Influence of hydroxyethyl starch on coagulation in patients during the perioperative period.

The perioperative use of hydroxyethyl starch (HES) has been implicated as a possible cause of intracranial bleeding. The purpose of this study was to compare the influence on blood coagulation of the isovolemic replacement of 1-L blood loss with either 6% HES (molecular weight [MW] average: 450,000) or 5% human albumin during neurosurgery or lower abdominal surgery. Twenty patients scheduled for brain tumor surgery and 20 patients undergoing transabdominal hysterectomy were studied. The activated partial thromboplastin time, prothrombin time, fibrinogen concentration, factor VIII coagulant, von Willebrand factor antigen, platelet count, and the activated clotting time were compared after induction of anesthesia, after administration of 500 and 1000 mL of colloid solution, and 24 and 48 h postoperatively. All measured coagulation variables remained within physiologic range. Changes in coagulation indices were identical in neurosurgical and hysterectomy patients, except for a larger increase in fibrinogen concentration 24 and 48 h after hysterectomy. The acute phase reaction of factor VIII coagulant and von Willebrand factor, which plays a role in postoperative hypercoagulability, was attenuated by the use of HES. We conclude that isovolemic replacement of 1-L blood loss with either 6% HES (MW average: 450,000) or 5% human albumin does not interfere with normal hemostasis during and after neurosurgery or lower abdominal surgery.

[Alternative mechanical autotransfusion. Hemofiltration vs. hemoseparation]. / Alternative maschinelle Autotransfusion. Hämofiltration vs. Hämoseparation.

The effect of haemoconcentration of shed blood from operative field during vascular surgery by either centrifugation (cell separation, n = 10) or haemofiltration (n = 10) was investigated. Interest in this in-vitro-study was focused on the quality of the blood concentrated. Various parameters were measured in the patient (before onset of anaesthesia), and in the blood after suction from operative field: 1. shed blood, 2./3. after haemoseparation/-filtration. Both procedures were easy to perform but haemofiltration produced whole blood quicker than the cell-separation technique (1.2:3.0 minutes). All patients had normal parameters. Suction led to an activation of plasma coagulation and an increase of free haemoglobin and elastase. Haemoseparation in contrast to filtration led to an elimination of thrombocytes, elastase, free hemoglobin and all proteins including antithrombin III and fibrinogen; concentration of red cells was more pronounced after separation (hct 55 vs. 35%). Heparin reduction was better after separation but plasma-heparin-levels were in a tolerable range after both procedures (0.21 vs. 0.75 U/ml). None of the procedures was followed by the appearance of activated clotting factors (F XII a). The data presented demonstrate that haemofiltration may be an alternative in intra- and postoperative autotransfusion. The particular advantage of this method is the preservation of plasma proteins after concentration procedure thus avoiding the need for additional application of fresh frozen plasma in patients with significant blood loss.

[Recombinant erythropoietin in autologous blood donation]. / Rekombiniertes Erythropoetin während autologer Blutspenden.

