Platelet preservation during cardiopulmonary bypass with aprotinin

A remarkable reduction of postoperative blood loss after cardiopulmonary bypass (CPB) has been achieved by prophylactic treatment with the proteinase inhibitor aprotinin. To reveal the mode of action of aprotinin, 23 CPB patients were randomised for aprotinin (2 × 10⁶ KIU in the pump prime) or placebo treatment during CPB. Blood samples were collected before and during operation. Blood loss and blood requirements were 50% lower in the aprotinin treated patients than in the untreated patients. The adhesive capacity of platelets assessed by the amount of platelet membrane glycoprotein Ib (GP Ib) decreased by 50% in the untreated patients within 5 min of CPB and remained low during CPB, whereas GP Ib did not decrease in the aprotinin treated patients. Fibrinogen degradation products indicating plasmin activity could only be measured after 30 min of CPB in the untreated, but not in the aprotinin treated patients. The kallikrein inhibiting capacity was 34% decreased in the untreated patients within 5 min of CPB, while it increased by 84% and remained high during CPB in the aprotinin treated patients. Our results demonstrate that the improved haemostasis during and after CPB in patients treated with aprotinin can be attributed to the preserved adhesive capacity of platelets. It remains to be found whether aprotinin has a primary effect on platelets or a secondary effect by plasmin or kallikrein inhibition.     

Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass.

BACKGROUND: Aprotinin therapy is now widely used during cardiac surgery. This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo. METHODS: In a double blind, randomized study, three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient (AUS$ = Australian dollars), low-dose aprotinin costing AUS$220 per patient or placebo. Resource use influenced by aprotinin therapy was measured. RESULTS: Both doses were effective in reducing chest drainage and postoperative transfusion requirements, high-dose being more effective than low-dose. Both doses reduced the rate of reoperations for hemostasis. A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient, respectively. If the demonstrated less significant reductions in operating room and ward stay are included, these savings become AUS$463 and AUS$715, respectively. Alternately, if cross-matches are replaced by group-and-hold and cell savers are not used, the savings per patient would be AUS$196 and AUS$467, respectively. CONCLUSIONS: While high-dose aprotinin is clinically more effective than low-dose aprotinin, low-dose therapy demonstrates greater cost savings.     

小剂量抑肽酶用于体外循环肺保护的临床研究

目的：探讨小剂量抑肽酶对体外循环（CPB）所致急性损伤的保护作用。方法：28例首次择期心脏瓣膜置换术患者随机分为抑肽酶组和对照组，各14例。于麻醉诱导前，CPB前，CPB结束后1h及24h测定TNF－α和IL－10血浆水平，于CPB前，CPB结束后10min,1h测定呼吸指数（RI）。结果：CPB结束后1h及24h，对照组TNF－α明显高于诱导前及相同时点抑肽酶组的水平（P＜0．05），CPB结束后1h，两组IL－10均明显增加，但抑肽酶组明显高于对照组（P＜0．05）；CPB结束后10min及1h，对照组RI较基础值及抑肽酶组明显增高（P＜0．05）。结论：小剂量抑肽酶具有抗炎及肺保护作用。     

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。     

Effect of low-dose aprotinin on renal function after coronary after bypass grafting under cardiopulmonary bypass

Indian Journal of Thoracic and Cardiovascular Surgery -     

体外循环下心脏手术肺保护策略

背景 肺损伤是心脏手术体外循环(cardiopulmonary bypass,CPB)的主要并发症之一,肺保护一直是临床、实验研究热点.目的 为CPB下心脏手术肺保护提供参考.内容 就近年来心脏手术CPB期间通气策略和麻醉药物、CPB设备和技术、肺动脉灌注技术、药物干预对肺保护作用的进展进行综述.趋向 CPB下心脏手术...     

Increased anticoagulation during cardiopulmonary bypass by aprotinin.

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.     

Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery

Heparin is the standard agent used for systemic anticoagulation during cardiopulmonary bypass in cardiac operations. Alternatives are needed when patients with heparin-induced thrombocytopenia type II are encountered. We present a patient with a clinical picture of heparin-induced thrombocytopenia type II who was effectively anticoagulated with bivalirudin, a direct thrombin inhibitor, during cardiopulmonary bypass for a cardiac operation.     

Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass

BACKGROUND AND OBJECTIVE: The aim was to determine whether the administration of aprotinin can cause deleterious effects on renal function in cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Sixty consecutive patients with normal preoperative renal function undergoing elective coronary artery bypass surgery with CPB using the same anaesthetic; CPB and surgical protocols were randomized into three groups. Patients received placebo (Group 1), low-dose aprotinin (Group 2) or high-dose aprotinin (Group 3). Renal parameters measured were plasma creatinine, alpha1-microglobulin and beta-glucosaminidase (beta-NAG) excretion. Measurements were performed before surgery, during CPB and 24 and 72 h, and 7 and 40 days postoperatively. RESULTS: In the three groups, alpha1-microglobulin and beta-NAG excretions significantly increased during CPB, at 24 and 72 h, and 7 days postoperatively (P < 0.05) and had returned to preoperative levels at postoperative day 40. Plasma creatinine levels were within normal values at times recorded. In Groups 2 and 3, alpha1-microglobulin excretion during CPB was significantly higher than in Group 1 (P < 0.001), and 24h after surgery it still remained significantly higher in Group 3 compared to Groups 1 and 2 (P < 0.05). CONCLUSIONS: Aprotinin caused a significant increase in alpha1-microglobulin excretion but not in beta-NAG excretion during CPB, which may be interpreted as a greater renal tubular overload without tubular damage. This effect persisted for 24 h after surgery when high-dose aprotinin doses had been administered. Creatinine plasma levels were not sensitive to detect these prolonged renal effects in our study.     

Platelet protection by aprotinin in cardiopulmonary bypass: electron microscopic study.

To evaluate the functional integrity of platelets in patients administered the proteinase inhibitor aprotinin during cardiopulmonary bypass, 20 patients undergoing a complicated and prolonged open heart operation were studied. They were randomized to receive either a high dose of aprotinin (total dose, 6 to 7 x 10(6) KIU) before and during cardiopulmonary bypass (10 patients) or a placebo (10 patients). Blood samples were collected preoperatively, at the termination of bypass, and 90 minutes thereafter to assess platelet count and aggregation on extracellular matrix, which was studied by scanning electron microscopy. On a scale of 1 to 4, mean preoperative platelet aggregation grades were similar in both groups (3.5 +/- 0.5). Postoperatively, at the termination of cardiopulmonary bypass and 90 minutes thereafter, all 10 patients treated with aprotinin revealed normal, unchanged platelet aggregation (grade, 3.5 +/- 0.5), whereas all placebo-treated patients showed severely disturbed aggregation (grade, 1.4 +/- 0.5) (p less than 0.001). The platelet count was similar in both groups before and after operation (preoperatively, 182 +/- 75 x 10(9)/L and 146 +/- 30 x 10(9)/L, and postoperatively, 87 +/- 13 x 10(9)/L and 80 +/- 27 x 10(9)/L for the aprotinin and placebo groups, respectively). Total 24-hour postoperative bleeding and blood requirement were significantly lower in the aprotinin group (371 +/- 84 mL and 2 +/- 0.7 units, respectively) compared with the placebo group (608 +/- 28 mL and 3.4 +/- 1.3 units, respectively) (p less than 0.01). These results demonstrate that improved postoperative hemostasis is directly related to the complete preservation of platelet function achieved by the protective properties of aprotinin.     

抑肽酶在体外循环心脏手术中的局部应用

目的 探讨体外循环(CPB)心脏手术中在采取综合性血液保护措施的基础上(转流中预充小剂量抑肽酶4～5万KIU/kg、手术失血和术后机器余血回输),再局部应用抑肽酶的血液保护效果.方法 体外循环心脏手术病人20例随机分为对照组(C组10例)、局部应用抑肽酶组(A组10例).手术后0、2、6h分别测定纵隔心包引流液中D-二聚体(D-D)含量、组织型纤溶酶原激活物(t-PA)活性、组织型纤溶酶原激活物抑制物(PAI)活性、蛋白C(PC)含量,记录各组术后纵隔心包引流量、24h血红蛋白丢失量.结果 局部应用抑肽酶组引流液中D-D含量、t-PA活性、PC含量均显著低于对照组(P＜0.01、P＜0.05、P＜0.01),PAI活性高于对照组(P＜0.05),术后24h纵隔心包引流量、血红蛋白丢失量也较对照组明显降低(P＜0.05,P＜0.01).结论 在常规采用综合性血液保护措施的基础上,局部应用抑肽酶可收到更佳的血液保护效果.     

