Dextran and hydroxyethyl starch interfere with fibrinogen assays.

We studied the haemostatic and volume effects of synthetic plasma substitutes and Ringer's solution in 48 surgical patients and found that the measured fibrinogen concentrations of patients receiving either dextran or hydroxyethyl starch (HES) were significantly higher than those predicted by the dilutional effects. The groups given Ringer's solution showed no apparent disproportion between fibrinogen concentration and plasma volume change. The results suggested that the presence of artificial colloids might interfere with the indirect fibrinogen assay used in the study. The method of analysis was based on light scattered from the reaction mixture during prothrombin time (PT) measurement. To test the hypothesis, plasma was obtained from nine volunteers to prepare 20, 40 and 60% dilutions in normal saline, 6% dextran 70, 6% HES 120/0.7 or 6% HES 200/0.5 solutions. Fibrinogen was measured on a ACL-300R coagulometer by two indirect methods, PT derived and the Clauss method. Relative concentrations were compared by analysis of variance and Sheffé's multiple comparisons. Dilutions containing either dextran or HES gave significantly higher values (P < 0.001) than samples diluted with normal saline. We conclude that the results of indirect fibrinogen assays should be interpreted cautiously, when HES or dextran is used for volume replacement. This may be particularly true when hypofibrinogenaemia is encountered after extensive use of synthetic colloids during massive transfusion.

The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery.

BACKGROUND: Thrombin formation during cardiac surgery could result in disordered hemostasis and thrombosis. The aim of the study was to examine the effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic activity in patients undergoing cardiac surgery. METHODS: Data were collected prospectively from 60 patients undergoing coronary artery bypass grafting using cardiopulmonary bypass (CPB). In a randomized sequence, 20 patients received aprotinin, 20 patients received tranexamic acid, and in 20 patients placebo was used. RESULTS: Significant thrombin activity was found in all the studied patients. Thrombin generation was less in the aprotinin group than in the tranexamic acid and the placebo group (thrombin/anti-thrombin III complexes 33.7 +/- 3.6, 53.6 +/- 7.0 and 44.2 +/- 5.3 microg/l 2 h after CPB and F1 + 2 fragment 1.50 +/- 0.10, 2.37 +/- 0.37 and 2.04 +/- 0.20 nmol/l 6 h after surgery, respectively). The inhibition of fibrinolysis was significant with both anti-fibrinolytic drugs (D-dimers 0.427 +/- 0.032, 0.394 +/- 0.039 and 2.808 +/- 0.037 mg/l 2 h after CPB, respectively). The generation of d-dimers was inhibited until 16 h after CPB in the aprotinin group. The plasminogen activation was significantly less in the aprotinin group (plasmin/anti-plasmin complexes 0.884 +/- 0.095, 2.764 +/- 0.254 and 1.574 +/- 0.185 mg/l 2 h after CPB, respectively). CONCLUSION: Thrombin formation is inevitable in coronary artery bypass surgery when CPB is used. The suppression of fibrinolytic activity, either with aprotinin or with tranexamic acid interferes with the hemostatic balance as evaluated by biochemical markers. Further investigations are needed to define the role of hemostatic activation in ischemic complications associated with cardiac surgery.

Replacement of massive blood loss.

Treatment of massive blood loss has experienced major changes during the recent decade. The transition towards pure component therapy has been the most significant issue, which has compelled the clinician to revise some of their basic strategies in treatment of massively bleeding patients. The importance of adequate volume resuscitation with crystalloids and colloids is still unrefutable, but the therapy of hemorrhagic derangements has changed. Plasma-poor red cells (RC) are now commonly used instead of whole blood (WB) or packed red blood cells (PRBC) to correct oxygen carrying capacity during massive blood loss. As the plasma content of RC is minimal, deficit of plasma and coagulation factors develops earlier than during transfusion of WB and PRBC. Hypofibrinogenemia develops first followed by other coagulation factor deficits and later by thrombocytopenia. Therefore the use of fresh frozen plasma (FFP) is the primary intervention to treat abnormal bleeding encountered in the replacement of massive blood loss with RC. As the development of thrombocytopenia is a highly individual phenomenon, the transfusion of platelets should be guided by repeatedly determined platelet counts.

Perioperative volume effect of HES 120/0.7 compared with dextran 70 and Ringer acetate.

