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Ann Thorac Surg 1996;62:130-135
© 1996 The Society of Thoracic Surgeons
Departments of Anesthesiology and Intensive Care Medicine aand Cardiovascular Surgeryb, Justus-Liebig-University Giessen, Giessen, Germany
Accepted for publication February 27, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentReferences |
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Methods. According to a randomized sequence, 30 patients undergoing aortocoronary bypass grafting underwent either hypothermic (rectal temperature, 27°C to 28°C, n = 15) or normothermic CPB (rectal temperature, more than 35°C, n = 15). Arterial blood samples were taken after induction of anesthesia (baseline values), before, during, and immediately after CPB, 5 hours after CPB, and on the morning of the first postoperative day. Circulating thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from these samples. Platelet function was assessed by aggregometry (turbidometric technique) induced by adenosine diphosphate (2 µmol/L), collagen (4 µg/L), and epinephrine (25 µmol/L).
Results. Hypothermic patients showed a significantly higher blood loss and need for homologous blood than the normothermic patients. Thrombomodulin plasma level increased more in the hypothermic (from 28 ± 5 ng/mL to 60 ± 10 ng/mL) than in the normothermic group (from 28 ± 7 ng/mL to 41 ng/mL); p < 0.05). Both protein C and (free) protein S were reduced significantly in the hypothermic (protein C, from 88% ± 25% to 60% ± 11%; protein S, from 71% ± 10% to 40% ± 8%) than in the normothermic patients. Platelet aggregation was significantly more decreased in the hypothermic (adenosine diphosphate, maximum decrease by -43% relative to baseline) than in the normothermic patients (adenosine diphosphate, maximum decrease by -22% relative to baseline). In the hypothermic CPB group, platelet aggregation had recovered incompletely, whereas in the normothermic patients platelet aggregation even slightly exceeded baseline values.
Conclusions. Hypothermic CPB resulted in more pronounced alterations of platelet aggregation and endothelial-related coagulation than normothermic CPB. Plasma levels of soluble thrombomodulin were more increased in hypothermic than in normothermic CPB indicating more extensive endothelial damage or activation associated with hypothermic CPB.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Abnormalities in hemostasis can be related either to changes of factors of the plasmatic coagulation cascade, changes in platelet function, or alterations in endothelial-associated coagulation. Acquired defects in platelet function during CPB have been well described and appear to be very important for extensive postbypass bleeding [2]. Thus, several approaches were aimed at preservation of platelet function during CPB.
In recent years, it has been shown that the endothelium is not only a passive barrier between the intravascular and interstitial space, but represents a metabolic active organ that mainly participates in regulation of immunology, vascular tone, and coagulation [3]. It secretes and expresses compounds by which it is markedly involved in the modulation of hemostasis [4–6]. Thrombomodulin (TM) is one of the substances that is expressed by the endothelial cell [7, 8]. It neutralizes thrombin clotting activity and accelerates thrombin-catalyzed activation of protein C to activated protein Ca [8], thus converting thrombin from a procoagulant protease to an anticoagulant [9]. The TM/thrombin complex and protein Ca together with protein S (a cofactor of protein C that accelerates the activity of protein C significantly) are potent inhibitors of coagulation factors Va and VIIIa [8]. In addition, protein C enhances fibrinolysis by proteolyzing a plasminogen activator inhibitor [10]. These factors are responsible for inhibiting the perpetuation of thrombin generation [4]. Furthermore, TM also possesses direct antithrombin properties [11].
Moderate hypothermic CPB (28° to 30°C) is still most commonly used to protect the tissue from ischemia secondary to inadequate perfusion and oxygenation during CPB. Hypothermic CPB, however, may result in alterations in microperfusion associated with reduced microcirculatory flow rates and tissue perfusion [12]. It is a subject of ongoing controversy whether hypothermic CPB results in more or less production of some cytokines than normothermic CPB [13, 14], by which organ function may be influenced. The coagulation system may also be affected considerably by hypothermia [15, 16]. Thus, more moderate (more than 30°C) or even normothermic CPB (more than 35°C) has gained more and more acceptance in recent years and there appears to be an increasing trend to perform normothermic CPB.
