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Effect on primary haemostasis of prophylactic regimens of low molecular weight heparin, unfractionated heparin, dextran and their combinations. An animal experimental study.

The aim of the study was to determine whether an impairment of the haemostasis could be observed experimentally when thromboprophylactic substances, which act differently on the haemostatic mechanism, were given single or in combination in prophylactic doses. In 36 rabbits we measured the primary haemostatic plug formation time (PHT), rebleedings and total haemostatic plug formation time (THT) after transection of venules and arterioles using an intravital microscope. We combined unfractionated heparin (UH) and low molecular weight heparin (LMWH) in low dose with either dextran 70 or polygeline (placebo volume expander) in a randomized double-dummy set up. In the placebo group (NaCl and polygeline) the median PHT was 55 and 101 seconds for arterioles and venules respectively, which are well-comparable to earlier results from our group. Most prolonged PHT and THT for arterioles were seen for dextran+NaCl, actually less prolongation was seen for UH+dextran. We did not observe any differences, except for a prolongation of THT for venules in rabbits given dextran+NaCl (p less than 0.05). Thus, in thromboprophylactic doses used, there does not seem to be an impaired or additive effect between heparins and dextran 70 in primary haemostasis in rabbits.

Animals↗

Effect of synthetic colloids on major histocompatibility complex class II expression.

STUDY OBJECTIVE: Synthetic colloids are used for perioperative fluid management. We hypothesized that their use may be associated with changes in major histocompatibility complex (MHC) class II expression. This could affect patients' morbidity and mortality during clinical intervention. SETTING: University research laboratory. SUBJECTS: Whole blood samples from healthy volunteers. INTERVENTIONS: Whole blood samples from healthy volunteers (n = 6) were incubated with different concentrations of hydroxyethyl starch (HES) from maize and potato (pHES), dextran, and polygelin (gelatine) for 24 hours with or without 100 U/mL human interferon gamma (IFN-gamma; stimulus for MHC class II expression). The expression of human leukocyte antigen (HLA): HLA-DR, HLA-DQ, and HLA-DP was detected simultaneously by a fluoresceinisothiocyanate (FITC)-labeled antibody and analyzed by flow cytometry on lymphocytes and monocytes. MEASUREMENTS AND MAIN RESULTS: Hydroxyethyl starch, pHES, and dextran induced a significant increase in HLA expression. The induction of MHC class II was independent of the structure (50 mg/mL: control, 8.7+/-1.4%; HES, 28 +/- 9.7%; pHES, 29.8 +/- 11.7%; and dextran, 50.2 +/- 8.1%). In contrast, polygelin increased HLA expression only at the highest concentration of gelatine (5 mg/mL, 7.8 +/- 1%; 50 mg/mL, 7.6 +/- 0.8%; 100 mg/mL, 7.3 +/- 1%; 200 mg/mL,16.2 +/- 2.3%). The addition of IFN-gamma decreased HLA expression in presence of highest concentration of HES and dextran. CONCLUSION: In an ex vivo laboratory setting, we demonstrate that high concentrations of plasma expanders are associated with increased HLA expression on lymphocytes and monocytes. However, further in vivo studies are necessary to demonstrate the clinical significance of this observation.

Colloids↗

TBE booster immunization in adults--first experience with a new tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer.

A total of 222 adult subjects, all of whom received primary immunization according to the rapid immunization schedule in a preceding clinical trial with either a new (i.e. polygeline free) or formerly licensed (i.e. polygeline containing) TBE vaccine were invited for extension studies. The subjects received the first booster immunization with the new TBE vaccine at 12 to 18 months after primary immunization. Subsequently, a total of 191 of the 222 subjects could be enrolled in a serological follow-up one year after the booster immunization. Neutralizing TBE antibody titers were determined prior to, 21 days after and approximately 12 months after booster immunization. Prior to first booster immunization, TBE antibodies (GMTs) had remained on a high level and were far above the detection limit of the neutralization test used. All subjects of the per protocol population who were primarily immunized with the new TBE vaccine formulation and all but one subject of the control group were still seropositive prior to the booster. All subjects showed a sharp increase of TBE antibodies following the booster immunization. Within the 12 months follow-up period, neutralizing TBE antibody titers remained on a high level. The booster vaccination was well tolerated by the subjects. Only very few febrile reactions (< 1%) none higher than 38.5 degrees C were reported. No serious or unexpected adverse events related to vaccination were reported. These successful results in terms of both immunogenicity and safety indicate that TBE vaccination with this new TBE vaccine can be used safely in adults. A long lasting immunity can be concluded from the strong immune response following the booster immunization.

