1Department of Anaesthesiology and Intensive Care Medicine and 2Clinic of Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany*Corresponding author: Department of Anaesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany
Accepted for publication: May 2, 2001
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Abstract |
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Br J Anaesth 2001; 87: 43540
Keywords: surgery, abdominal; age factors; blood, haemostasis; blood, platelet function
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Introduction |
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Methods |
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All patients received premedication with lorazepam 1 to 2 mg. Anaesthesia was induced by weight-related doses of thiopental, sufentanil, and atracurium. Anaesthesia was maintained by giving sufentanil, atracurium and isoflurane according to the patients need. The lungs of all patients were mechanically ventilated with 60% nitrous oxide in oxygen to keep SaO2 >95% (continuous oximetry). Ventilation patterns were adjusted to keep end-expiratory carbon dioxide between 35 and 40 mm Hg (continuous capnography). After surgery all patients were transferred to the intensive care unit (ICU). On ICU, ventilation was continued if the body temperature was <36°C, gas exchange was insufficient or if there was haemodynamic instability. Regional anaesthesia was not used in the patients. The entire perioperative management was carried out by physicians who were not involved in the study.
Heart rate, mean arterial blood pressure, and central venous pressure (CVP) were measured continuously in all patients. The CVP was maintained between 12 and 14 mm Hg using crystalloid and/or gelatin infusions. Packed red blood cells were administered when the haemoglobin concentration was <9 g dl 1. Crystalloids were administered to compensate for fluid loss by sweating, gastric tubes, and urine output or as a solvent for drugs (e.g. antibiotics). During surgery, 500 ml h1 of crystalloids were given routinely in all patients. When the mean arterial pressure was <60 mm Hg despite sufficient volume therapy, dopamine was given followed by epinephrine if the mean arterial pressure was still <60 mm Hg.
From arterial blood samples standard coagulation variables (AT III, fibrinogen, platelet count and aPTT) were measured using routine laboratory tests. Additionally, D-dimer (turbidimetric method, Roche Diagnostics, Mannheim, Germany; <0.5 ng litre1), prothrombin fragments F1+2 (commercially available solid-phase enzyme-linked immonosorbent assay kit [ELISA], Dade-Behring, Marburg, Germany; normal values from healthy volunteers: 0.41.0 nmol litre 1), thrombin/antithrombin III complex (TAT; using commercially available ELISA, Dade-Behring, Marburg, Germany; normal values from healthy volunteers: 1.04.0 µg litre1), factor VIII activity (one-stage clotting assay; Roche Diagnostics, Mannheim, Germany; normal values from healthy volunteers: 60150 U ml1), von Willebrand factor antigen (vWF-Ag; turbidimetric method, Roche Diagnostics, Mannheim, Germany; normal values from healthy volunteers: 60160 U dl1), collagen-binding activity of von Willebrand factor (vWF:CBA; by sandwich ELISA, Immuno-Diagnostika, Heidelberg, Germany; normal values from healthy volunteers: 0.61.8 U ml 1) were measured from the same arterial blood samples. Platelet volume was measured using Coulter counter STKS (Coultronics, Margency, France). Platelet function was assessed by the Platelet Function Analyser PFA-100TM (Dade-Behring, Marburg, Germany) using adenosine diphosphate (ADP) as inductor. The time required for the platelet plug to occlude the aperture is the closure time and is indicative for platelet function.11 12 The normal range for the PFA-100TM test using ADP in healthy volunteers has been determined to be 77133 s. 11 All analyses were performed in duplicate by a single operator according to the instructions of the manufacturer. Measurements were performed after induction of surgery (before surgery, defined as baseline value; T0), at arrival on ICU (T1), 4 h after arrival on ICU (T3), and on the morning of the first postoperative day (T4).