Because there are only sporadic reports on the influence of temperature on changes of coagulation, the aim of the present study was to compare the effects of hypothermic and normothermic CPB on platelet function and the TM/protein C/protein S system in patients undergoing cardiac operations.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Preoperatively the patients were randomly divided into two groups. Cardiopulmonary bypass was carried out either in moderate hypothermia (rectal temperature was kept between 27° and 28°C) (hypothermic CPB, n = 15) or almost normothermia (rectal temperature more than 35°C) was maintained during CPB (normothermic CPB, n = 15). Premedication, induction, and maintenance of anesthesia were similar for both groups consisting of weight-dependent doses of fentanyl, midazolam, and pancuronium and did not show significant differences between the two groups. No volatile anesthetics were used within the entire study period. The patients remained on controlled mechanical ventilation at least until 5 hours after the operation on the intensive care unit. All physicians who cared for the patients in the postoperative period were not involved in the study and were blinded to the grouping.
Cardiopulmonary Bypass
Five minutes before the start of CPB, 300 IU/kg of bovine lung heparin was administered to achieve anticoagulation. Additional heparin was administered to keep the activated clotting time greater than 400 seconds. Aprotinin was not used in any of the patients. Cardiopulmonary bypass was carried out using a nonpulsatile pump and a capillary oxygenator (Sorin 41; Sorin, Torino, Italy). The circuit was primed with 1,000 mL of Ringer's solution, 1,000 mL of 5% dextrose, and 250 mL of 5% human albumin. During CPB, perfusion flow was maintained at 2.4 L • min-1 • m-2 in all patients. Bretschneider's cardioplegic solution (1,000 mL) was infused initially for myocardial preservation followed by additional 200 mL every 20 minutes. Extensive myocardial surface cooling was done by rinsing with ice-cold saline solution. Within 20 minutes after start of CPB, the blood of the circuit was concentrated by a hemofiltration device (HF-80; Fresenius, Bad Homburg, Germany; a hollow-fiber device with polysulfon membrane) with the aim to adjust hemoglobin between 8 and 9 g/dL during CPB. To maintain adequate filling volume of the circuit, Ringer's solution was added when necessary. Packed red blood cells were given when the hemoglobin was less than 7 g/dL. When perfusion pressure was less than 50 mm Hg norepinephrine was given; when it exceeded 100 mm Hg despite sufficient anesthesia, nitroglycerin was administered.
The patients undergoing hypothermic CPB were cooled by both surface cooling and the CPB system. Rewarming was done by both the heater of the CPB system (blood temperature in the circuit never exceeding 40°C) and by a warming mattress. Nasopharyngeal, rectal, and blood temperature in the oxygenator were measured continuously. Weaning from CPB was started when rectal temperature was 36°C. During weaning from CPB, as much pump blood as was necessary to keep pulmonary capillary wedge pressure between 10 and 12 mm Hg was infused. After weaning from CPB was completed, the residual blood of the circuit was salvaged by the hemofiltration device, and this autologous blood was retransfused until the end of the operation. Protamine sulfate was given in the same dosage as the initially administered heparin dose to antagonize heparin effects. All patients were operated on by the same surgical team.
Ringer's solution and low molecular weight hydroxyethyl starch solution were given to maintain stable hemodynamics postoperatively (aim: pulmonary capillary wedge pressure between 10 and 12 mm Hg and cardiac index more than 2.25 L • min-1 • m-2). Packed red blood cells were given when the hemoglobin was less than 9 g/dL, fresh frozen plasma was administered when bleeding exceeded 200 mL for 3 hours, platelet count was more than 50,000/mL, and the activated clotting time was less than 200 seconds. Shed mediastinal blood was not collected and retransfused during the postoperative period. Inotropic support (epinephrine) was administered when cardiac index was less than 2.25 L • min-1 • m-2 in spite of optimal volume therapy.
Measured Parameters and Data Points
Arterial blood samples were drawn after induction of anesthesia (baseline value), before CPB, 20 minutes after start of CPB, immediately after CPB (before protamine administration), end of operation, 5 hours after CPB, and on the morning of the first postoperative day.
