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[Clinical experiences with the acute normovalemic hemodilution (author's transl)].

Acute normavolemic hemodilution is a mean of autotransfusion and allow hepatitis prophylaxis in major surgical procedures which general require homologous blood transfusions. The dilutional drop in blood viscosity is followed by an increased cardiac output, while blood pressure and heart rate remain stable. The CO incerase compensates for the reduced oxygen capacity of the diluted blood. Hemodilution was applied in a total of 88 patients. In 46 cases thorough circulatory and laboratory investigations were performed. While an average of 1785 ml blood was withdrawn and replaced synchronically by plasma substitutes, hematocrit was lowered to 24.8% mean and CO rose from 4.4 to 6.01 l/min. In one half of the patients side reactions were observed that occurred in combination as a syndrome in 8 patients: rise in systemic blood pressure and pulmonary artery pressure, disproportional CO increase, peripheral vasoconstriction, and ST-depression in ECG. The possible pathomechanisms of these side reactions are discussed. A sympathetic adrenergic reaction could be excluded by catecholamine estimation. Hyposia may be assumed to be the more probable reason. Since severe side reactions only occured at hematocrit levels below 26%, the dilution waslimited lately to hct 27%. Patients with coronary heart disease, age greater than 70 years, and anemia less than 12 g% hgb were excepted. In 70% of major surgical procedures, e.g. colonic surgery, homologous blood becomes necessary, in 50% in the amount of 2-4 units. The corresponding blood loss of 1000-2000 ml may be compensated by acute normovolemic hemodilution and autotransfusion. In fact, only 15% of our patients required homologous blood transfusions.

Adult↗

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

After withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days. Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.

Adult↗

Terlipressin and gelafundin: safe therapy of hepatorenal syndrome.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) occurs in about 20 % of patients with liver cirrhosis and ascites and is characterized by intensive renal vasoconstriction, low glomerular filtration rate but preserved tubular function and normal renal histology. The potential of terlipressin and albumin to reverse HRS after a time period of 14 days has already been shown. However, intravenous albumin is expensive (approximately 25 per 50 ml 20% albumin in Germany) and has limited availability in some settings. Therefore we used an artificial plasma substitute, Gelatinepolysuccinat, which is less expensive (approximately 12 per 500 ml). The aim of our present study was to examine the effects of terlipressin and Gelatinepolysuccinat on renal function and hemodynamics in a time period of six days. METHODS AND PATIENTS: Seven consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (6 mg /24 h iv) therapy associated with i.v. Gelatinepolysuccinat (Gelafundin 4% Infusionslösung, Company Braun, Mw: 30 000 D). RESULTS: In five of the seven patients treatment was associated with a marked reduction of serum creatinine after six days (3.85 +/- 0.44 mg/dl vs.1.9 +/- 0.32 mg/dl; p< 0.018). Creatinine clearance improved (20 +/- 8.8 ml/min vs. 43 +/- 11.7 ml/min; p<0.12). There was a remarkable improvement in circulatory function in all patients, with an increase in mean arterial pressure (58+/-4.4 mmHg vs. 75 +/- 4.5 mmHg, p< 0.001). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS: Terlipressin and Gelatinepolysuccinat appear to be a safe and effective treatment of hepatorenal syndrome.

Antihypertensive Agents↗

Influence of hydroxyethyl starch 130/0.4 in pulmonary neutrophil recruitment and acute lung injury during polymicrobial sepsis in rats.

BACKGROUND: Acute lung injury (ALI) is a progressive syndrome associated with significant mortality in sepsis patients. Neutrophils are key cells in the inflammatory response that characterizes ALI. This study was designed to explore the effects of hydroxyethyl starch (HES) 130/0.4 (a novel plasma substitute) on pulmonary neutrophil recruitment and associated ALI in a rat sepsis model induced by cecal ligation and puncture (CLP). METHODS: Animals were randomly assigned to six groups [saline control; CLP and saline; CLP and HES (7.5, 15 and 30 ml/kg); and HES control], subjected to CLP and infused with or without HES 130/0.4 4 h after CLP. Six hours later, the pulmonary capillary permeability (PCP), myeloperoxidase (MPO) activity, lung histological changes, tumor necrosis factor-alpha, interleukin-1beta and cytokine-induced neutrophil chemoattractant levels, P-selectin mRNA expression and nuclear factor-kappa B (NF-kappaB) activation were measured. RESULTS: Resuscitation with HES 130/0.4 significantly attenuated the CLP-induced increase in PCP, MPO activity, cytokine/chemokine levels, mRNA expression of P-selectin and NF-kappaB activation, all of which are involved in the recruitment of neutrophils. Groups receiving the higher doses of HES 130/0.4 (15 and 30 ml/kg) were more adequately resuscitated. CONCLUSION: HES 130/0.4 can inhibit CLP-induced neutrophil recruitment and subsequent ALI by attenuating cytokines/chemokines, adhesion molecule-mediated inflammation and NF-kappaB activation.