Hydroxyethyl starch 120 (HES 120/0.7, Plasmafusin) is the smallest medium molecular weight HES preparation used as a plasma substitute for all clinical purposes. We compared the volume and colloid osmotic effect of 6% HES 120 with 6% dextran 70 and Ringer's solution during and after surgery with minimal blood loss. Patients (n = 48) having general anaesthesia were randomly divided into six groups. A thirty-minute bolus infusion was started at the induction of anaesthesia, and thereafter the infusions were continued at two different rates for five hours. The volume of the bolus was 10% and 30% of the calculated volume (CPV) in colloid and Ringer groups, respectively. The constant infusion rates were 2% and 6% of the CPV for the colloids, and 10% and 20% for the two Ringer groups. Blood samples for the measurement of serum proteins and colloid osmotic pressure (COP) were obtained before induction, after the bolus, and thereafter hourly throughout the study. Albumin, prealbumin and total serum protein concentrations were used to calculate relative plasma volumes. After the bolus infusion, plasma volumes increased significantly in all six groups and the increments were sustained throughout the study. At the lower infusion rates of the volume changes of HES and Ringer groups were almost identical and comparable to dextran group up to the third floor. At the higher infusion rates, dextran 70 produced greater plasma volume expansions than HES 120, and the volume effect of Ringer's solution was clearly exceeded by both colloids. The hourly estimated half-lives of dextran were constantly longer compared with HES. With both infusions rates the COPs of dextran and HES groups were higher compared with Ringer groups. There were no differences in COP between the dextran and HES groups. It is concluded, that in this clinical setting the volume effect of 6% dextran 70 exceeds that of the HES 120/0.7, and that both colloids are superior to Ringer's solution.

Intravenous regional anaesthesia of the arm. Effect of the technique of exsanguination on the quality of anaesthesia and prilocaine plasma concentrations.

The effects of different techniques of exsanguination of the upper arm during intravenous regional anaesthesia on prilocaine plasma concentrations, quality of anaesthesia, toxic symptoms after deflation of the tourniquet and injection pressure of the anaesthetic were studied in 10 healthy male volunteers. The nondominant arm was exsanguinated using either Esmarch's bandage or elevation of the arm for 2 minutes plus arterial occlusion by compression of the brachial artery. The injection pressure after the prilocaine dose (3 mg/kg) was significantly higher in the elevation group (maximally 98 mmHg). There were no statistically significant differences in the onset of, or recovery from, anaesthesia between the groups. Various mild toxic symptoms were experienced in the central nervous system after deflation of the tourniquet. However, there was no correlation between the two techniques and the degree of severity of the toxic symptoms. The highest single venous plasma concentration (total) of prilocaine was 2.3 micrograms/ml measured from the contralateral cubital vein (elevation group, 2 minutes). The differences in prilocaine concentrations between the groups were not statistically significant.

Massive blood transfusion exceeding 50 units of plasma poor red cells or whole blood: the survival rate and the occurrence of leukopenia and acidosis.

The survival rate after bleeding requiring massive blood transfusions exceeding 50 units has been reported to be low or zero. There seems to be no reports of leukopenia in connection with massive blood transfusion. This retrospective study was carried out to investigate the survival rate and the occurrence of leukopenia and acidosis in patients who were transfused with more than 50 units of plasma poor red cells or whole blood. The survival rate was 16 of 23. Three of the five patients with a blood transfusion of over 100 units survived. Pure component therapy was used on 18 occasions. All patients had a leukopenia, which lasted up to five days. All patients had an acidosis. The range of the lowest pH values in patients who did not survive was from 6.77 to 7.27 and in survivors from 6.87 to 7.28. The survival rate was considerably higher than reported in previous studies. Pure component therapy appeared to be particularly suited to massive transfusion. Leukopenia was a regular phenomenon. Severe acidosis did not predict a poor outcome.

Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates.

The purpose of this study was to assess the change of platelet and fibrinogen concentrations and the change of activities of prothrombin and factors V and VII when major surgical blood loss was replaced with plasma-poor red cell concentrates (RCCs) and colloid plasma substitutes. Sixty patients were studied. The average blood loss was 65% +/- 41% of the calculated blood volume (CBV). Blood loss was monitored carefully and replaced without delay to ensure stable blood volume. Blood samples were obtained at the induction of anesthesia and at the end of the recovery room period, or before the patient was given fresh frozen plasma. In addition, a platelet count was determined after each 20% blood loss. The results were converted to relative values, and simple linear regression with logarithmic transformation was applied. The initial platelet concentration was 257 +/- 89 x 10(3)/mm3 and the extrapolation of the regression line intercepted the critical level of 50 x 10(3)/mm3 at 230% (confidence interval 169%-294%) blood loss. The initial fibrinogen concentration was 3.7 +/- 1.1 g/L and the hemostatically significant level of 1.0 g/L was already reached at 142% (117%-169%) blood loss (r2 = 0.90). Activities of prothrombin and coagulation factors V and VII reached their critical levels at 201% (160%-244%), 229% (167%-300%), and 236% (198%-277%) blood loss, respectively. We conclude that deficiency of fibrinogen develops earlier than any other hemostatic abnormality when plasma-poor RCCs are used for the replacement of major blood loss.

Albumin, HES 120 and dextran 70 as adjuvants to red blood cell concentrates: a study on colloid osmotic pressure changes in vitro.

