Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass

Cardiopulmonary bypass (CPB) is associated with activation of humoral systems, which results in the release of proteases. These proteases may affect platelets and stimulate granulocytes. In the present study, the protease inhibitor aprotinin was given in high doses to 11 patients to achieve plasma concentrations of more than 150 kallikrein inactivator units per milliliter during CPB. At such concentrations, kallikrein and plasmin are effectively inhibited. This treatment resulted in platelet preservation during CPB. Platelet numbers were virtually unaffected, and thromboxane release was prevented in the aprotinin-treated group in contrast to the control group. Postoperatively, hemostasis was significantly better preserved after aprotinin treatment (blood loss of 357 ml in the treated group versus 674 ml in the untreated group; p less than 0.01). Since tissue-plasminogen activator activity was similar in both groups, the improved hemostasis most likely should be attributed to platelet preservation. Furthermore, aprotinin lessened neutrophilic elastase release, which might contribute to decreased pulmonary dysfunction in patients at risk.     

Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management

BACKGROUND: Cardiac surgery involving cardiopulmonary bypass (CPB) leads to fulminant activation of the hemostatic-inflammatory system. The authors hypothesized that heparin concentration-based anticoagulation management compared with activated clotting time-based heparin management during CPB leads to more effective attenuation of hemostatic activation and inflammatory response. In a randomized prospective study, the authors compared the influence of anticoagulation with a heparin concentration-based system (Hepcon HMS; Medtronic, Minneapolis, MN) to that of activated clotting time-based management on the activation of the hemostatic-inflammatory system during CPB. METHODS: Two hundred elective patients (100 in each group) undergoing standard cardiac surgery in normothermia were enrolled. No antifibrinolytic agents or aprotinin and no heparin-coated CPB systems were used. Samples were collected after administration of the heparin bolus before initiation of CPB and after conclusion of CPB before protamine infusion. RESULTS: There were no differences in the pre-CPB values between both groups. After CPB there were significantly higher concentrations ( < 0.05) for heparin and a significant reduction in thrombin generation (25.2 +/- 21.0 SD vs. 34.6 +/- 25.1), d-dimers (1.94 +/- 1.74 SD vs. 2.58 +/- 2.1 SD), and neutrophil elastase (715.5 +/- 412 SD vs. 856.8 +/- 428 SD), and a trend toward lower beta-thromboglobulin, C5b-9, and soluble P-selectin in the Hepcon HMS group. There were no differences in the post-CPB values for platelet count, adenosine diphosphate-stimulated platelet aggregation, antithrombin III, soluble fibrin, Factor XIIa, or postoperative blood loss. CONCLUSION: Compared with heparin management with the activated clotting time, heparin concentration-based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.     

抑肽酶剂量对体外循环炎性反应的作用及影响

目的：观察不同剂量抑肽酶对体外循环（ＣＰＢ）心脏手术炎性反应的作用及差异。方法：３２例拉膜置换病人,随机双盲分为３组：对照组、抑肽酶小剂量组、抑肽酶大剂量组,分别于ＣＰＢ前、ＣＰＢ结束、停机后２h取桡动脉血,测定中性粒细胞ＣＤ１１b表达及细胞因子ＴＮＦ－α、ＩＬ－６血浆清凉,:凶肽酶大剂量组中性粒细胞ＣＤ１１b的表达,细胞因子ＴＮＦ－α血浆水平各时间点无明变化,且ＩＬ－６释放减少,小剂量抑肽酶只在停机后２h部分下调ＣＤ１１b表达及降低ＴＮＦ－α血浆水平,两组相比,小剂量抑肽酶作用明显减弱,结论：抑肽酶的抗赕作用存在量效关系,大剂量抑肽酶的效能好于小剂量抑肽酶。     

Reducing hemostatic activation during cardiopulmonary bypass: a combined approach