As a result of the AIDS crisis, public and physician pressure have increased the utilization of autologous blood products. Attitudes about homologous blood transfusion, however, have changed dramatically in recent years. A large segment of the population undergoing elective surgery is elderly and therefore has a significant incidence of cardiovascular disease and a slow response of the erythropoietic system when acute anemia occurs. However, preoperative autologous blood donation programs require 2-5 weeks to complete; the average yield is only 2.2 units per patient. As a consequence, autologous predonation is underused and homologous transfusion cannot be completely avoided in all patients. For several years recombinant human erythropoietin (rHuEPO) has been available and has been successfully used in the treatment of patients with renal anemia. This study evaluated the effect of r-HuEPO on patients with preoperative autologous blood collection. METHODS. Ten patients of both sexes scheduled for hip arthroplasty underwent a preoperative autologous program. During a period of 23 days prior to surgery autologous blood donation was performed with 7.5 ml/kg withdrawal on four occasions, the last one 5 days prior to surgery. Five patients were randomly treated with subcutaneous injections of rHuEPO (Erypo, Cilag GmbH, Sulzbach; Distributor: Fresenius AG, Oberursel, FRG) 200 IU/kg seven times, starting 3 days after the first blood withdrawal. All patients (n = 10) received oral iron therapy with iron sulphate 304 mg/die (= 100 mg iron/die). Patients with hypertension or recent myocardial infarction were excluded from the study. The hemoglobin level before donation had to be at least 11.0 g/dl. On each study day, a complete blood count and platelets, differential, and reticulocyte count were determined by standard methods as were transferrin, ferritin, and total iron-binding capacity. Blood loss and blood consumption during and after the operation were registered. The indication for blood transfusion (autologous/homologous) was based on hemoglobin values, which were not acceptable below 8.5 g/dl. RESULTS. No side effects of rHuEPO treatment were observed. Blood loss ranged from 650 to 1100 ml intraoperatively and 400 to 950 ml postoperatively with no differences between the groups. Patients with rHuEPO had no autologous red cell concentrates (aRCC) during the operation; two of them had two units of aRCC on the 2nd postoperative day. Two of the patients in the control group had intraoperative blood transfusions (2 and 3 units aRCC, respectively); all patients in this group were transfused postoperatively: 12 of the 20 units collected were utilized. At the onset of the operation the mean hemoglobin value in patients with rHuEPO was 13.5 +/- 0.4 g/dl compared to 11.3 +/- 0.3 g/dl in the controls. Reticulocytes increased significantly during the investigation period. On the 2nd, 3rd, and 4th days of autologous blood collection and before the onset of surgery, the number of reticulocytes was significantly greater in rHuEPO patients than in the controls. Further laboratory variables such as transferrin, ferritin, and total iron-binding capacity did not change significantly during the investigation period; there were no significant differences between the two groups. DISCUSSION. The results of the present study show that rHuEPO leads to an increase in reticulocytes with maintenance of hemoglobin levels during the phlebotomy program. As a consequence, patients with anemia and particular contraindications to homologous blood derivatives (irregular antibodies, Jehovah's Witnesses) may be able to undergo major surgery successfully. The possibility of shortening the intervals between phlebotomies would seem to be of major advantage; our data also suggest that an aggressive autologous blood collection program would increase yields over present programs. In our institute a minimum hemoglobin level of 11.5 g/dl is accepted for autologous donation.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetic parameters as criteria for clinical use of hydroxyethyl starch preparations]. / Pharmakokinetische Merkmale als Kriterien für den klinischen Einsatz von Hydroxyethylstärke.

Pharmacokinetic Parameters as Criteria for Clinical Use of Hydroxyethyl Starch Preparations In a study with volunteers (n = 2 x 6) pharmacokinetic data of two only marginally differing starch preparations were investigated. We were able to demonstrate that there exist significant differences in raw materials used which determined the pharmacokinetic data in humans. Newly implemented analyzing methods (LALLS) were used. In addition to the degree of substitution, further differences concerning the position of hydroxyethylization at the anhydroglucose molecule could be documented. The C2/C6 positions of hydroxyethylization at the molecule seem to be most essential. To classify and to differentiate starch preparations we propose to include these data in general informations for clinicians because these differences might determine clinical usage and efficacy.

Acute preoperative hemodilution in cardiac surgery: volume replacement with a hypertonic saline-hydroxyethyl starch solution.

Preoperative hemodilution (HD) is a recommended practice in cardiac surgery that conserves blood and reduces the complications of homologous blood transfusion. In 45 patients undergoing myocardial revascularization, HD was performed preoperatively. Withdrawn volume (10 mL/kg) was replaced either by a new hypertonic saline (HS) solution prepared in hydroxyethyl starch (HES) (2,400 mOsm/L, HS-HES group, n = 15) or by a standard low molecular weight hydroxyethyl starch solution (6% HES 200/0.5, HES group, n = 15) to maintain baseline PCWP (acute normovolemic hemodilution [ANH]). Fifteen comparable patients without HD served as controls. Significantly less HS-HES (210 +/- 20 mL) than HES 6% (890 +/- 90 mL) was necessary to sustain hemodynamics during HD. Stable cardiocirculatory conditions were obtained even after termination of bypass. Fluid balance during cardiopulmonary bypass as well as in the postoperative period was significantly lower in HS-HES-treated patients. With regard to hemodynamics, CI increased most in the HS-HES group (+36%), whereas systemic vascular resistance was lower in these patients. Right ventricular ejection fraction increased only in HS-HES patients (+15%). However, sodium concentration as well as osmolarity increased after volume replacement with HS-HES, without exceeding normal values. None of the patients suffered from organ failure. Pulmonary gas exchange (PaO2) was less compromised in the HS-HES patients. There were no renal function differences between the groups. In conclusion, HS solution prepared in HES is an attractive alternative for blood substitution in cardiac patients undergoing acute hemodilution for blood conservation.

Cardioprotective effects of carnitine in extensive aortocoronary bypass grafting: a double-blind, randomized, placebo-controlled clinical trial.

