in autologous blood donors with cardiovascular disease. LRS at a 3:1 volume ratio to blood loss was associated with a high rate of systolic hypertension.

Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating interleukin-6 levels.

OBJECTIVES: To determine the effects of resuscitation with the colloidal solution (hydroxyethyl starch) vs. crystalloid solution on cell-mediated immune functions after trauma-hemorrhage. DESIGN: Prospective, multiexperimental, randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Thirty-six inbred male C3H/HEN (endotoxin-sensitive) mice, aged 6 to 7 wks, and weighing 18 to 23 g. INTERVENTIONS: Crystalloid (lactated Ringer's solution) with and without 6% hydroxyethyl starch after trauma-hemorrhage. MEASUREMENTS AND MAIN RESULTS: Mice underwent laparotomy, were bled to and maintained at a blood pressure of 40 mm Hg for 60 mins, then resuscitated with either 4x the shed blood volume as lactated Ringer's solution or 2x the shed blood volume as lactated Ringer's solution plus 1 x 6% hydroxyethyl starch. Sham mice were neither hemorrhaged nor resuscitated. At 2 or 24 hrs posthemorrhage, serum, splenocytes, peritoneal macrophages, and splenic macrophages were obtained. Bioassays were used to determine interleukin-2, interleukin-3, and interleukin-6 concentrations, while splenocyte proliferation was assessed by 3H-thymidine incorporation. Trauma-hemorrhage markedly depressed splenocyte proliferation, interleukin-6 release by macrophages, and lymphokine release at 2 and 24 hrs postresuscitation. The combination of lactated Ringer's solution and hydroxyethyl starch neither restored, nor exacerbated lymphocyte functions. Interleukin-6 release by peritoneal macrophages was restored 24 hrs after hydroxyethyl starch infusion; serum interleukin-6 concentrations remained at sham levels. CONCLUSIONS: Since the use of lactated Ringer's solution and hydroxyethyl starch after hemorrhage did not adversely affect cell-mediated immune functions, but produced salutary effects on macrophage functions, hydroxyethyl starch is a safe and beneficial resuscitation adjunct.

Successful treatment of hydroxyethyl starch-induced pruritus with topical capsaicin.

We report a case of recalcitrant pruritus after infusion therapy with hydroxyethyl starch (HES) for sudden deafness. The diagnosis was confirmed by detection of typical HES storage vacuoles within dermal macrophages and perineural cells. Treatment with antihistamines and antipruritic agents, UVB irradiation, and neuroleptic drugs, was ineffective. Topical capsaicin (0.05%) twice daily produced excellent symptomatic relief, without side-effects.

[Autotransfusion with leap-frog technique in patients with coronary heart disease and planned aortocoronary venous bypass]. / Autotransfusion in Bocksprung-Technik bei Patienten mit koronarer Herzkrankheit und geplantem aortokoronarem Venenbypass.

OBJECTIVE: The goal of the study is to test and control the quality of a special leap-frog technique which enables saving heterologous blood. DESIGN: In a randomized double-blind placebo-controlled study homologous blood was taken in 40 out of 100 patients with coronary heart disease before aortocoronary bypass operation. The leap-frog technique was used. Within 8 weeks 3-4 erythrocyte concentrates and 0.9-1.2 liters plasma were sampled. The volume (verum: HES 200/0.5 10%; placebo: 0.9% NaCl solution) substituted corresponding to the volume of blood donated. Each patient received 200 mg Fe2+/day p.o. RESULTS: Clinically, only patients treated with HES in stage of autologous blood sampling benefited significantly. Two patients showed adverse effects. The peri- and postoperative course was comparable. In the NaCl group one of the patients received homologous erythrocyte concentrates. None of the patients died pre-, peri- or post-operatively. CONCLUSIONS: 40% of the cardiosurgical patients could be considered for autologous blood donation. Isovolemic hemodilution with HES 200/0.5 10% was a suitable and safe measure in preoperative blood sampling. Physical exercise should be performed before and after autologous blood donation. A reduced exercise tolerance suggests that autologous blood donation should be stopped.

[Ginkgo extract EGb 761 (tenobin)/HAES versus naftidrofuryl (Dusodril)/HAES. A randomized study of therapy of sudden deafness]. / Ginkgoextrakt EGb 761 (Tebonin)/HAES versus Naftidrofuryl (Dusodril)/HAES. Eine randomisierte Studie zur Hörsturztherapie.

80 patients with idiopathic sudden hearing loss existing no longer than 10 days were included in a randomised reference-controlled study. The therapeutic value of Ginkgo EGb 761 (Tebonin) + HAES was compared to that of Naftidrofuryl (Dusodril)+HAES. The main mechanisms of action of EGb 761 are a vasoregulating activity (increased blood flow), the platelet activating factor antagonism and a prevention of membrane damage caused by free radicals. Naftidrofuryl has antiserotonergic and therefore vasodilatory properties. The statistical analysis of the audiometric data was performed in measuring the relative hearing gain as described by Eibach 1979. After one week of observation, 40% of the patients in each group showed a complete remission of hearing loss. This was also observed by other authors who had compared other drugs. Therefore, in these cases, it is most likely that spontaneous recovery is the most important factor. After two and three weeks of observation, measuring the relative hearing gain, there was a significant borderline benefit of EGb 761 (p = 0.06) without any side effects. Some patients of the reference group developed side effects such as orthostatic dysregulation or headache or sleep disturbances. Minimising side effects should be one of the most important goals in therapy of sudden hearing loss until the efficiency of infusion therapy is proved.