Statistics
We decided that a 40% change of prothrombin fragment F1+2 from baseline values would reflect abnormal changes in coagulation. The appropriate standard deviation (SD) of F1+2 has been found to be 0.4 nmol litre1.10 For a study with a power of 0.8, a minimum of 20 patients in each group would be required to detect a difference in F1+2 at the 0.05 level.13 Statistical analysis has been carried out using a SPSS/PC+ software (V4.0 SPSS, Inc., Chicago, USA). Data are presented as mean (SD), unless otherwise indicated. Two-way analysis of variance for repeated measurements (ANOVA) followed by post hoc Scheffés test on the matrix of pairwise comparison probabilities was used for all serially measured variables. P values <0.05 were considered significant. Other variables were analysed by one-way analysis of variance (for normally distributed) and Kruskall-Wallis one-way analysis of variance of ranks (when data were not normally distributed data). Chi-square test and Mann-Whitney U test was additionally used when appropriate.
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Results |
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D-dimer levels were higher than normal (>0.5 ng litre1) at baseline in the elderly and significantly different compared to the younger patients (Fig. 1). D-dimer increased in both groups without the changes showing significant group differences. F1+2 plasma levels at baseline were elevated beyond normal (>2 nmol litre1) only in the elderly (Fig. 1). F1+2 increased in both groups, being significantly higher in the elderly than in the younger patients at T1 and T2. TAT plasma levels were higher than normal (>4 µg litre1) at baseline only in the elderly. TAT increased similarly in both groups (elderly: from 8.1 (1.8) to 14.6 (2.9) µg litre1; younger: from 4.9 (1.7) to 13.2 (4.5) µg litre1) (Fig. 1). vWF, factor VIII, and vWF:CAB did not differ between the two groups throughout the study period (Fig. 2).
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Discussion |
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One major result of our study was that elderly patients showed evidence of activated coagulation at baseline (elevated F1+2 and TAT complex) associated with increased fibrinolytic activation (elevated D-dimer) and increased inhibitor consumption (lower AT III, elevated TAT complex). Thrombin production plays a pivotal role in the development of coagulation dysfunction. Excessive thrombin generation may result in consumption of platelets and fibrinogen. Continuous activation of coagulation will result in a hypocoagulable state which is complicated by further (hyper-)fibrinolysis. At baseline, TAT and F1+2 were elevated only in our elderly patients. Both are regarded as indicators of hypercoagulability. 19 The reasons for this phenomenon can only be speculated upon: intravascular volume deficit, (occult) microcirculatory perfusion deficit, or an age-related general change in the balance between procoagulant and anticoagulant mechanisms may be possible explanations. Since liver function was normal in the elderly throughout the study period, reduced synthesis of antithrombin activity appears to be less likely. Platelet function assessed with the PFA-100TM was altered in the elderly at baseline possibly due to elevated thrombin concentration and an ongoing activation of coagulation. Hypercoagulability may be beneficial in reducing surgical bleeding, but it may also have considerable negative effects, e.g. development of venous thrombosis, pulmonary embolism or coronary artery thrombosis.20 Tuman et al. found that postoperative hypercoagulability increased cardiac morbidity and affected outcome considerably in patients undergoing major vascular surgery. 21 Our study population was much too small to draw conclusions with regard to development of thrombosis, outcome or survival.
With the exception of F1+2, AT III and platelet function all other serially measured coagulation variables did not show significant differences between the elderly and younger patients during and after surgery. Measurement of F1+2 appears to be a sensitive tool for detecting accelerated thrombin generation. Thrombin generation and consecutive activation of fibrinolysis are physiological responses to tissue damage.21 F1+2 in the elderly after surgery was moderately but significantly higher than in our younger patients.
Ongoing activation of the coagulation system may imbalance the haemostatic system and result in increased postoperative bleeding. Reduced platelet function may contribute to a disturbed coagulation process. Our data are in agreement with a study assessing the importance of molecular markers of coagulation in patients undergoing different surgical procedures showing that F1+2 was the best predictor of intraoperative haemostatic disorders, followed by D-dimer.21
There is a tendency to assume that the elderly patient has a worse prognosis than the younger patient because of the presence of pre-existing comorbidity with age.3 In addition to the established age-related changes in lungs, kidneys, and cardiovascular system, there may also be differences with regard to haemostasis. This was confirmed by our data showing a moderate imbalance of the coagulation network prior to surgery. This may be of particular importance in those elderly patients who are scheduled for complex surgery and in whom complications arise postoperatively. In this situation activation of inflammatory pathways may result in additional modifications of the haemostatic network associated with the risk of bleeding or microthrombosis with subsequent development of organ failure.22
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