Antithrombin III and fibrinogen plasma levels, activated partial thromboplastin time, platelet count, and standard laboratory parameters were measured. Thrombomodulin plasma levels were measured by a one-step sandwich enzyme-linked immunosorbent assay (ELISA; Diagnostica Stago, Asnieres Cedex, France). Normal values of thrombomodulin in healthy volunteers measured by this method were reported to be less than 30 to 40 µg/L [17]. Protein C and protein S (assessed as free protein S after bound protein S was removed from the plasma by precipitation with polyethylene) were also measured by ELISA (Boehringer-Mannheim, Mannheim, Germany). Protein C normally ranged between 60% and 100%, normal free protein S is defined as more than 30%. Thrombin/antithrombin III complex was measured by ELISA (Behringwerke, Marburg, Germany; normal values, less than 10 µg/L). All results from ELISA measurements represent the means from duplicate measurements. Corrections for hemodilution was not calculated for any of the coagulation parameter.
Platelet aggregation was studied by turbidometric method [18] using a double-channel APACT-aggregometer (LAbor, Ahrensburg, Germany). Arterial samples were collected in 3.8% trisodium citrated tubes (9:1 vol/vol). Immediately after sampling, the tubes were centrifuged to obtain platelet-rich plasma (1,500 g for 10 minutes at 25°C). The same blood sample was centrifuged again to obtain platelet-poor plasma (2,500 g for 15 minutes at 25°C). Before aggregometry was carried out, platelet count was adjusted to approximately 150,000 platelets/µL by addition of (autologous) platelet-poor plasma when necessary. Platelet aggregation was induced by 2.0 µmol/L adenosine diphosphate (Dia-Adin; Diamed, Murten, Switzerland), 4 µg/mL collagen (Dia-Colgen; Diamed), 25 µmol/L epinephrine (Dia-Nephrin; Diamed), and NaCl (control). Different doses of inductors of platelet aggregation (ie, agonists) were tested before the study. The finally used doses of agonists were shown to be effective to produce sufficient platelet aggregation. The maximum increase in light transmission after addition of the aggregating agent was defined as maximum platelet aggregation (read as percentage increase). Aggregation measurements were carried out in duplicate within 2 hours after blood sampling by the same investigator.
Postoperative blood loss (drained in special tubes) and use of banked blood or blood products were also documented.
Statistics
All data are expressed as mean values ± standard deviation. Percental changes of platelet aggregation from baseline were additionally calculated (changes expressed as relative percentage). One- and two-factorial analyses of variance for repeated measurements (including Scheffé's test) were used to determine the effects of group, time, and group–time interaction for each measured parameter. A p value less than 0.05 was considered significant.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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). The patients showed no differences regarding neurologic sequelae. Total amount of heparin and activated clotting time did not differ statistically between the two groups (Table 1). In 2 patients of the hypothermic and 3 patients of the normothermic group, norepinephrine was necessary to maintain perfusion pressure more than 50 mm Hg. Postoperative blood loss and need for homologous blood or fresh frozen plasma were higher in the hypothermic than in the normothermic patients (p < 0.05) (Table 1).
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)tab 2.
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). Protein C (hypothermic: from 88% ± 25% to 60% ± 11%) and (free) protein S (hypothermic: from 71% ± 10% to 40% ± 8%) were also more altered in the hypothermic patients (Figs 1, 2). During and after CPB, thrombin/antithrombin III complex plasma concentrations were higher in the hypothermic (increase from 16 ± 8 ng/mL to 77 ± 15 ng/mL) than in the normothermic group (increase from 15 ± 7 ng/mL to 35 ± 12 ng/mL) (p < 0.05) (see Fig 2).
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). At the end of the study period on the morning of the first postoperative day, platelet aggregation had completely recovered in the normothermic patients, whereas it did not reach baseline values in the hypothermic CPB group.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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One major result of the present study was that platelet aggregation was significantly more reduced in the hypothermic than in the normothermic CPB group. Recovery of platelet function in the hypothermic patients was not complete at the end of the study period, whereas in the normothermic patients aggregation data had reached or even slightly exceeded baseline values. Other investigators have confirmed that hypothermia appears to be an important factor concerning platelet function [21, 22]. Lu and colleagues [23] demonstrated that a reduction of incubation temperature from 37°C to 22°C resulted in an increase in the expression of fibrinogen receptors, in platelet release, and platelet aggregation.
