Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome?

BACKGROUND: Aprotinin, a non-specific serine protease inhibitor, has been used for two decades to reduce perioperative blood loss and the risk for allogeneic transfusion in cardiac surgery. This study evaluated the effects of aprotinin on outcome (mortality, cardiac events, renal failure, and cerebrovascular events) in such patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: Data were obtained in patients who received a strict blood conservation protocol: no antifibrinolytic therapy when at low risk (n = 854) and aprotinin (n = 1210) when at high risk for blood transfusion. Relative risk of different pre- and intra-operative variables was calculated for the different outcome variables. Backward stepwise logistic regression analysis was used to identify the independent risk factors associated with the different outcome variables. Statistical significance was accepted at P < 0.01. RESULTS: Postoperative mortality and morbidity were higher in the aprotinin group but this was related to an increased incidence of perioperative risk factors. Mortality was similar to that predicted by the Euroscore. Complex surgery was the only independent variable associated with postoperative cardiac events. Preoperative heart failure, preoperative creatinine > 1.5 mg dl(-1), urgent, and redo surgery were the independent variables associated with postoperative haemodialysis. Age > 70 yr was identified as the only independent variable associated with neurologic dysfunction. CONCLUSIONS: In the present study, patients receiving aprotinin as part of a strict blood conservation strategy represent a population at high risk for postoperative complications. For the outcome variables studied, aprotinin administration was not identified as an independent risk factor.

Simultaneous determination of aortic valve area by the Gorlin formula and by transesophageal echocardiography under different transvalvular flow conditions. Evidence that anatomic aortic valve area does not change with variations in flow in aortic stenosis.

OBJECTIVES: The purpose of this study was to determine the impact of changes in flow on aortic valve area (AVA) as measured by the Gorlin formula and transesophageal echocardiographic (TEE) planimetry. BACKGROUND: The meaning of flow-related changes in AVA calculations using the Gorlin formula in patients with aortic stenosis remains controversial. It has been suggested that flow dependence of the calculated area could be due to a true widening of the orifice as flow increases or to a disproportionate flow dependence of the formula itself. Alternatively, anatomic AVA can be measured by direct planimetry of the valve orifice with TEE. METHODS: Simultaneous measurement of the planimetered and Gorlin valve area was performed intraoperatively under different hemodynamic conditions in 11 patients. Left ventricular and ascending aortic pressures were measured simultaneously after transventricular and aortic punctures. Changes in flow were induced by dobutamine infusion. Using multiplane TEE, AVA was planimetered at the level of the leaflet tips in the short-axis view. RESULTS: Overall, cardiac output, stroke volume and transvalvular volume flow rate ranged from 2.5 to 7.3 liters/min, from 43 to 86 ml and from 102 to 306 ml/min, respectively. During dobutamine infusion, cardiac-output increased by 42% and mean aortic valve gradient by 54%. When minimal flow was compared with maximal flow, the Gorlin area varied from (mean +/- SD) 0.44 +/- 0.12 to 0.60 +/- 0.14 cm2 (p < 0.005). The mean change in Gorlin area under different flow rates was 36 +/- 32%. Despite these changes, there was no significant change in the planimetered area when minimal flow was compared with maximal flow. The mean difference in planimetered area under different flow rates was 0.002 +/- 0.01 cm2 (p = 0.86). CONCLUSIONS: By simultaneous determination of Gorlin formula and TEE planimetry valve areas, we showed that acute changes in transvalvular volume flow substantially altered valve area calculated by the Gorlin formula but did not result in significant alterations of the anatomic valve area in aortic stenosis. These results suggest that the flow-related variation in the Gorlin AVA is due to a disproportionate flow dependence of the formula itself and not a true change in valve area.

Measurement of heparin concentration in whole blood with the Hepcon/HMS device does not agree with laboratory determination of plasma heparin concentration using a chromogenic substrate for activated factor X.

UNLABELLED: Measurement of circulating heparin concentration has been suggested to optimize anticoagulation during cardiopulmonary bypass. The Hepcon/HMS device (Medtronic HemoTec, Inc., Parker, Colo.) uses heparin/protamine titration to quantitatively determine heparin concentration. Extensive validation of this instrument is still lacking. METHODS: Agreement between heparin concentrations measured by the Hepcon/HMS system and by laboratory determination was evaluated in 16 patients undergoing cardiac operations. For laboratory determinations, plasma heparin concentration was derived from the measure of anti-Xa activity by means of chromogenic substrate technique. The Hepcon/HMS instrument and cartridges measured whole blood heparin concentration. Samples were analyzed 5 minutes after administration of heparin, 15 and 30 minutes after the start of cardiopulmonary bypass, 5 minutes after aortic unclamping, at the end of cardiopulmonary bypass, and after administration of protamine. Data were plotted and interpreted according to the method of Bland and Altman: First, a difference less than 1.4 U/ml (i.e., +/- 0.7 U/ml) was chosen as acceptable, because it would not cause major difficulties in clinical interpretation; second, the difference between the two measurement techniques was plotted against the mean of the two measures. RESULTS: The mean difference (bias) between heparin concentrations derived by the Hepcon/HMS device and those obtained by laboratory determination was as expected for measures performed on whole blood versus plasma (1.45 U/ml). Nevertheless, heparin concentrations derived by the Hepcon/HMS device may be as much as 2.76 U/ml above or 6.17 U/ml below the concentrations measured in the laboratory, differences well outside the predetermined limits of agreement and clearly unacceptable for clinical purposes. CONCLUSION: We conclude that heparin concentrations determined with the Hepcon/HMS instrument do not agree with laboratory determination of heparin concentration. Monitoring of heparin concentrations during bypass with the Hepcon/HMS device cannot be recommended.