Adult↗

Stimulation of the immune system by different TBE-virus vaccines.

Tick-borne encephalitis (TBE) is one of the most frequent arthropod-transmitted viral diseases in Europe. Different vaccines against TBE-virus have been developed; a thimerosal-free and also albumin-free vaccine [Ticovac (Baxter Hyland Immuno, Vienna)] was approved in 2000. Contrary to previous experience, 779 cases of fever occurred following the first vaccination of children under 15 years of age and in 62 children febrile convulsions were even observed. Consequently, the composition of the vaccine was changed and albumin was again added [FSME-Immun (Baxter Vaccines, Vienna)] in 2001. The new Encepur Kinder (Chiron-Behring, Marburg) from 2002 is a TBE-vaccine for children without any protein as stabilizer but with a relatively high concentration of sucrose, while the former vaccine Encepur K from 1991 contained polygeline as the stabilizer. The induction of the immune system by the different TBE virus vaccines was compared in an in vitro test in order to find an explanation for the unexpected fever attacks. Whole blood was stimulated with complete vaccine suspension, and TNF-alpha, IL-1beta, IL-6, and IL-8 were determined from heparin/EDTA-plasma and culture supernatants. It was shown that Ticovac and the new Encepur Kinder can induce relatively high amounts of TNF-alpha and lower amounts of IL-1beta. An increase of both cytokines was first observed following an incubation of 4 hours, with a maximum after 15 hours. Concentrations returned to base-line values within 26 hours. The behaviour of both cytokines correlates with the febrile phases in children up to two years old. Albumin or other proteins like polygeline and also immunoglobulins prevented a rise of cytokines.

Adjuvants, Immunologic↗

Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men.

OBJECTIVES: Elevated plasma endothelin (ET)-1 levels have been described in insulin-resistant states such as syndrome X, obesity, non-insulin-dependent diabetes mellitus, and in some studies in essential hypertension. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/or insulin sensitivity in humans, we assessed these variables during low, non-pressor-dose ET-1 compared with placebo infusion. DESIGN: In a randomized, single blind, crossover design, 10 lean normotensive male subjects received either an intravenous infusion of subpressor doses of ET-1 dissolved in polygeline or a control infusion of polygeline only (placebo). Using dynamic assessment by the minimal model approach with the modified frequent sampling intravenous glucose tolerance test (FSIGT) the following and other parameters were measured: insulin sensitivity; acute insulin response to glucose (AIR(G)) calculated as the average of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were subtracted; the initial area under the curve (AUC(1-19)) from insulin values between time 0 and 19 min and the first-phase insulin secretion (phi1) from insulin kinetics parameters. RESULTS: ET-1 infusion reduced AIR(G) (to 34.85 +/- 4.27 compared with 49.3 +/- 6.9 microU/ml during placebo, P=0.017) and the acute C-peptide response to glucose (to 2.33 +/- 0.41 compared with 3.1 +/- 0.44 ng/ml, P=0.018), decreased plasma insulin levels during the FSIGT compared with placebo (analysis of variance P<0.0001) and decreased the AUC(1-19) (to 2.1 +/- 0.2 compared with 2.9 +/- 0.3 U/l per 20 min, P<0.01) while phi1 tended to be lower. S1 measured during ET-1 infusion was unaltered (11.11 +/- 1.91 x 10(-4) versus 10.88 +/- 2.11 10(-4)/min per mU per l, NS). CONCLUSIONS: These findings demonstrate that an increase in circulating ET-1 to levels observed in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity.

Adult↗

Complement activation during and after open-heart surgery is only marginally affected by the choice of fluid for volume replacement.

Forty patients undergoing CPB for coronary artery surgery, using a standardized technical setting, were randomized to receive either Ringer's acetate, dextran 70 (Macrodex), polygeline (Haemaccel) or albumin 4% for volume replacement during and after surgery. The choice of fluid did not affect early complement activation (C3 activation products). Higher values of the terminal complement complex (TCC) were found only at the end of the operation in patients receiving polygeline. There were no differences between any two of the four groups during the postoperative course. The use of blood transfusion or autotransfusion and the degree of haemodilution and hypothermia did not affect complement activation. We conclude that complement activation in association with open-heart surgery is only marginally affected by the choice of fluid for volume replacement.

Adult↗

Interaction of penicillins with the components of plasma expanders.

