1Department of Anaesthesiology and Intensive Care Medicine, and 2Clinic of Surgery, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany*Corresponding author
Accepted for publication: 16 April 2000
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Abstract |
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Br J Anaesth 2000; 85: 41723
Keywords: surgery; haemorrhage; blood, platelets; measurement techniques
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Introduction |
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Methods |
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According to preoperative randomization (using blinded envelopes), the patients were prospectively separated into three groups (each group n=20). Patients received either 4% modified gelatin solution (Gelafundin (B. Braun, Melsungen, Germany)), a low-molecular weight (LMW) HES solution (mean molecular weight (Mw) 70 000 dalton, degree of substitution (DS) 0.5; 6% HES 70/0.5 (Rheohes, B. Braun)), or a medium-molecular weight (MMW) HES (Mw 200 000 dalton, DS 0.5; 6% HES 200/0.5 (Hemohes, B. Braun)). Volume was given to maintain central venous pressure (CVP) between 10 and 14 mm Hg. Packed red blood cells (PRBC) were administered when the haemoglobin was <9 g dl1. Fresh frozen plasma (FFP) was given only to maintain haemostasis (when aPTT >70 s, fibrinogen <2 g dl1, antithrombin III <40%, and bleeding occurs). Platelets were infused when the platelet count was <30x109 litre1. Ringers lactate was given to compensate fluid loss by sweating, gastric tubes and urine output, or as a solvent for drugs (e.g. antibiotics). Ringers lactate 500 ml h1 was administered routinely in all patients during surgery.
The patients were premedicated with lorazepam 2.0 mg. Anaesthesia was induced in all groups with fentanyl 3 µg kg1, thiopental 5 mg kg1 and atracurium 0.5 mg kg1. Anaesthesia was maintained by titrating sufentanil, atracurium and isoflurane as indicated clinically. The lungs of all patients were mechanically ventilated with 60% N2O in oxygen to keep the SaO2 >95% (continuous oximetry) and the end-expiratory CO2 between 35 and 40 mm Hg (continuous capnography). To maintain normothermia during surgery, a rewarming system (WarmtouchTM) and fluid warmers were used. After surgery, the patients were transferred either to an intensive care unit (ICU) or to an intermediate care unit. Perioperative monitoring included continuous arterial pressure measurement (radial artery), ECG, pulse oximetry, CVP, body temperature (oesophageal), urine output and arterial bloodgas analysis. The anaesthetists who were responsible for the patients management were not involved in the study and blinded to the grouping.
Coagulation measurements
From central venous blood samples, standard coagulation data (antithrombin III (AT III), fibrinogen, platelet count, activated partial thromboplastin time (aPTT)) were measured using routine laboratory tests. D-dimer (turbidimetric method, Roche Diagnostics, Mannheim, Germany, inter-assay coefficient of variability in normal ranges (CV): <10%), F1+2 (ELISA, Dade/Behring, Marburg, Mannheim, CV: 613%), thrombin/anti-thrombin III (TAT; ELISA, Dade/Behring, Marburg, CV: 69%), factor VIII activity (one-stage clotting assay; Roche Diagnostics, Mannheim, Germany, CV: 7%), von Willebrand factor (vWF; turbidimetric method, Roche Diagnostics, Mannheim, Germany, CV: <10%), collagen-binding activity of von Willebrand factor (vWF: CBA; sandwich ELISA, Immuno-Diagnostika, Heidelberg, Germany, CV: 17%) were also measured from the blood samples. Platelet function was measured using a Platelet Function Analyser PFA-100TM system (Dade/Behring, Marburg, Germany). The time required for the platelet plug to occlude the aperture is called the closure time and is indicative of platelet function.8 When the PFA-100TM data using ADP as an inductor are abnormal, it is likely that patients have a platelet defect that impairs primary haemostasis.9 The normal range for PFA-100TM system using ADP as an inductor has been determined to be 77130 s.9 Results from all coagulation data represent the mean from duplicate measurements. Blood sampling was performed at T0 (prior to surgery), T1 (end of surgery), T2 (4 h after surgery) and T3 (first postoperative day).