Interventions such as heparin-coated circuits, epsilon-aminocaproic acid, and reduced shed blood reinfusion have shown mixed results when applied individually for limiting hemostatic activation during cardiopulmonary bypass (CPB). We compared coagulation and fibrinolytic activation during conventional CPB (control) (CTRL) using noncoated circuits, no antifibrinolytics, and open cardiotomy with a combined strategy (HAC) that used heparin-coated circuits, epsilon-aminocaproic acid, and closed cardiotomy. Blood samples were drawn before, during, and after CPB for primary coronary bypass grafting surgery from 9 CTRL patients and 10 HAC patients. Thrombin-antithrombin complex and fibrinopeptide A levels (markers of thrombin and fibrin generation) were reduced in the HAC versus CTRL group after 30 min of CPB (P < 0.05). Average tissue plasminogen activator (tPA) levels were significantly lower in the HAC group by 30 min on CPB (P < 0.05), resulting in preservation of plasminogen activator inhibitor (PAI)-1 during CPB (P < 0.05). D-Dimer, a measure of intravascular fibrin formation and removal, was reduced in the HAC group during and after CPB (P < 0.005). Overall, the combined strategy was associated with a reduction in CPB-induced increases in markers of thrombin generation, fibrin formation, tPA release, and fibrin degradation and better preservation of PAI-1. IMPLICATIONS: A combined approach during cardiopulmonary bypass (CPB) that uses heparin-coated circuits, epsilon-aminocaproic acid, and limited reinfusion of shed pericardial blood is associated with reduced activation of the coagulation and fibrinolytic systems that typically occurs during conventional CPB.     

氨甲环酸减少体外循环心脏手术后失血的作用及与抑肽酶的比较研究

目的 观察氨甲环酸减少体外循环（ＣＰＢ）心脏手术后失血的作用,探讨其其作用机制,并与抑肽酶比较。方法 随机选取ＰＣＢ心脏手术病人３０例,分为氨甲环酸用药组（ＴＡ组,１０例）,抑肽酶用药组（ＡＰ组,１０例）和对照组（Ｃ组,１０例）。于ＣＰＢ前、中、后２ｈ分别测定ｔ－ＰＡ和ＰＡＩ－Ｉ活性、ＴＸＢ２和６－ｋｅｔｏ－ＰＧＦ１α含量、ＡＤＰ诱导的血小板最大聚集率和血小板超微结构变化,记录各组术后纵隔心包引流     

Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation

OBJECTIVE: Attenuation of hemostatic activation is a central goal during CPB. However, this poses a problem in patients insensitive to heparin. The present investigation was performed to assess different strategies of managing patients with heparin resistance during CPB. DESIGN: A randomized, prospective clinical investigation. SETTING: A major European heart center. PARTICIPANTS: Five groups with 20 patients each were investigated. INTERVENTIONS: The groups were handled as follows: (1). maintenance of a target ACT, (2). maintenance of the target unfractionated heparin (UFH) level and supplementation of a UFH level-based strategy with (3). AT III, (4). the direct thrombin inhibitor r-hirudin, or (5). the short-acting platelet glycoprotein (GP) IIb/IIIa antagonist tirofiban. Platelet count and generation of contact factor XIIa, thrombin, and soluble fibrin were assessed. Samples were obtained before CPB and after CPB before protamine infusion. MEASUREMENTS AND MAIN RESULTS: There were no differences observed in the generation of factor XIIa. The UFH-based strategy and supplementation with AT III, r-hirudin, and tirofiban resulted in significantly reduced (p < 0.05) thrombin generation compared with ACT management. A significant reduction of fibrin formation was seen only in patients who received AT III, r-hirudin, or tirofiban supplementation to the UFH. The administration of tirofiban resulted in a significant preservation of the platelet count compared with the other groups. There were no significant differences in the postoperative blood loss. CONCLUSIONS: Activation of hemostasis during CPB in heparin-resistant patients most likely has to be attributed to stimulation of the tissue factor pathway. Even the sole use of high concentrations of UFH does not effectively inhibit this activation. Therefore, in these patients anticoagulation during CPB with UFH should be supplemented with either AT III, a short-acting direct thrombin inhibitor, or a short-acting platelet glycoprotein IIb/IIIa antagonist.     

Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study

OBJECTIVE: Bivalirudin has been successfully used as a replacement for heparin during on-pump coronary artery bypass grafting. This study was conducted to assess the effects of the currently suggested protocol for bivalirudin on hemostatic activation during cardiopulmonary bypass with and without cardiotomy suction. METHODS: Ten patients scheduled for coronary artery bypass grafting were enrolled. Bivalirudin was given with a bolus of 50 mg in the priming solution and 1.0 mg/kg for the patient, followed by an infusion of 2.5 mg . kg(-1) . h(-1) until 15 minutes before the conclusion of cardiopulmonary bypass. Cardiopulmonary bypass was performed with a closed system in 5 patients with and in 5 patients without the use of cardiotomy suction. Blood samples were obtained before and after cardiopulmonary bypass. D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, thrombin-antithrombin, and factor XIIa were determined. RESULTS: Values for factor XIIa remained almost unchanged in both groups, indicating a minor effect of contact activation. In patients without cardiotomy suction, post-cardiopulmonary bypass values for D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, and thrombin-antithrombin were not significantly increased compared with pre-cardiopulmonary bypass values. In patients with cardiotomy suction, values obtained for these parameters had significantly increased compared with pre-cardiopulmonary bypass values and the values obtained in the group without cardiotomy suction after cardiopulmonary bypass. CONCLUSIONS: With this protocol, hemostatic activation during cardiopulmonary bypass was almost completely attenuated when cardiotomy suction was avoided. Cardiotomy suction results in considerable activation of the coagulation system and should therefore be restricted and replaced by cell saving whenever possible.     

去氨加压素对体外循环术后病人减少出血量的观察

目的 观察去氨加压素（ＤＤＡＶＰ）对体外循环术后在及凝血功能的影响。评价其临床实用价值。方法 择期手术的非紫绀性先心病病人４１例ＡＳＡⅠ－Ⅱ级,随机分为对照组（ｎ＝２１）,用药组（ｎ＝２０）,采用双盲法进行试验,用药组在鱼精蛋白中和肝素后１５ｍｉｎ,ＡＣＴ〈１３０ｓ后,ＤＤＡＶＰ０．３μｇ／ｋｇ,稀释至５０ｍｌ、１５ｍｉｎ静脉输入,对照 输入等量生理盐水,测定两组病人术隧、鱼精蛋白中和肝素后和经１     

Effect of recombinant aprotinin on postoperative blood loss and coronary vascular function in a canine model of cardiopulmonary bypass.

OBJECTIVE: Aprotinin is a widely used serine protease inhibitor during cardiopulmonary bypass to reduce blood loss and preserve platelet function. However, the bovine-derived aprotinin can induce hypersensitivity reaction with fatal complications. Furthermore, vascular effects of aprotinin are not completely elucidated. The current study is designed to investigate the effects of recently developed recombinant aprotinin on blood loss and coronary vascular function in a clinically relevant canine model of cardiopulmonary bypass without aortic cross-clamping and cardioplegia. METHODS: Twenty-four dogs underwent cardiopulmonary bypass without aortic cross-clamping and cardioplegia. Dogs were divided into three groups in a blinded fashion: control animals (n=8) received placebo, aprotinin treatment groups received bovine (n=8) or recombinant aprotinin (n=8) according to the Hammersmith method. The doses of bovine and recombinant aprotinin were the same. Coagulation parameters and blood loss were measured regularly at different time points. Endothelium-dependent and -independent vasorelaxation were investigated in isolated left anterior descendent coronary arterial rings by using acetylcholine and bradykinin or sodium nitroprusside and adenosine, respectively. RESULTS: Postoperative blood loss was significantly reduced in the aprotinin-treated groups in comparison to control and there was no significant difference between the two aprotinin-treated groups. Endothelium-dependent relaxation of coronary arteries to acetylcholine and bradykinin was unaffected in the aprotinin treatment groups. Both types of aprotinin significantly increased vasorelaxation to adenosine when compared with controls, but did not affect that to sodium nitroprusside. CONCLUSIONS: The effectiveness of recombinant aprotinin on blood loss was equivalent to bovine-derived aprotinin. Neither types of aprotinin impaired endothelium-dependent relaxation in a canine model of cardiopulmonary bypass.     

Effects of hemodilution, blood loss, and consumption on hemostatic factor levels during cardiopulmonary bypass