The interaction of penicillin with high molecular components of plasma expander such as dextran, 6-hydroxyethylstarch, and polygeline were studied. The formation of penicilloyl polysaccharides and smaller amounts of penicilloyl polygeline during incubation were confirmed by ultrafiltration and gelfiltration. The ultrafiltration through Collodion-Bags SM 13 200 was found to be a rapid and convenient method for the determination of macromolecular penicilloates. The accelerated degradation by the formation of penicilloyl esters with glucose and lactic acid was also suggested.

Drug Interactions↗

Anaphylactoid reactions to plasma substitutes.

Anaphylactoid reactions have been reported in association with all of the currently available plasma substitutes. The clinical picture ranges from skin reactions only to severe and life-threatening complications, which can be conveniently classified into four grades of severity. The pathomechanism of these anaphylactoid reactions varies for the different colloids. Anti-dextran antibodies (most likely IgG) seem to be responsible for severe DIAR representing an immune complex anaphylaxis. IgE has not been implicated in reactions of this type. Skin tests seem to be of limited value in the diagnosis of dextran reactions and should be performed with great caution. Administration of a specific hapten (low-molecular-weight dextran) prior to dextran infusion reduces the frequency of DIAR in animals and humans. The principal mediator of anaphylactoid reactions due to gelatin infusion is histamine, and this has been established for urea-linked gelatin. It is likely that the diisocyanate present in some polygeline batches is the histamine-releasing substance. Better purification of polygeline and pretreatment with histamine H1-receptor and H2-receptor antagonists have both substantially reduced the frequency of clinical reactions. Changes in plasma complement levels have been observed in patients with anaphylactoid reactions to HES. Antibodies against HES have been detected in humans, but no correlation has been found between the titer of antibodies and anaphylactoid reactions to HES. A further problem with repeated HES infusions is its potentially irreversible storage. Anaphylactoid reactions to colloids should be treated according to the grade of severity. Epinephrine should only be given in severe (grades III and IV) reactions. The early application of glucocorticosteroids (500-1,000 mg of prednisolone equivalent) also may be helpful.

Anaphylaxis↗

The fluid of choice for resuscitation of severe shock.

The choice of fluid for resuscitation in severe shock remains controversial. The various solutions commercially available have been compared in a standardized canine refractory shock model. The use of colloidal solutions proved preferable to the use of crystalloid solutions alone, as judged by oxygen debt, the volume required and the evidence of pulmonary overload. The three colloidal solutions studied, namely dextran 70, hydroxyethyl starch and Haemaccel (polygeline), produced very similar results. The clinical absence of reported serious side effects would suggest that Haemaccel is likely to be the colloidal fluid of choice. However, in the model studied, the use of a mixture of crystalloid and colloid produced results that were significantly better than either crystalloid or colloid alone. It is concluded that much of the controversy between crystalloid and colloid is artificial and that a mixture of these substances will be required in the resuscitation of the severely shocked patient.

Animals↗

[Assessment of right ventricular function using contrast echocardiography in patients with myocardial infarction].

OBJECTIVE: To evaluate right ventricular size, motility, and ejection fraction (RVEF) by contrast echocardiography. METHODS: We studied consecutive patients admitted to the coronary intensive care unit with acute inferior myocardial infarction, without prior infarction and with or without right ventricle involvement, according to accepted electrocardiographic findings. Polygelin, 3.5% solution, was used for contrast echocardiography. The reference standard was equilibrium radionuclide angiography. RESULTS: We studied 44 patients using contrast echocardiography, average patient age 60.8 +/- 10.6 years, 38 men and 6 women. Abnormal right ventricular size (more than 25 mm) yielded a sensitivity of 79%, specificity of 87%, positive and negative predictive values of 92 and 68%, respectively, and a likelihood ratio of 6. Abnormal right ventricular motility had a sensitivity of 70%, specificity of 94%, positive and negative predictive values of 95 and 67%, respectively, and a likelihood ratio of 11.6. Right ventricular ejection fraction < 30% with contrast echocardiography had a sensitivity of 69%, specificity of 97%, positive and negative predictive values of 90 and 88% respectively, and a likelihood ratio of 6.9. CONCLUSION: In patients with acute inferior myocardial infarction, contrast echocardiography with the area-length method is a valid and reproducible technique for evaluating right ventricular ejection fraction, which is easy to perform and can be done at the patient's bedside.

Contrast Media↗

Long-term immunity after vaccination against tick-borne encephalitis with Encepur using the rapid vaccination schedule.