Renal function changes after elective cardiac surgery with cardiopulmonary bypass

Cardiac surgery can either induce acute renal failure or improve GFR by improving the cardiac performance. In order to study renal function changes after elective cardiac surgery (CS) with cardiopulmonary bypass (CPBP), 21 patients undergoing valvular CS (VCS) or coronary artery bypass (CAB) were prospectively evaluated in three time periods: before, 24 hours after surgery and 48 hours after surgery. Patients were divided in 2 groups according to the GFR percent change in comparison to the baseline value found 24 hours after CS (deltaGFR24): Group 1, deltaGFR24 decrease higher than 20% (n = 11) and Group 2, deltaGFR24 decrease < or = 20% or deltaGFR24 increase (n = 10). In Group 1, 73% of the patients underwent VCS (p = 0.05 vs. Group 2) and all of them had previous VCS in sharp contrast with Group 2, where none of the patients had previous CS (p = 0.006). Patients in Group I required more volume replacement than Group 2 during the first 24 hours after CS: 2,699+/-704 mL versus 217+/-603 mL respectively, p = 0.019. Despite similar baseline GFR, Group 1 presented lower GFR 24 hours after CS when compared to Group 2 (39+/-5 versus 75+/-8 mL/(min x 1.73m2), p = 0.001) and a significantly different deltaGFR 48 hours after CS as compared to Group 2 (-21+/-11 versus +88+/-36%, p<0.01). Baseline sodium fractional excretion (FENa) in Group 1 was lower than in Group 2 (0.27+/-0.04 versus 0.70+/-0.12%, p = 0.01). No changes were observed after CS in urinary osmolality (Uosm) and urinary pH (UpH) in both groups. The deltaGFR24 showed positive correlation with baseline FENa (r = 0.44 p = 0.04) and negative correlation with volume balance during the first 24h after CS (r = -0.63, p = 0.007). More patients in Group 1 required nitroprusside than in Group 2 (66% vs. 14%, p = 0.04). Anesthesia time was shorter in Group 1 as compared to Group 2: 323+/-21 vs. 395+/-26 min, p = 0.04. No significant hemolysis occurred during CS in either group. There were no differences in age, gender, CPBP time, need for dopamine and/or dobutamine between the two groups. In conclusion, patients who presented GFR decrease after CS underwent VCS more frequently, had more prevalence of previous CS, presented lower baseline FENa, required more volume infusion and more nitroprusside use. On the other hand, no tubular dysfunction was detected in the early follow-up of CS. These results suggest that the observed renal function changes should be the result of an appropriated renal response to a low effective blood volume. In fact, a low baseline FENa anticipated a GFR decrease in these patients. Consistently, CAB patients that usually improve their cardiac output after surgery showed a clear GFR improvement.     

Platelet activation and aggregation during cardiopulmonary bypass.

Increases in plasma concentrations of platelet granule products such as platelet factor 4 and beta-thromboglobulin during cardiopulmonary bypass suggest that platelets are activated during extracorporeal circulation. Subsequent circulation of these activated platelets may be responsible for the ubiquitous platelet dysfunction associated with cardiopulmonary bypass. Using flow cytometry and a monoclonal antibody directed against an alpha-granule membrane protein, granule membrane protein 140 (GMP-140), which is expressed on the platelet surface membrane after activation, we directly measured the percentage of circulating activated platelets in 41 patients before, during, and after cardiopulmonary bypass. In addition, we compared the GMP-140 expression with platelet aggregation in response to adenosine diphosphate (ADP). Cardiopulmonary bypass produced a significant increase in the percentage of GMP-140-positive platelets persisting in the circulation; the percentage peaked at a mean of 29% (range 10-58%) before separation from extracorporeal circulation. A significant percentage of these activated platelets continued to circulate in the early postoperative period. Simultaneous measurement of platelet aggregation in response to ADP demonstrated an aggregation defect that had a time course distinct from platelet activation and whose magnitude did not correlate with the degree of platelet activation in individual patients. We conclude that cardiopulmonary bypass causes a complex constellation of platelet defects, which include alpha-granule release, prolonged circulation of activated, "spent" platelets, and impaired platelet aggregation.     