OBJECTIVES: The purpose of this study was to determine quantitatively the effects of consumption, hemodilution, and blood loss on coagulation and fibrinolytic factor levels during cardiopulmonary bypass. DESIGN: A combination of measured levels of prothrombin, antithrombin, fibrinogen, plasminogen, and antiplasmin along with their activation markers F1.2, thrombin-antithrombin complex, fibrinopeptide A, plasmin-antiplasmin complex, and D-dimer were used with a computer model of each patient's vascular and hemostatic systems to estimate the cardiopulmonary bypass-associated loss of each factor because of hemodilution, blood loss, and consumption. SETTING: University hospital. PARTICIPANTS: Nine patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At baseline, it was estimated that on average 2%, 3%, and 25%, respectively, of the baseline liver secretion of plasminogen, prothrombin,and fibrinogen were consumed by activation of these proteins. During cardiopulmonary bypass, thrombin and plasmin generation were increased, whereas fibrin generation was decreased because of heparin. Compared with baseline, hemodilution during cardiopulmonary bypass resulted in an average 35% +/- 7% decrease in the concentration of coagulation and fibrinolytic proteins, whereas blood loss was responsible for an average 6% +/- 5% decrease in these proteins. Blood loss varied substantially among patients, resulting in <1% to 14% decreases in hemostatic protein levels. On average, consumption because of activation resulted in less than a 1% drop in the concentration of coagulation and fibrinolytic factors during cardiopulmonary bypass. CONCLUSIONS: Hemodilution is the primary cause of the drop in coagulation and fibrinolytic proteins during routine cardiopulmonary bypass, followed by blood loss, whereas consumption accounts for less than a 1% drop in most patients.     

The effects of cardiopulmonary bypass temperature on inflammatory response following cardiopulmonary bypass.

OBJECTIVES: The inflammatory response to cardiopulmonary bypass is believed to play an important role in end organ dysfunction after open heart surgery and may be more profound after normothermic systemic perfusion. The aim of the present study was to investigate the effects of cardiopulmonary bypass temperature on the production of markers of inflammatory activity after coronary artery surgery. METHODS: Forty-five low risk patients undergoing elective coronary artery surgery were prospectively randomized into three groups: hypothermia (28 degrees C, n = 15), moderate hypothermia (32 degrees C, n = 15), and normothermia (37 degrees C, n = 15). All patients received cold antegrade crystalloid cardioplegia and topical myocardial cooling with saline at 4 degrees C. Serum samples were collected for the estimation of neutrophil elastase, interleukin 8, C3d, and IgG under ice preoperatively, 5 min after heparinisation, 30 min following start of CPB, at the end of CPB, 5 min after protamine administration, and 4, 12 and 24 h postoperatively. RESULTS: Patients were similar with regard to preoperative and intraoperative characteristics (age, sex, severity of symptoms, number of grafts performed, aortic cross clamp time, cardiopulmonary bypass time). Neutrophil elastase concentration increased markedly as early as 30 min after the onset of cardiopulmonary bypass and peaked 5 min after protamine administration. Levels were not significantly different between the three groups. A similar finding was apparent for C3d release. Interleukin 8 concentrations also demonstrated a considerable increase related to cardiopulmonary bypass in all groups, but there was a significantly more rapid decline in interleukin 8 concentrations in the normothermic group in the postoperative period. Eluted IgG fraction showed a much earlier peak concentration than the other markers, occurring within 30 min of the start of cardiopulmonary bypass. Levels reached a plateau, before declining soon after the end of bypass and remained higher than preoperative values at 24 h. There was no difference between the three groups. The cumulative release of all markers was calculated from the concentration-time curves, and was not statistically different between groups. CONCLUSION: Normothermic systemic perfusion was not shown to produce a more profound inflammatory response compared to hypothermic and moderately hypothermic cardiopulmonary bypass.     

小剂量抑肽酶对体外循环中血小板的保护

选择４５例心脏瓣膜置换术患者，其中２３例应用小剂量抑肽酶作为用药组，观察体外循环期间小剂量抑肽酶降低术后失血量的作用。结果显示：用药组术后失血量比对照组减少了５０．２％，输血量减少了６７．０％。抑肽酶可减缓血小板计数的骤然下降趋势，但并不阻止其下降。血小板聚集功能及粘附功能的下降在用药组明显较轻，而胞浆游离［Ｃａ２＋」ｉ、膜磷脂酶Ａ２和环氧化酶活性的上升明显被抑制。结论：小剂量抑肽酶可明显减少术后失血量及输血量，具有与大剂量抑肽酶同样的临床效果。对于血小板胞浆游离［Ｃａ２＋］ｉ及膜磷脂酶Ａ２、环氧化酶活性升高的抑制作用是抑肽酶作用机制的一个重要方面。     