The cardioprotective effects of carnitine were tested in patients undergoing multiple aortocoronary bypass grafting. Intermittent aortic cross-clamping at 28 degrees C was used. Mean total cross-clamping time was 30 +/- 11 min. Patients were randomized into three groups: a control group receiving placebo (group 1), a group pretreated with 3 g carnitine intravenously before cardiopulmonary bypass (CPB) (group 2), and a group pretreated with 6 g carnitine intravenously (group 3). The markers of myocardial ischemia included levels of adenosine triphosphate, its catabolites, and creatine phosphate in transmural left ventricular biopsy specimens taken at the beginning and end of CPB, as well as hemodynamic recovery during weaning from CPB and for the next 24 h. The intravenous infusion of carnitine (3 or 6 g) had no hemodynamic effect. At the end of CPB myocardial tissue levels of adenosine triphosphate and creatine phosphate did not differ significantly among the groups (P greater than 0.05). Recovery of cardiac function during weaning from CPB and for the following 24 h was similar in all three groups (P greater than 0.05). It is concluded that pretreatment with carnitine neither facilitates weaning from cardiopulmonary bypass in patients undergoing aortocoronary bypass surgery nor favorably affects hemodynamic function during the next 24 h.

[Antioxidant status after surgical stress]. / Untersuchungen zum Antioxidantienstatus nach operativem Stress.

Trauma and anaesthetics are responsible for local and general change in the organism. The characteristic changes in metabolism are caused by hormones. In addition, the increased glycogenolysis, gluconeogenesis, proteolysis and lipolysis are characteristic of this catabolic metabolism. Three groups (injured patients, patients with pulmonary disease, multiple trauma patients) showed an elevated lipid peroxidation as indicated by increased formation of TBA-reactive substances in the post-trauma or after surgery phase. The production of free radicals is supported by several stress factors. In this connection, the state of metabolism of the patients, several anaesthetics and the artificial respiration is very important. Enzymatic protecting systems (SOD, GSH-Px, Catalase) react to oxidative stress by positive adaptation. The non-enzymatic antioxidative systems (tocopherol, ascorbic acid, selen) are diminished, indicating an increased requirement.

[Routine postoperative parenteral feeding with a complete solution]. / Routinemässige postoperative parenterale Ernährung mit einer Komplettlösung.

A total of 20 patients of both sexes received total parenteral nutrition with an all-in-one solution (excluding fat). All patients underwent a medium-sized surgical intervention. The solution was applied throughout 4 postoperative days in a medium dosage of 30 ml/kg B.w./day. Additional electrolyte solutions (200-500 ml/day) were allowed, to substitute fluid losses. Routine laboratory parameters remained in hemostasis; even blood sugar was stabilized between 120 and 150 mg% (x) without insulin. The authors conclude that short-term parenteral nutrition using this all-in-one solution exclusively could achieve hemostasis in clinically relevant parameters. No side effects were detected.

[Perioperative anemia and erythropoiesis]. / Perioperative Anämie und Erythropoese.

50 consecutive patients with hip arthroplasty had acute normovolaemic haemodilution and intra- and postoperative autotransfusion using Autotrans, Dideco GmbH. 18 of 50 patients received homologous blood products additionally to autotransfusion (Hb less than 8 g/dl, hemodynamic instability). There was no evidence for coagulation disorders, hypoxia or hypovolaemia during the whole investigation period (until the 10th p.o. day) though in some cases haemoglobin-levels less than 7 g% were accepted. No variations of erythropoietin levels could be observed postoperatively, suggesting that acute anaemia alone does not affect erythropoiesis. Reticulocytes, however, increased significantly from the 4th postoperative day. There was no correlation between number of reticulocytes and erythropoietin levels. Lactate levels stayed within normal range during the whole investigation period thus indicating normal microcirculation. The present data demonstrate that postoperative anaemia can be tolerated even in elder patients if intravascular volume is kept constant (normovolaemia). In accordance with recent literature the course of erythropoietin levels seemed to prove that there was no functional reduction in oxygen-availability.

Effects of an intravenous application of dl-alpha-tocopheryl acetate on tocopherol status in man.

The effects of intravenously administered dl-alpha-tocopheryl acetate on the plasma, erythrocyte and thrombocyte vitamin E levels were investigated in male subjects. 110 mg dl-alpha-tocopheryl acetate were applied as a single dose in the form of a rapid infusion. After 60 min, 89% of the dl-alpha-tocopheryl ester had been eliminated. The vitamin E ester injected was hydrolyzed and was detected in the plasma and the erythrocytes as free alpha-tocopherol. No significant change in the tocopherol concentration was observed in the thrombocytes. The results show that intravenously applied, esterified tocopherol is hydrolyzed relatively rapidly in the plasma, leading to an increase of free alpha-tocopherol content in the plasma and erythrocytes. The ratio of erythrocyte/plasma tocopherol 2 h after injection was 61% higher than the initial value; after 24 h the elevation was still 36%.