Statistics
SPSS/PC+ software (V4.0 SPSS, Chicago, USA) was used for statistical analysis. All measured and calculated data were normally distributed (tested by the KolmogorovSmirnov test) and all data are presented as mean (SD). Perioperative data were analysed using the Students t-test, Fishers exact test, or Wilcoxon rank sum test as appropriate. A two-way analysis of variance for repeated measurements (ANOVA, followed by Scheffes test) was used to determine the effects of group, time and grouptime interactions for each measured coagulation variable. In the presence of significant time differences, pair-wise comparisons against baseline values were evaluated using multiple paired t-tests. P-values <0.05 were considered significant.
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Results |
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Discussion |
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Some in vitro studies have described advantages of gelatin compared to HES with regard to coagulation.1820 However, in healthy volunteers, 1000 ml of gelatin (Gelofusin) resulted in a significant decrease in vWF (32%) most likely due to a binding of vWF to gelatin at its binding sites.21 Additionally, TAT (45%) and F1+2 (40%) decreased significantly more than could be expected by haemodilution, indicating that gelatin in healthy volunteers resulted in a significant impairment of primary haemostasis and thrombin generation.21 The defect in primary haemostasis appears to be related to a gelatin-induced reduction in von Willebrand factor. In an in vitro study, Tabuchi et al.22 found that gelatin reduced the velocity and the extent of ristocetin-induced platelet aggregation, whereas aggregation by ADP was not affected. They concluded that gelatin interfered with plasma vWF, not with platelet-vWF or with platelet GpIb.
The results of clinical trials may differ from in vitro studies. In thromboelastograph (TEG) studies, Karoutsos et al.23 revealed no hypocoagulability after moderate doses of gelatin, HES (200/0.5) or albumin (mean doses 13001800 ml). They found a hypercoagulability state only after administration of gelatin. Studies in volunteers and in vitro studies reproduce poorly the multiple in vivo interactions leading to coagulation.23 After surgery, a hypercoagulable state may develop,10 but in all in vitro studies this natural hypercoagulability is absent. In the present study, TAT, F1+2, D-dimer and factor VIII increased significantly during the study period, indicating thrombin generation and reactive hyperfibrinolyis during and after surgery. Hobisch-Hagen and colleagues24 showed that global tests of coagulation (PT, Quick, aPTT) were only slightly influenced by gelatin used in orthopaedic patients undergoing acute normovolaemic haemodilution. They found, however, increased concentrations of activation markers for coagulation (F1+2), TAT and fibrinolysis (D-dimer). The influence of intravascular volume replacement with synthetic colloids on platelet function is another subject of debate. Infusion of HMW-HES in patients undergoing orthopaedic surgery resulted in a clear trend towards decreased platelet aggregation.5 In a case report, a reduced level of all three main factor VIII parameters (VIII : C, vWF, vWFag) was found in a patient after infusion of HMW-HES.25 With reduced VIIIR-RCo there is reduced binding to platelet membrane receptor proteins GPIb and GPIIb/IIIa which results in a decreased platelet adhesion. After large doses of HMW-HES, the platelets appeared swollen and platelet adhesion was reduced.26 Thurner27 observed a significant decrease of ristocetin-induced platelet aggregation in gelatin-treated patients, whereas in a HES 200/0.5-treated group, significantly less change in platelet function was found. Evans and co-workers28 showed that gelatin was associated with varying effects on platelet function: Haemaccel® resulted in more severe disturbances of platelet aggregation than Gelofusine® most likely due to its higher Ca2+ concentration. In the present study, we used the PFA-100TM system to assess platelet function. This system uses whole blood and thus provides a more realistic environment to the aggregation of platelets than other tests (e.g. using platelet aggregometry with platelet-rich plasma).8 The closure time increased slightly during the study, indicating reduced platelet function. This, however, was within the normal range and without differences between the groups. It is summarized that in patients undergoing major abdominal surgery infusing moderate amounts of gelatin, HES 70/0.5 or HES 200/0.5 did not differ with regard to bleeding tendency and use of allogeneic blood. Serially measured molecular markers of haemostasis and indicators of platelet function revealed no relevant differences among the three groups. All three regimens of volume replacement appear to be safe concerning haemostasis in these patients.
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References |
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