不同剂量抑肽酶对体外循环心脏手术炎性反应的作用

目的 观察不同剂量抑肽酶对体外循环（ＣＰＢ）心脏手术炎性反应的影响。方法 ２６例双瓣膜替换椁病人,随机分为大剂量组,ＣＰＢ前静给抑肽酶２００万ＫＩＵ,预充波中加入２００万ＫＩＵ,术中静滴５０万ＫＩＵ／ｈ,至关胸结束（ｎ＝１３）,小剂量组,ＣＰＢ前静给抑肽酶１００万ＫＩＵ,预充液中加入１００万ＫＩＵ,术中静滴２５万ＫＩＵ／ｈ,至关胸结束（ｎ＝１３）。分别于ＣＰＢ前、ＣＰＢ结束、停机后２ｈ取桡动脉血测     

Effect of aprotinin on postoperative blood loss in off-pump coronary artery bypass surgery

BACKGROUND AND AIM OF THE STUDY: Off-pump coronary artery bypass (OPCAB) enables a reduction in postoperative complications, particularly bleeding and transfusion. Nevertheless, a significant percentage of patients still needs transfusion. The effect of antifibrinolytic therapy on postoperative bleeding as part of OPCAB is still not widely described. The purpose of this study was to investigate the potential benefit of aprotinin in OPCAB. METHODS: We conducted a retrospective comparative study with a historical control group. Consecutive patients undergoing off-pump coronary bypass were divided in two groups: 40 patients were operated without any antifibinolytic drug (group C); 40 patients received aprotinin (group A) during surgery. Patients in group A received a bolus of 2 x 10(6) KIU during 30 minutes, followed by a continuous infusion of 0.5 x 10(6) KIU per hour until the end of surgery. The same protocol was used during the whole study period. RESULTS: Preoperative data of the two groups did not differ except for the number of grafts performed, which was higher in group A. Prothrombin time and activated clotting time increased in both groups after surgery. The use of packed red blood cells or fresh frozen plasma was not significantly different between both groups. Postoperative blood loss was significantly reduced in the aprotinin group (540 mL +/- 320 vs. 770 mL +/- 390, p = 0.006). No increase in postoperative troponin values was found in group A. CONCLUSIONS: Aprotinin significantly reduced postoperative blood loss without reducing the transfusion rate. Aprotinin was not associated with any increase in postoperative complications.     

Effect of combined anticoagulation using heparin and bivalirudin on the hemostatic and inflammatory responses to cardiopulmonary bypass in the rat

BACKGROUND: Despite high-dose heparin anticoagulation, cardiopulmonary bypass (CPB) is still associated with marked hemostatic activation. The purpose of this study was to determine whether a reduced dose of bivalirudin, added as an adjunct to heparin, would reduce thrombin generation and circulating markers of inflammatory system activation during CPB as effectively as full-dose bivalirudin, without adversely affecting postoperative hemostasis. METHODS: Using a model of normothermic CPB in rats, the authors prospectively compared markers of thrombin generation (thrombin-antithrombin complexes) and inflammatory markers (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 10) in three groups: conventional high-dose heparin (H), full-dose bivalirudin (B), and a combined group (standard high-dose heparin with the addition of reduced dose bivalirudin or H&B), at baseline, after 60 min of CPB, and 60 min after CPB. Postoperative hemostasis was also assessed. RESULTS: Groups H&B and B showed reduced thrombin-antithrombin complex formation during CPB compared with group H (P = 0.0003), and this persisted after CPB for group B (P = 0.009). Perioperative increases in interleukin 6 and interleukin 10 showed a trend toward being reduced in animals receiving bivalirudin (P = 0.06). Evidence of residual anticoagulation was found in group H&B as measured by activated clotting time (P = 0.04) and activated partial thromboplastin time (P = 0.02), but no intergroup difference in primary hemostasis was found. CONCLUSIONS: Bivalirudin attenuates hemostatic activation during experimental CPB with potential effects on markers of the inflammatory response. However, with this dosing regimen, the combination of heparin and bivalirudin does not seem to confer any measurable advantages over full-dose bivalirudin anticoagulation.     