Animals↗

Mechanism of the effect of hydroxyethyl starch on reducing pulmonary capillary permeability in a rat model of sepsis.

Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. Recent studies have indicated that HES may reduce capillary leakage. The present in vivo study was performed to investigate the effects of HES on pulmonary capillary permeability, inflammatory mediators, and transcription factors in sepsis. Septic rats induced by cecal ligation and puncture (CLP) were treated with different doses of HES (7.5, 15, or 30 ml/kg, iv). At 5 or 12 hr after CLPq the rat lung tissues were collected. Pulmonary microvascular permeability, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6), mRNA expressions (cytokine-induced neutrophil chemoattractant (CINC), P-selectin, CD 11b/CD18 (Mac-1), and intercellular adhesion molecule-1 (ICAM-1)), and activities of nuclear factor (NF)-kappaB and activator protein (AP)-1 were determined in each group. HES, in a dose-related manner, significantly reduced pulmonary capillary permeability in the CLP model of sepsis. HES also down-regulated pulmonary proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and mRNA expressions (CINC and P-selectin), and inhibited pulmonary activities of NF-kappaB and AP-1. The results suggest that during sepsis HES reduces pulmonary capillary permeability and this beneficial effect of HES may act through down-regulation of inflammatory mediators and suppression of NF-kappaB and AP-1 activation.

Animals↗

Determination of the clearance factor for transmissible spongiform encephalopathy agents during the manufacturing process of polygeline.

OBJECTIVE: To determine the safety of polygeline, a gelatine-derived plasma substitute produced from bovine bones, in terms of safety for bovine spongiform encephalopathy (BSE) by evaluating the ability of the manufacturing process of polygeline to eliminate agents related to transmissible spongiform encephalopathy (TSE) through the validation of three main production steps. DESIGN: Laboratory scale experimental process (in duplicate) using 20% hamster-adapted 263K scrapie-infected brain homogenate as infective titrated source (10(9) LD50/2 ml), added to each material before being processed and titrated in hamsters. Experiment 1: time/temperature dependency of gelatine autoclaving. Experiment 2: cross-linking and distillation. Experiment 3: final sterilization. Monitoring period: 1 year with daily animal clinical observation. Histology of all brains. SETTING: LCG-RBM laboratories, Italy; strict GLP compliance. MEASUREMENTS AND RESULTS: Heating the gelatine (at conditions lower than those used in production process) was very effective in inactivating the infectivity of TSE agents. Clearance factors were reproducible, dependent upon time and temperature, reaching a total theoretical process clearance in the range of 9.2-13.8 [6.9 + 2.3 (+ 4.6)] log10 LD50. CONCLUSIONS: These experimental results provide further important data confirming the safety of the procedural steps; this complements the safety due to the careful sourcing of the raw material. There is high assurance that there is no significant risk of TSE transmission to humans by the therapeutic administration of polygeline.

Animals↗

Effect of hydroxyethyl starch (HAES) on degree and kinetics of erythrocyte aggregation studied with dielectric spectroscopy method.

BACKGROUND: Colloidal fluids, e.g. hydroxyethyl starch (HAES), used as blood plasma substitutes during acute controlled normovolemic hemodilution may cause erythrocyte aggregation. The aim of the presented study was to assess the degree and rate of erythrocyte aggregation in the media containing different concentrations of HAES. MATERIAL/METHODS: The experiments were carried out on heparinized venous blood and on erythrocyte suspension in 0.9% NaCl. RESULTS: Under stationary conditions, an increase of blood and erythrocyte suspension relative electric permitivity (e), with an increase of HAES concentration in the sample, was observed after HAES supplementation. Sample flow through a measuring chamber resulted in decrease of the eL value (determined for 100 kHz). Stopping the flow led to non-linear increase of eL values in the function of time, where two components - characterized by rapid and slow variability, respectively, could be distinguished. The increase was characterized by t1 and t2 relaxation times, which can be related respectively to the process of erythrocyte rouleaux formation and to the formation of 3-D network aggregates. CONCLUSIONS: 1) The values of eL are differentiated by the degree of erythrocyte aggregation due to the presence of HAES, both in whole blood and in erythrocyte suspension in 0.9% NaCl solution, 2) The degree of erythrocyte disaggregation due to flow increases with the increase of flow intensity and correlates with decreasing eL value, 3) t1 and t2, which characterize the kinetics of erythrocyte aggregation, indicate a difference between aggregation processes taking place in whole blood and after hemodilution with HAES.