[Alpha-mercaptopropionylglycine in the experimental hemorrhagic shock animal model]. / Alpha-Mercaptopropionylglycin im tierexperimentellen hämorrhagischen Schock-Modell.

Oxygen radicals may have an important role in the shock process. Several studies showed that stimulated polymorphological granulocytes altered biological membranes to a varying degree, especially in the pulmonary circulation. It could be demonstrated on isolated mitochondria that substances of the thiol group carrying SH-groups are capable of counteracting this damaging influence of toxic O2-metabolites. Furthermore the use of the thiol reagents was associated with an improvement in the mitochondrial energy situation (adenosine triphosphate increase). A total of 12 dogs were included into the study. Using standardised conditions haemorrhagic shock was induced by controlled bleeding. After reaching a mean blood pressure of 40 mmHg and a stabilisation of this stage, alternatively either 250 mg of alpha-mercaptopropionylglycine (therapy group T) or an equivalent volume of physiologic saline (controls K) were administered at random. In the dogs on controlled respiration the effect of the above-mentioned substance upon the haemodynamic of the total organism was monitored by means of continuous measuring of the arterial pressure by a Swan-Ganz catheter. Furthermore the acid-base balance, the electrolytes sodium, potassium and calcium were analyzed. Whereas the sodium and potassium values as well as the acid-base balance did not show any difference between both groups, the haemodynamic parameters partly showed very distinct differences, however, without being statistically significant in most cases. The administration of the thiol reagent (group T) led to a reduction in mean arterial pressure, heart rate, peripheral resistance and rate-pressure product. As far as the survival rate at the end of the study was concerned, no difference between the control and therapy group was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of tryptophan, tyrosine and related dipeptides in mouse brain by isocratic high-performance liquid chromatography with switchable wavelength fluorescence detection.

Tryptophan (Trp) and tyrosine (Tyr) are pharmacologically active compounds which, after administration of adequate doses, are increased in level in the brain, and stimulate neurotransmitter synthesis. Trp and Tyr containing dipeptides were tested as possible substitutes with regard to the effect on precursor level in the brain. Glycyltryptophan, alanyl-tryptophan and glycyl-tyrosine were intravenously applied to young female mice and the brain levels of dipeptides, Trp and Tyr measured 30 min after application. Neurotransmitter precursor levels in the brain increased similarly in all cases. The results suggest that the dipeptides are as effective as the single amino acids and may be superior because of their better solubility.

[Combination autotransfusion in heart surgery. Use of acute normovolemic hemodilution in coronary heart disease]. / Kombinierte Autotransfusion in der Herzchirurgie. Anwendung der akuten normovolämischen Hämodilution bei koronarer Herzkrankheit.

Normovolemic hemodilution (15 mg/kg body-weight: group I) was undertaken in 100 patients immediately before the start of coronary-artery surgery. In addition, a Cell-Saver (Haemonetics, Munich) was used for intra-operative autotransfusion. Another group of 100 patients (group II) was similarly operated on without autotransfusion (the study was conducted on 200 consecutive patients undergoing aorto-coronary bypass). Before blood (autologous or homologous) was administered a reduction of hemoglobin to 9 g/100 ml and hematocrit to 0.28 was well tolerated (during extracorporeal circulation: 6.5 g/100 ml and 0.16, respectively). Due to intra- and postoperative complications, such as infarct bleeding (including reoperation) or septicemia, the number of patients placed in group I fell to 94, that in group II to 90. Acute normovolemic hemodilution increased cardiac output and oxygen transport capacity, while other hemodynamic parameters remained unchanged, and there was no effect on extravascular lung water. Autotransfusion reduced the need for homologous blood derivatives by 71% (fresh blood, fresh plasma, RBC concentrates). No clinically significant disadvantages occurred.

[Effect of particle size and emulsifier on pharmacokinetic values of a parenterally administered fat emulsion]. / Uber den Einfluss von Teilchengrösse und Emulgator auf pharmakokinetische Kenndaten einer parenteral applizierten Fettemulsion.