148 of 157 invited adult subjects who had participated in previous studies were enrolled in this extension study for evaluation of immunogenicity and safety of the second TBE booster immunization. All subjects had been previously immunized in studies with Chiron's formerly marketed TBE vaccine (containing polygeline as the stabilizer) according to the rapid vaccination schedule (i.e. primary immunization on days 0, 7, 21 and first booster immunization at month 15). All subjects were administered the second booster with Chiron's new TBE vaccine, which is free of protein-derived stabilizers, 36 months after the first booster vaccination applied at study month 15. Blood samples were taken prior to booster and 1 month later. In 145 out of 148 subjects, blood samples suitable for measurements of TBE antibodies (ELISA assay) were provided. Prior to second booster immunization with Chiron's new TBE vaccine, TBE antibodies (GMTs) had remained at a high level and were far above the detection limit of the used ELISA test. All subjects were still seropositive prior to the second booster immunization. The second booster immunization resulted in a further increase of TBE antibodies. The booster vaccination with Chiron's new TBE vaccine was well tolerated by all the vaccinees. Neither febrile post-immunization reactions nor unexpected adverse events or serious adverse events were reported. To summarize, these data clearly show that the TBE vaccination with this new TBE vaccine can be used safely to boost subjects pre-immunized with the former TBE vaccine formulation. Long-lasting immunity following this second TBE booster immunization can be concluded.

Adolescent↗

Kinin-mediated anaphylactoid reaction implicated in acute intra-operative pulseless electrical activity.

A 65-year-old patient undergoing total hip replacement under general anaesthesia suffered acute pulseless electrical activity with a fatal outcome. A kinin-mediated analphylactoid reaction following administration of a polygeline plasma expander (Haemaccel) was implicated by in vitro testing. This case report illustrates the diagnostic difficulties posed by non-histaminoid anaphylactoid reactions and the resistance to epinephrine of kinin-mediated hypotension.

Aged↗

Fluid resuscitation with Haemaccel vs. human albumin following coronary artery bypass grafting.

Several colloid preparations are available for fluid resuscitation following heart surgery. We conducted a randomized prospective trial to compare a polygeline infusion versus human albumin with respect to hemodynamic and pulmonary function. 20 patients were randomly assigned to receive either Haemaccel or human albumin using a standardized protocol for the first 8 hours following heart surgery. The double-indicator dilution method was used to measure total blood volume index (TBVI), intrathoracic blood volume index (ITBVI) and extravascular lung water index (EVLWI) three times during the study period. Pulmonary shunt fraction, time on ventilator, and chest tube drainage were measured as well. Hemodynamic stability was achieved in both groups throughout the study period, as judged from mean arterial pressure, pulmonary capillary wedge pressure, and cardiac index. ITBV and TBVI were higher in the albumin group, although only significant at 4 hours for TBVI. There was no significant difference in EVLWI, pulmonary shunt fraction, and time on mechanical ventilation. Likewise, chest tube drainage was not significantly different in both groups. Haemaccel is effective in maintaining hemodynamic stability following heart surgery without ill effects of lung function or chest tube drainage. Treatment costs are substantially lower compared to human albumin.

Aged↗

Hypotension during subarachnoid anaesthesia: haemodynamic effects of colloid and metaraminol.

We have studied 45 patients, aged 60-95 yr, receiving subarachnoid block for neck of femur fractures. Patient received either colloid (polygeline, Haemaccel) 8 ml kg-1 (n = 15), metaraminol 5 micrograms kg-1 and 1.7 micrograms kg-1 min-1 (n = 15) or a combination of both treatments to maintain systolic arterial pressure (SAP) between 75 and 100% of baseline. If necessary, additional colloid 2 x 4 ml kg-1 or metaraminol 3 x 2.5 micrograms kg-1 was given. Arterial pressure was measured by automated oscillotonometry, central venous pressure (CVP) by a manometer and cardiac index (CI), stoke index (SI) and heart rate (HR) by transthoracic electrical bioimpedance. Systemic vascular resistance index (SVRI) was derived. Colloid was less effective than metaraminol (P < 0.05). In the colloid group, SAP and SVRI decreased and CVP, CI and SI increased (P < 0.001). In the metaraminol group, initial decreases in SAP, SVRI and CVP were restored after 10-15 min and HR decreased after 12 min (P < 0.001). In the combined group, initial decreases in SAP and SVRI were restored after 4 and 16 min, and CVP, CI, SI and HR increased (P < 0.001). Metaraminol was more effective than colloid because it increased SVRI, whereas colloid increased CVP without significantly increasing CI.

Aged↗

Reduced quality of clot formation with gelatin-based plasma substitutes.