Electric Conductivity↗

Neonatal polycythemia: effects of partial exchange transfusion using fresh frozen plasma, Haemaccel and normal saline.

BACKGROUND: Neonatal polycythemia remains a significant clinical problem in Thailand. Partial exchanges transfusion (PET) with fresh frozen plasma (FFP) has been the mainstay of management for this condition in Thailand. Since FFP is difficult to find in certain areas and can cause concerns of transfusion related diseases, this study was undertaken to investigate the possibility of using plasma substitute and normal saline (NSS) for PET in the newborn infant with polycythemia. OBJECTIVE: 1. To compare the rate and duration of decrease of venous hematocrit (Hct) before and after PET with FFP, Haemaccel and NSS. 2. To compare any complications from using FFP, Haemaccel and NSS such as coagulation defect, electrolytes change, etc. in PET. METHODS AND SUBJECTS: A randomized prospective trial was conducted in Neonatal Unit, Department of Pediatrics, Ramathibodi Hospital. The first phase of study: July 1, 1993 to June 30, 1994: randomized prospective trial using FFP or Haemaccel for PET in 26 newborn infants with polycythemia. The second phase of study: July 1, 1994 to June 30, 1995: consecutive enrollment trial using NSS for PET in 38 consecutive newborn infants with polycythemia. RESULTS: There was significant decrease in Hct in both groups after PET but there was no statistically significant difference in the rate of decrease of Hct. There was no significant difference in biochemical profiles in both groups of infants 24 hours after PET. In the NSS group, there was significant decrease of Hct level after PET. There was no significant change of biochemical profiles and coagulation activity in these patients 24 hours after exchange transfusion. There were 2 patients with complications related to umbilical venous catheter and PET. CONCLUSION: Haemaccel and NSS can be safely used for PET to treat neonatal polycythemia. However, the attending physician should be aware of possible complications related to umbilical venous catheterization and PET.

Exchange Transfusion, Whole Blood↗

Effects of hydroxyethyl starch on hepatic production of cytokines and activation of transcription factors in lipopolysaccharide-administered rats.

BACKGROUND: Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. Some studies have indicated that HES may have anti-inflammatory effects. The present in vivo study was performed to investigate the effects of HES on hepatic production of cytokines and activation of transcription factors in sepsis. METHODS: Adult male Sprague-Dawley rats were randomly divided into four groups: rats challenged with lipopolysaccharide (LPS) (5 mg kg(-1)) and treated with saline (64 ml kg(-1)); challenged with LPS (5 mg kg(-1)) and treated with HES (16 ml kg(-1)); injected with saline and treated with HES (16 ml kg(-1)); and saline control. Each hepatic tissue was collected in groups of rats 2 h after induction of endotoxemia for determination of tumour necrosis factor (TNF)-alpha levels, TNF-alpha mRNA expressions, and nuclear factor (NF)-kappaB, activator protein (AP)-1 activities or 3 h after LPS challenge for IL-1beta, IL-6, IL-8, IL-10 levels and the mRNA expressions. RESULTS: Endotoxemia was associated with significant increases in hepatic proinflammatory cytokine productions and transcription factor activities. HES significantly reduced the increased hepatic levels of TNF-alpha, IL-1beta, IL-6, IL-8 and the mRNAs in the endotoxemic rats. Similarly, HES could inhibit hepatic NF-kappaB and AP-1 activations. CONCLUSION: The results suggest that in sepsis HES may down-regulate hepatic inflammatory mediators production and these anti-inflammatory effects may act through inhibition of NF-kappaB and AP-1 activations.

Animals↗

Influence of low and medium molecular weight hydroxyethyl starch on platelets during a long-term hemodilution in patients with cerebrovascular diseases.

It is a well-known fact that plasma substitutes reduce the number of platelets after one-time administration due to a dilution effect. So far, it has not been sufficiently investigated how a long-term hemodilution therapy affects platelet number, volume distribution and function. In 20 patients with cerebrovascular diseases a 10-day hemodilution therapy was carried out. The patients were randomly and double-blind treated with either medium molecular weight (MMW) hydroxyethyl starch (HES) 200/0.5 or low molecular weight (LMW) HES 40/0.5. On the first day of therapy, both groups showed a significant reduction in the number of platelets (-13.2% and -8.4%, respectively, p < 0.05), which was smaller than the dilution effect. During the course of the therapy, the platelet number increased, reaching its initial value. Mean platelet volume decreased in both groups significantly (MMW HES -4.7%, p < 0.05, LMW HES -4.6%, p < 0.01). The share of large platelets decreased disproportionately (MMW HES -15.4%, p < 0.01, LMW HES -11.4%, p < 0.01). Spontaneous platelet aggregation was not affected by HES. During the course of a long-term hemodilution therapy, the initial dilution-induced drop in platelet number is quickly compensated. The decline in mean platelet volume, which increases towards the end of the therapy, is due to a great extent to a decline in the number of large platelets. This in turn is probably caused by a colloid-osmotic shrinkage of the platelets and increased degradation. There were no signs for a clinically relevant impairment of platelet function.