An in vitro model of surgical bleeding was developed to simulate continuous blood loss and replacement therapy with plasma substitutes and red cell concentrates. The model was used to determine the lowest colloid concentration in vitro for each of the plasma substitutes that sustains colloid osmotic pressure above 2.4 kPa (or 18 mmHg) when used up to the recommended maximal total dose. Plasma, supernatant separated from red cell concentrates and dextran 70, hydroxyethyl starch 120 or albumin were mixed to create dilutions imitating plasma composition in the course of clinical blood loss and replacement therapy. The relative volume of each component was calculated according to the model when the bleeding was equal to multiples of 10% of blood volume up to a blood loss of 120%. Our measurements indicate that the colloid concentrations of 5.0% for albumin, 4.0% for hydroxyethyl starch 120 and 3.5% for dextran 70 preserve colloid osmotic pressure above 2.4 kPa.

Replacement of major surgical blood loss by hypo-oncotic or conventional plasma substitutes.

The purpose of the study was to examine the effects of hypooncotic 4% hydroxyethyl starch 120/0.7, 3% dextran 70, 5% albumin and hyperoncotic 6% hydroxyethyl starch 120/0.7 on the perioperative colloid osmotic pressure (COP), albumin and protein concentrations and fluid balance. The plasma substitutes were used with red cell concentrates to replace blood loss with equal volume in sixty major abdominal or urological surgeries. A special effort was made to keep replacements and losses at even volumes constantly and to avoid fluctuation of blood volume. The blood specimen were obtained before induction, after each 20% blood loss, at the end of the recovery room phase and on the three following postoperative mornings. There were significant differences in the peroperative and immediate postoperative COPs. However, these differences had vanished by the first postoperative morning. COP was preserved above 16 mmHg in all groups throughout the study. The identical peroperative albumin and protein concentrations of the synthetic colloid groups suggests that their volume effect was the same, regardless of the varying COP. During the observation period there were no significant differences among the groups concerning the diuresis and the fluid balances. We conclude, that the hypooncotic 4% HES 120 and 3% dextran 70 solutions provide the same clinical effect as 6% HES 120 solution. Consequently less colloid is needed, which allows the use of greater volumes of the dilute colloid solutions in replacement therapy.

Tranexamic acid (Cyklokapron) reduces perioperative blood loss associated with total knee arthroplasty.

In this prospective, randomized, double-blind study, we have investigated the effect of an antifibrinolytic agent, tranexamic acid (Cyklokapron), on blood loss and transfusion requirements associated with total knee arthroplasty. Twenty-nine patients were allocated randomly to receive either tranexamic acid 15 mg kg-1 or an equal volume of placebo a few minutes before a tourniquet was deflated. Blood loss during surgery, in the recovery room and on the surgical ward was recorded, together with the number of units of blood transfused in hospital. Mean blood loss during surgery was 428 (SD 254) ml in the tranexamic acid group (n = 15) compared with 415 (244) ml in the placebo group (n = 13). In the recovery room the tranexamic acid group lost 127 (95) ml and the placebo group 576 (245) ml (P < 0.001). On the ward the respective volumes were 293 (200) ml and 558 (293) ml (P < 0.01). Total blood loss was 847 (356) ml in the tranexamic acid group and 1549 (574) ml in the placebo group (P < 0.001). During the hospital stay the treatment group received 1.5 (1.3) units of blood compared with 3.3 (1.8) in the control group (P < 0.005). Two patients in the placebo group experienced a thrombotic complication compared with none in the treatment group. We conclude that tranexamic acid reduced perioperative blood loss and transfusion requirements associated with total knee arthroplasty.

Tranexamic acid radically decreases blood loss and transfusions associated with total knee arthroplasty.

The application of a pneumatic tourniquet in orthopedic procedures enhances local fibrinolysis. Consequently, a short-term antifibrinolytic therapy may be indicated in this clinical situation to reduce postoperative blood loss. The purpose of this prospective double-blind study was to investigate the effect of tranexamic acid (TA) on blood loss associated with total knee arthroplasty (TKA). Seventy-five patients scheduled for 77 TKAs were randomized to receive either TA (n = 39) or equal volume of normal saline (NS, n = 38). Before deflation of the tourniquet, 15 mg/kg of TA was given intravenously followed by two 10-mg/kg additional doses. Perioperative blood loss gathered in surgical gauzes, suction reservoirs, and postoperative drainage system was measured. The number of transfusions given during hospitalization was registered. Total blood loss (mean +/- SD) was 689 +/- 289 mL in the TA group and 1509 +/- 643 mL in the NS group (P < 0.0001). The mean number of transfused red cell units in the TA group was 1.0 +/- 1.2 compared to 3.1 +/- 1.6 in the NS group (P < 0.0001). Twenty-two patients in the TA group and four patients in the NS group were treated without transfusion (P < 0.00003). Two patients in the TA group and three in the NS group had a deep venous thrombosis, including a fatal case of pulmonary embolism in the NS group. We conclude that short-term TA therapy significantly reduces TKA-associated blood loss and transfusion requirements without increasing thromboembolic complications.