We have studied, over a wide range of dilutions using techniques of clot weight, thrombelastography and scanning electron microscopy, the physical properties of a blood clot formed in vitro when fresh blood was diluted with gelatin-based colloid solutions compared with crystalloid controls. The colloid solutions tested (3.5% polygeline (Haemaccel) and 4% succinylated gelatin (Gelofusine)) produced clots that had reduced median weight (P < 0.001 and P = 0.018, respectively) and reduced mean shear modulus (P < 0.001) compared with crystalloid controls. Scanning electron microscopy showed that the fibrin formed a less extensive mesh in the presence of the gelatin-based colloids compared with crystalloid. Reduction in clot quality with gelatin-based colloids has not been noted previously and further work is needed to ascertain if this occurs in vivo as these solutions are used frequently in patients who require full haemostatic competence.

Blood Cells↗

Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis.

BACKGROUND: The development of metabolic acidosis during cardiopulmonary bypass (CPB) is well recognized but poorly understood. The authors hypothesized that the delivery of pump prime fluids is primarily responsible for its development. Accordingly, acid-base changes induced by the establishment of CPB were studied using two types of priming fluid (Haemaccel, a polygeline solution, and Ringer's Injection vs. Plasmalyte 148) using quantitative biophysical methods. METHODS: A prospective, double-blind, randomized trial was conducted at a tertiary institution with 22 patients undergoing CPB for coronary artery bypass surgery. Sampling of arterial blood was performed at three time intervals: before CPB (t1), 2 min after initiation of CPB at full flows (t2), and at the end of the case (t3). Measurements of Na+, K+, Mg2+, Cl-, HCO3-, phosphate, Ca2+, albumin, lactate, and arterial blood gases at each collection point were performed. Results were analyzed in a quantitative manner. RESULTS: Immediately on delivery of pump prime fluids, all patients developed a metabolic acidosis (base excess: 0. 95 mEq/l (t1) to -3.65 mEq/l (t2) (P < 0.001) for Haemaccel-Ringer's and 1.17 mEq/l (t1) to -3.20 mEq/l (t2). The decrease in base excess was the same for both primes (-4.60 vs. -4.37; not significant). However, the mechanism of metabolic acidosis was different. With the Haemaccel-Ringer's prime, the metabolic acidosis was hyperchloremic (Delta Cl-, +9.50 mEq/l; confidence interval, 7.00-11.50). With Plasmalyte 148, the acidosis was induced by an increase in unmeasured anions, most probably acetate and gluconate. The resolution of these two processes was different because the excretion of chloride was slower than that of the unmeasured anions (Delta base excess from t1 to t3 = -1.60 for Haemaccel-Ringer's vs. +1.15 for Plasmalyte 148; P = 0.0062). CONCLUSIONS: Cardiopulmonary bypass-induced metabolic acidosis appears to be iatrogenic in nature and derived from the effect of pump prime fluid on acid-base balance. The extent of such acidosis and its duration varies according to the type of pump prime.

Acid-Base Equilibrium↗

Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.

BACKGROUND: The question of which colloid (albumin or synthetic colloids) used for plasma expansion following paracentesis or other complications requiring fluid loading in patients with cirrhosis remains controversial. AIMS: To compare outcome and hospital-related cost in patients with cirrhosis treated with 20% human albumin with those treated with a synthetic colloid (3.5% polygeline). METHODS: The primary end point was occurrence of a first liver-related complication. RESULTS: When the trial was prematurely discontinued because of safety concerns about bovine-derived products, 30 patients were assigned to receive albumin and 38 were assigned to receive a synthetic colloid. Sixty-three patients were included for ascites removal by paracentesis and five patients for ascites removal by paracentesis and renal impairment. The median time to first liver-related complication was not significantly longer in the albumin group (20 vs. 7 days). However, the total number of liver-related complications adjusted to a 100-day period was significantly lower in the albumin group. The median hospital cost for a 30-day period was significantly lower in the albumin group (1915 euros vs. 4612 euros). CONCLUSIONS: In patients with cirrhosis and ascites, human albumin appears to be more effective in preventing liver-related complications than synthetic colloid. This may be associated with decreased hospital costs.

Adult↗

Acute renal failure in cardiac surgical patients, potentiated by gentamicin and calcium.

A retrospective study in coronary artery bypass graft patients was undertaken to assess the effect of gentamicin and a bypass prime with a high calcium on the incidence of renal failure. Patients who received both Haemaccel (polygeline, Hoechst Marion Roussel) (calcium concentration 6.25 mmol/l) in the bypass prime and gentamicin perioperatively had a higher incidence of renal failure compared with those who received only Haemaccel (P = 0.005), only gentamicin (P = 0.002) or neither (P = 0.0001). We suggest that the combination be avoided in this group of patients.

Acute Kidney Injury↗