Blood Platelets↗

Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study.

Hydroxyethyl starch (HES) is widely used as a plasma substitute. Serious side effects occur only rarely, whereas a high incidence of severe pruritus has been reported. Moreover, tissue storage of HES has been demonstrated in various organs. The aim of the current study has been to examine precisely the intracellular uptake and long-term storage of HES in the skin. Skin biopsies from 119 patients who received HES of various preparations and cumulative dosage were obtained 30 min to 130 months after infusion therapy. The samples were analysed by ultrastructural and immunoelectron microscopy with HES-specific monoclonal and polyclonal antibodies. A characteristic vacuolisation of perivascular histiocytes was a regular finding in all skin biopsies as early as 1 day after a single infusion of 30 g. Immunoreactivity for HES was demonstrable within the vacuoles. Generally, the size and number of vacuoles in the histiocytes increased concomitantly with the cumulative dosage. Following administration of higher HES dosages, vacuoles were demonstrable in endothelial cells of blood and lymphatic vessels, basal keratinocytes, epithelia of sweat glands and in small peripheral nerves, the last mentioned being associated with pruritus. A subsequent reduction of the vacuoles in size and number could be demonstrated within 52 months. In nerves, HES deposits persisted no longer than 17 months paralleling the cessation of pruritus. Biopsies taken after 94 months exhibited no HES deposits in the skin. The condensation and final dissolution of the vacuoles may either indicate the release and subsequent redistribution of HES into the circulation or lysosomal degradation.

Adolescent↗

Effect of in vitro hemodilution with hydroxyethyl starch and dextran on the activity of plasma clotting factors.

OBJECTIVE: A recent thrombelastography study indicated a compromised in vitro blood coagulation after 10:10 (equal parts of blood and infusion) and 10:4 (10 parts blood to four parts infusion) hemodilution with several plasma substitutes. Oncovertin N (Oncovertin) (a 10% dextran 40 solution) had the strongest anticoagulant effect of all solutions tested, and HAES-sterile 10% (HAES) (a 10% hydroxyethyl starch 200/0.5 solution) showed the strongest effect of five different hydroxyethyl starch preparations. The aim of this study was to determine how in vitro hemodilution with HAES and Oncovertin affects the activity of coagulation factors. DESIGN: HAES and Oncovertin were tested to determine the intrinsic effect of colloid molecules, as opposed to hemodilution. Normal saline (NaCl) and nonlactated Ringer solution were used as noncolloidal controls. SETTING: University research institute. PATIENTS: Six healthy volunteers. INTERVENTIONS: Twenty milliliters of blood was obtained from each subject. MEASUREMENTS AND MAIN RESULTS: Prothrombin index, activated partial prothrombin time, soluble fibrin monomers, and the activity of coagulation factors I, II, V, VII, VIII, IX, X, XI, and XII were measured with the Behring Chromotimer according to the manufacturer's instructions. Two dilution ratios of citrated blood to infusion were used: 10:10 (equal parts of blood and infusion) and 10:4 (10 parts blood to four parts infusion). Baseline was undiluted. Hemodilution with NaCl at both 10:4 and 10:10 influenced the coagulation variables measured. The activities of factors I, VII, and soluble fibrin monomers were less influenced than expected by hemodilution alone. The activities of factors II, V, IX, and XI were significantly (p <.04) lower with both 10:4 and 10:10 dilution with NaCl. In the assays for factors IX, XI, and XII, clots formed immediately after adding the appropriate reagents in the presence of Ringer solution at 10:10 hemodilution, so that the activities of those factors could not be measured. For the other factors and for 10:4 dilution, the outcome after Ringer solution was similar to that of NaCl. The activities were less influenced after 10:4 hemodilution with both HAES and Oncovertin than after dilution with NaCl and Ringer solution, with no significant differences from baseline. At 10:10 hemodilution with both HAES and Oncovertin, several factor activities were significantly (p <.04) lower than baseline. CONCLUSIONS: Both NaCl and Ringer solution cause measurable effects on coagulation factors at 10:4 hemodilution that can be explained by hemodilution alone. The effects on clotting factors of 10:4 hemodilution with HAES and Oncovertin were not significant. Even at 10:10 hemodilution with HAES or Oncovertin, the reduction in factor activities, although significantly (p <.04) different from baseline, was less than what was expected by dilution alone.

Blood Coagulation Factors↗