The negative effects of hypothermia have been shown not only in patients undergoing cardiac operation, but also under different conditions. Ferraro and co-workers [16] added either saline solution (control group) or endotoxin (activated group) to aliquots of whole blood and then subjected them to normothermia or hypothermia. The recalcification times were determined using fibrin formation and the viscous drag as a determining factor. Recalcification time of the activated hypothermic group was significantly lower than that of the activated normothermic group indicating that hypothermia may modify the coagulation system.
In recent years it has become obvious that the endothelium appears to play an important role in the regulation of anticoagulant and procoagulant pathways [4]. The TM/protein C/protein S system appears to be the primary mechanism for inactivating cofactors of the coagulation cascade and thus appears to play an important role in the regulation of coagulation. Thrombomodulin plays a key role for the anticoagulant properties of protein C. The rate of conversion of protein C to (active) protein Ca by thrombin is rather slow. The presence of the cofactor TM increases the rate of protein C activation by thrombin about 10,000 to 20,000-fold [5, 7, 9]. Therefore, the rapid clearance of thrombin from the circulation could also be ascribed by TM, which functions as a high-affinity, active site-independent receptor for thrombin on the endothelium.
Thrombomodulin is normally expressed on the endothelial cell and bound to the endothelium. Soluble TM, however, has been found also in the circulating blood [17]. The soluble form of TM appears to be also active; when TM was purified from plasma it catalyzes protein C activation by thrombin. The apparent Michaelis constant for protein C was identical for both the soluble and cellular-bound TM [5]. Increased plasma levels of TM result either from increased expression of membrane-bound TM and subsequent release into the circulation or from increased proteolytic cleavage of membrane-bound TM secondary to endothelial activation or damage.
Plasma levels of TM were higher in our hypothermic than in the normothermic patients. Endothelial cell integrity may be altered by various mechanisms during CPB; hypoxia, microcirculatory abnormalities, release of proteinases from activated white cells, activation of mediator cascade systems (eg, the complement system) may contribute to endothelial function abnormalities with subsequent release of TM in the circulating blood [24, 25]. It has been reported that elevated plasma concentration of soluble TM even reflects the degree of endothelial cell damage [11, 26]. Endotoxin, cytokines, and tumor necrosis factor are increased during CPB [27], which also affect endothelial function. Thrombin generated during CPB in spite of anticoagulation with heparin (activated clotting time more than 400 seconds) may be another important stimulant for increased TM expression and/or liberation of TM from endothelial cells into the circulating blood. Thrombin/antithrombin III complex, which represents a sensitive marker for coagulation activation during CPB, was higher in our hypothermic than in our normothermic patients indicating that the coagulation system was more activated in the hypothermic patients. Altered microcirculation and a more activated coagulation system at the microcirculatory level may be one possible explanation for the higher thrombin/antithrombin III complex levels in the hypothermic than in the normothermic patients.
Protein C and protein S were significantly more decreased in our hypothermic than in our normothermic patients. Knöbl and colleagues [28] also documented that protein C decreased during (hypothermic) CPB and remained lower also in the period after bypass. This may contribute to the well-known bleeding tendency of patients undergoing cardiac operations [28]. In the period after bypass, protein C plasma levels remained significantly lower than baseline values in our hypothermic patients by which an increased consumption or reduced production can be assumed.
We conclude that optimizing CPB is a never-ending challenge. Hypothermic CPB has been used for several years. We have learnt much about the complexity of the pathogenesis of alterations of coagulation during CPB. Hypothermia appears to be associated with more pronounced alterations in both platelet-related and endothelial-associated coagulation. Endothelial damage reflected by a higher plasma levels of circulating TM was higher in the hypothermic than in the normothermic patients. Data from the present study may by another indication that it may be of benefit to change from a hypothermic to a normothermic CPB regimen in patients undergoing elective cardiac operations.
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Footnotes |
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