To evaluate pharmacokinetic data during parenteral application of a fat emulsion a controlled study in healthy volunteers was performed. Another aim of the study was to investigate whether these kinetics could be changed by modification of the emulsion. For this purpose, 10 male medical students--free of any metabolic disorders--received modified batches of one fat emulsion (Lipovenös), differing with respect to particle size or emulsifier. The emulsions were applied using a pump-controlled continuous infusion technique. The dosage was calculated according to body weight: 0.1 g/kg B.W./h. There was a 7-10 day interval between one application and the following study period, again using the same volunteers. Thus every volunteer served as his own control. Routine laboratory parameters as well as parameters relating to fat metabolism were measured. While routine laboratory parameters were not statistically different between the groups, pharmacokinetic data showed differences according to the batches used. Highest triglyceride and free fatty acid levels i.s. were present after application of the emulsion with low medium particle size, while lowest levels were found after increasing the particle size to 380 nm. In addition, it could be documented that an increase in medium particle size resulted in higher elimination rate, transfer and pool size. The modified emulsifier led to an additional increase of these effects, thus inducing beneficial metabolic profiles. The results of the present investigation might perhaps enable us to adjust the profile of future fat emulsions, with the aim of optimizing or restoring metabolic hemostasis.

[Parenteral use of a fat emulsion in the early postoperative period]. / Uber den parenteralen Einsatz einer Fettemulsion in der frühen postoperativen Phase.

Parenteral application of fat emulsions has been established as useful in long term artificial nutrition especially during weaning off the ventilator. In order to ascertain whether these advantages can also be proved in nonventilated patients in the immediate postoperative phase, alternatively carbohydrates versus a new fat emulsion were investigated. 30 patients were randomly allocated to three different nutrition regimens. The caloric and nitrogen supplementation was identical for all groups, while the carbohydrate and fat content was different. Group I: only carbohydrates (as caloric source), group II: high fat load (3 g/kg/day), group III: medium fat dosage (1.5 g/kg/day). Routine laboratory parameters as well as acid-base-status and fat metabolism were evaluated. While most of the routine parameters were not significantly different between the groups, triglyceride levels in serum were highest in group II but never exceeding 280 mg/dl (-x). Nitrogen balance as well as protein metabolism were significantly improved using regimen III, thus documenting the beneficial effect of a medium fat dosage in the immediate postoperative phase. Parenteral nutrition combining amino acids, carbohydrates and a fat emulsion seems to be the optimal postoperative regimen even in patients without ventilatory support.

[Modified substitution of intracellular cations]. / Modifizierte Substitution intrazellulärer Kationen.

In order to ascertain the effect of modified supplementation of electrolytes and trace metals on intracellular uptake, 75 patients undergoing mitral valve replacement were randomly divided into three groups: group A (n = 25) received potassium and sodium chloride while group B (n = 25) was treated with potassium aspartate; in group C (n = 25), a balanced solution of electrolytes and trace metals (Inzolen) with aspartate as the anion was given. The treatment in the three groups was administered on the basis of frequently measured plasma levels of potassium and sodium. Anesthesia was similar in all patients; cardiac arrest was performed by crossclamping of the aorta using "Bretschneider's cardioplegia" for sodium withdrawal. After removal of the mitral valve, a sample of papillary muscle was obtained and analyzed by atomic absorption for its content of sodium, potassium, magnesium, zinc, and copper (Na, K, Mg, Zn, Cu). Sodium levels in papillary tissue were below the normal range in all groups and without differences depending upon the kind of treatment. Potassium levels in group A, however, (KCl) were markedly below those in groups B and C (aspartates). A similar effect could be observed with respect to tissue levels of Mg, Zn, and Cu. Supplementation of trace metals (group C) had no additional effect on tissue concentrations: there were no significant differences between group B (K aspartate) and group C (K-, Mg-, Zn-, Cu-, Na aspartate). Our results stress the importance of effective treatment of electrolyte and trace metal deficiencies. The present data suggest that the utilization of intracellular cations can particularly be improved by using solutions with aspartate as the anion.

[Acute normovolemic hemodilution in extensive surgical interventions]. / Die akute normovolämische Hämodilution bei grossen operativen Eingriffen.

In order to ascertain the effect of acute isovolaemic haemodilution on haemodynamics and various laboratory parameters as well as homologous blood consumption 44 patients undergoing major liver surgery were investigated in two groups: group I (n = 22) underwent acute normovolaemic haemodilution after induction of anaesthesia; group II (n = 22) had no blood withdrawn and served as control. Haemodilution led to typical haemodynamic effects such as increase in cardiac index and decrease in systemic as well as pulmonary vascular resistance; no detrimental effect of the procedure could be observed. Haemodilution led to a marked reduction in the consumption of banked blood which was on the average 1.8 units/patient against control intraoperatively and 3.1 units/patient postoperatively summing up to a total of 4.9 units/patient.