Effect of dexamethasone on perioperative renal function impairment during cardiac surgery with cardiopulmonary bypass

Background. In cardiac surgery with cardiopulmonary bypass (CPB),corticosteroids are administered to attenuate the physiologicalchanges caused by the systemic inflammatory response. The effectsof corticosteroids on CPB-associated renal damage have not beendocumented. The purpose of this study was to evaluate the effectsof dexamethasone on perioperative renal dysfunction in patientsundergoing cardiac surgery with CPB. Methods. Renal damage was prospectively studied in 20 patientswithout concomitant morbidity undergoing coronary artery surgerywith CPB. Patients were randomized in a double-blind fashionto receive dexamethasone or placebo. Markers of glomerular function(creatinine clearance) and damage (microalbuminuria), and markersof tubular function (fractional excretion of sodium and freewater clearance) and damage (N-acetyl-ß-D glucosaminidase(NAG)) were evaluated in addition to plasma and urinary glucoselevels. Plasma and urinary specimens were obtained at the followingtime periods: (1) baseline, during the 12 h before surgery;(2) skin incision before heparinization; (3) from heparinizationuntil the end of CPB; (4) during the 2 h following weaning fromCPB; (5) in the intensive care unit from 2 to 6 h after weaningof CBP; (6) and from 36 to 60 h after weaning of CPB. Results. CPB was associated with an increase in markers in theplacebo group, which returned to baseline during the secondpostoperative day, demonstrating a transient impairment of glomerularand tubular renal function. Similar patterns were observed inpatients treated with dexamethasone. While postoperative glycosuriawas significantly higher in the dexamethasone-treated group,no other differences between groups were observed. Conclusion. Dexamethasone administration before CPB has no protectiveeffect on perioperative renal dysfunction in low-risk cardiacsurgical patients.     

The effects of aprotinin on hemostatic function during cardiac surgery.

The mechanism of action by which large doses of aprotinin decrease blood loss during cardiac surgery is not completely understood. In a prospective, controlled study, 30 patients undergoing cardiac surgery were given high-dose aprotinin in accordance with a commonly used regimen. Twenty untreated but otherwise comparable patients served as the control group. The effects of aprotinin therapy during cardiopulmonary bypass on coagulation parameters, the kallikrein-kinin system, fibrinolysis, platelet stimulation, and the release of elastase from neutrophils were studied. The fibrinolysis parameters were the only measurements that showed clear and significant differences between the two groups. Aprotinin almost completely inhibited the formation of fibrin and fibrinogen degradation products. It is assumed that inhibition of systemic fibrinolysis and suppression of local fibrinolysis contribute to the hemostatic action of aprotinin. The study did not demonstrate a significant protective effect of aprotinin on platelets. In addition, the dose of aprotinin administered did not affect the kallikrein-kinin system of elastase. Therefore, these data suggest that the previously demonstrated hemostatic effects of aprotinin derive primarily from its antifibrinolytic action.     

Changes in intraocular pressure during cardiac surgery with and without cardiopulmonary bypass

Purpose  

Data on intraocular pressure (IOP) during cardiac surgery with cardiopulmonary bypass (CPB) and anesthetic management are limited. This study was conducted to investigate changes in IOP during cardiac surgery with and without CPB.     

Platelet dysfunction associated with cardiopulmonary bypass.

The clinical significance and pathogenesis of the platelet dysfunction following cardiopulmonary bypass were studied in conjunction with the degree of functional impairment associated with the use of membrane and bubble oxygenators. Forty consecutive patients had the following tests preoperatively and postoperatively: complete blood count (CBC), platelet count, prothrombin consumption time, bleeding time, prothrombin time, partial thromboplastin time, fibrinogen, euglobulin clot lysis, fibrin degradation products, and platelet aggregation tests. Six patients were given 14C-serotonin tests before and after operation, and preoperative and postoperative electron micrographs were made of the platelets of 3 patients. The amount of blood lost, the blood transfused, and plasma hemoglobin levels were also measured. Abnormal aggregation of platelets was found, with no difference between the membrane and bubble oxygenators. In vitro aggregation tests with protamine sulfate and hemoglobin solutions, as well as the 14C-serotonin studies and electron micrographs, suggest that platelets acquire storage pool deficiency and an abnormal membrane during cardiopulmonary bypass.     

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.