乌司他丁和抑肽酶对体外循环小儿炎性反应及心肌损伤的影响

目的研究乌司他丁和抑肽酶对体外循环（CPB）小儿炎性反应及心肌损伤的影响。方法选择拟行CPB的先天性心脏病患儿90例,随机分成6组,每组15例：对照组（C组,不使用乌司他丁及抑肽酶）、小剂量乌司他丁组（UL组,乌司他丁1万U/kg）、大剂量乌司他丁组（UH组,乌司他丁2万U/kg）、小剂量抑肽酶组（AL组,抑肽酶7．5万KIU/kg）、大剂量抑肽酶组（AH组,抑肽酶15万KIU/ kg）、小剂量乌司他丁复合小剂量抑肽酶组（UL＋AL组,乌司他丁1万U/kg＋抑肽酶7．5万KIU/kg）。乌司他丁或/和抑肽酶按各组要求剂量在转机前一次性加入预充液中。于CPB前（T1）、升主动脉开放5 min（T2）、CPB结束后30 min（T3）、4 h（T4）抽取动脉血,测定血浆IL-6、IL-8、IL-10、TNF-α、cTnI浓度及CK-MB活性,记录术后辅助通气时间、24 h引流量、心脏复跳情况及围术期多巴胺使用情况。结果与C组比较,在T2～T4时,UH组、AH组、UL＋AL,组血浆IL-6、IL-8、TNF-α、cTnI浓度及CK-MB活性降低;AH组、UL＋AL组IL-10增高（P＜0．05）;UL＋AL组心脏自动复跳率（100％）增高,血管活性药物使用率较低,术后辅助通气时间较短（P＜0．05）;AH组术后出血量较少（P＜0．05）。结论大剂量乌司他丁、大剂量抑肽酶及小剂量乌司他丁复合小剂量抑肽酶,均可通过抑制CPB炎性反应、减轻小儿心肌损伤,小剂量乌司他丁复合小剂量抑肽酶效果更佳。     

The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass.

The effect of preoperative anticoagulant therapy on intraoperative heparin response in patients undergoing cardiac operations was examined in a prospective study. The study included 45 patients with different preoperative anticoagulant treatments: 10 patients received treatment with phenprocoumon (a warfarin analogue) (group M), 12 patients received treatment with intravenous heparin (group Hiv), and 13 patients received treatment with subcutaneous heparin (group Hsc). The control group consisted of 10 patients who did not receive anticoagulant therapy before operation (group C). Preoperative antithrombin III activity was highest in group M (85% +/- 6%) and lowest in group Hiv (70% +/- 15%, p less than 0.05). The activated clotting time, determined 10 minutes after bolus injection of 250 IU (group M) or 375 IU heparin (all other groups), was 529 +/- 109 seconds in group C, greater than 1000 seconds in group M, 483 +/- 99 seconds in group Hsc, and 406 +/- 63 seconds in group Hiv (p less than 0.05). Heparin consumption during cardiopulmonary bypass varied between 4.6 +/- 1.4 IU/kg.min (group Hiv) and 2.6 +/- 0.9 IU/kg.min (group M) (p less than 0.05). Despite this increased heparin consumption, the patients who had received heparin before operation demonstrated increased activation of coagulation at the end of cardiopulmonary bypass (thrombin-antithrombin III complex, 19 +/- 4.1 ng/ml in group M and 61 +/- 7 ng/ml in group Hsc, p less than 0.05; cross-linked fibrin fragments, 257 +/- 92 ng/ml in group M and 875 +/- 152 ng/ml in group Hiv, p less than 0.05). Increased platelet activation was also found in patients with preoperative heparin therapy (beta-thromboglobulin at the end of cardiopulmonary bypass was 585 +/- 88 ng/ml in group M versus 1341 +/- 190 ng/ml in group Hsc, p less than 0.05). Drainage from the chest tube 24 hours after operation was 815 +/- 305 ml in group C, 644 +/- 238 ml in group M, 1133 +/- 503 ml in group Hsc, and 950 +/- 505 ml in group Hiv (p less than 0.05 for group M versus group Hsc). This study suggests that patients who receive heparin therapy before operation face a high risk of insufficient anticoagulation during cardiopulmonary bypass if standard heparin doses are used. Therefore, for patients who receive preoperative heparin therapy, a larger (500 IU/kg) initial bolus of heparin is recommended before cardiopulmonary bypass. On the other hand, patients who undergo preoperative treatment with phenprocoumon receive sufficient anticoagulative effect with a heparin bolus of 250 IU/kg.(ABSTRACT TRUNCATED AT 400 WORDS)     

Activation of a neutrophil-derived inflammatory response in the airways during cardiopulmonary bypass

Cardiopulmonary bypass (CPB) is believed to cause postoperative lung dysfunction. To more closely examine the inflammatory processes occurring in the airways during CPB, we serially measured inflammatory mediators, with the assistance of a new bronchoscopic microsample probe, in 11 patients undergoing repair of aortic arch aneurysms. Epithelial lining fluid (ELF) and arterial blood were sampled simultaneously after induction of anesthesia, at the time of pulmonary reperfusion, and at the end of surgery. A decrease in the PaO2/FiO2 ratio was observed at the end of surgery (P = 0.029). Although the ELF concentrations of interleukin (IL)-8, IL-6, and neutrophil elastase had increased significantly at the end of surgery (median = 23,200, 1818, and 12,900 microg/mL, respectively), they did not correlate with the degree of hypoxemia. Neutrophil elastase increased significantly at the time of pulmonary reperfusion, before IL-8 and IL-6, and independently of blood transfusions. At the end of surgery, IL-6 in ELF correlated with total blood transfusion volume (rho = 0.731, P = 0.011). These results indicate that a neutrophil-derived inflammatory response is activated in the airway in the early phase of CPB.     

A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass: a pilot investigation

We developed a quick and easy method to perform anti-Xa-activity-based whole blood assay and assessed its reliability for online monitoring of unfractionated heparins (UFHs) during cardiopulmonary bypass. Seventy-five microliters of a mixture of 1:3 large- and small-range Heptest reagent were transferred into blank cartridges of the ACT II device. The plastic flags for clot detection and stirring the sample and reagent were inserted and overlaid with 75 microL of Recalmix for recalcification. One-hundred fifty microliters of citrated whole blood were added and measurements performed. In vitro, the linearity of the test over a range of 1-8 IU/mL UFH, as well as the influence of variations in hematocrit (60%, 30%, and 20%), plasma coagulation factors (50%, 30%, and 20%) and platelets (100, 50, and 20 x 10(3)/microL) on the test results were assessed. In vivo measurements performed during cardiopulmonary bypass were compared with the chromogenic assay. The test revealed linearity to concentrations of 6 IU/mL of UFH and was not significantly influenced by the variations in the in vitro set-up despite a prolongation in samples with a hematocrit of 60%. In vivo, the correlation to the chromogenic test was R: = 0.90. The ACT II anti-Xa-UFH assay performed in whole blood was reliable when used over a wide range of conditions that could be encountered clinically. Although the test is useful for point-of-care monitoring, the necessity of individual calibrations and pipetting in the operation room requires further automation before its use in clinical practice. IMPLICATIONS: The ACT II anti-Xa-unfractionated heparin assay allows for reliable monitoring of large concentrations of UFH over a wide range of hematocrit, platelet, and coagulation factor levels. Further evaluation of this point-of-care device is indicated.     

Reduced complement activation during cardiopulmonary bypass does not affect the postoperative acute phase response.

OBJECTIVE: In the present study the relationship was evaluated between perioperative inflammation and the postoperative acute phase response in patients undergoing elective coronary artery bypass grafting (CABG) assisted by cardiopulmonary bypass (CPB). CPB circuits contained either non-coated- (UMS), Carmeda- (BPS) or Trillium-coated oxygenators (BAS). METHODS: Prospectively, 71 CABG patients were randomly allocated to one of the oxygenator groups (UMS: n=25, BPS: n=25 and BAS: n=21). Terminal complement complexes (TCC) and elastase were determined in plasma samples collected before, during and after bypass. Secretory phospholipase A2 (sPLA2) and C-reactive protein (CRP) were determined before and after bypass. RESULTS: Demographic, CPB and clinical outcome data were similar for the three groups. TCC and elastase increased during CPB, and decreased thereafter. Significant differences between the groups were present in the levels of TCC at the end of CPB (P=0.002) and at the first (P=0.012) and second (P<0.001) postoperative days, the BPS and BAS groups having reduced levels of TCC compared to the UMS group. Also elastase concentrations differed significantly between the groups at the end of CPB (P<0.001). The postoperative sPLA2 and CRP levels increased in all three groups on the first and second postoperative days, but no significant differences were present between the groups. CONCLUSIONS: Material-induced reduction of the inflammatory response during CPB does not affect the postoperative acute phase response. Thus, in CABG patients this response seems relatively unaffected by the composition and/or biocompatibility of the modern CPB circuit and rather to be evoked by surgical trauma, anesthetics and organ perfusion.