Hemorrhage and the use of blood products after adult cardiac operations: myths and realities.

BACKGROUND: Several patient-, procedure-, and prescriber-related factors are thought to influence the decision to administer allogeneic blood products. We reexamine a number of assertions applied commonly to the practice of transfusion in cardiac operations. METHODS: More than 50 original articles including a total of more than 10,000 patients from 70 centers were reviewed. Data from 5,426 patients operated on between 1990 and 1994 at the Montreal Heart Institute are presented. RESULTS: From our review of the literature, we conclude that postoperative mediastinal fluid drainage averages 917 mL and that aspirin therapy increases drainage by less than 300 mL in most studies, which should not increase use of blood products, insofar as a strict transfusional protocol is adhered to. Across centers, transfusions can vary eightfold for the same postoperative drainage. Data from our institution show that postoperative mediastinal drainage per se is not influenced by reoperation or by the type of operation. However, total blood losses and transfusion requirements remain increased in reoperative and complex procedures. Excessive mediastinal drainage resulting in increased transfusions occurs in 29% of patients. CONCLUSIONS: Exposure to allogeneic transfusions remains institution dependent. Constant reevaluation of local practice is essential to implement efficient blood conservation strategies.

Reduction in requirements for allogeneic blood products: nonpharmacologic methods.

BACKGROUND: Various strategies have been proposed to decrease bleeding and allogeneic transfusion requirements during and after cardiac operations. This article attempts to document the usefulness, or lack thereof, of the nonpharmacologic methods available in clinical practice. METHODS: Blood conservation methods were reviewed in chronologic order, as they become available to patients during the perisurgical period. The literature in support of or against each strategy was reexamined critically. RESULTS: Avoidance of preoperative anemia and adherence to published guidelines for the practice of transfusion are of paramount importance. Intraoperatively, tolerance of low hemoglobin concentrations and use of autologous blood (predonated or harvested before bypass) will reduce allogeneic transfusions. The usefulness of plateletpheresis and retransfusion of shed mediastinal fluid remains controversial. Intraoperatively and postoperatively, maintenance of normothermia contributes to improved hemostasis. CONCLUSIONS: Several approaches have been shown to be effective. An efficient combination of methods can reduce, and sometimes abolish, the need for allogeneic blood products after cardiac operations, inasmuch as all those involved in the care of cardiac surgical patients adhere thoughtfully to existing transfusion guidelines.

Low-dose aprotinin is ineffective to treat excessive bleeding after cardiopulmonary bypass.

BACKGROUND: Uncontrolled clinical experience at our institution suggested that low-dose aprotinin could control excessive bleeding after cardiopulmonary bypass (CPB). A randomized clinical trial was conducted to determine the efficacy of low-dose aprotinin in the treatment of hemorrhage after cardiac surgery. METHODS: One hundred seventy-one patients undergoing cardiac surgery with CPB were included. Forty-four patients (26%) bled significantly in the intensive care unit (>100 mL/h) and received either aprotinin (200,000 KIU bolus + 100,000 KIU/h for 8 hours) or placebo in addition to our standard management of excessive bleeding. RESULTS: Median bleeding before study drug administration was not different between aprotinin (200 mL) and placebo (212.5 mL) groups. Bleeding decreased significantly with time and similarly in both groups. Ninety-five percent of patients required transfusions in both groups. Median blood products transfused were 13 and 8 units per patient in the aprotinin and placebo groups respectively (p = NS). CONCLUSIONS: Routine administration of low-dose aprotinin as part of the treatment protocol to control hemorrhage after CPB does not reduce bleeding or transfusion requirements and, therefore, cannot be recommended.

Extracorporeal circulation, hemocompatibility, and biomaterials.

BACKGROUND: Performance of a majority of cardiac surgical procedures requires the use of extracorporeal circulation. Contact of the patients' blood with the nonendothelial surface of the cardiopulmonary bypass circuit is responsible for several, potentially harmful systemic reactions. METHODS: The patients' response to extracorporeal circulation is reviewed briefly. The interactions between patient and circuit are discussed not only as they relate to blood-material contact, but also from a mechanical and rheologic standpoint. The theoretic benefits of the newer, more hemocompatible materials are presented, along with a review of published clinical experience with heparinized cardiopulmonary bypass circuits. RESULTS: The response to extracorporeal circulation extends far beyond a simple derangement of hemostasis. This inflammatory response is strongly influenced by the rheologic design of the circuit and by the physical and chemical properties of the surface. Heparinized circuits decrease inflammation, but the clinical benefits of this reduction remain unclear, except for extended cardiopulmonary support. The safe use of these circuits requires full heparinization and does not reduce allogeneic transfusions. CONCLUSIONS: Clinicians are still in the search of the ideal material and the ideal extracorporeal circuit design. Newer, heparinized materials offer real but limited clinical benefits.

Prophylactic tranexamic acid and epsilon-aminocaproic acid for primary myocardial revascularization.

BACKGROUND: The efficacy of prophylactic epsilon-aminocaproic acid and tranexamic acid to reduce transfusions after primary myocardial revascularization was evaluated in a teaching hospital context. METHODS: Patients (n = 134) received either epsilon-aminocaproic acid (15-g bolus + infusion of 1 g/h), high-dose tranexamic acid (10-g bolus + placebo infusion), or normal saline solution in a double-blind fashion. Anticoagulation and conduct of cardiopulmonary bypass were standardized. RESULTS: Tranexamic acid and epsilon-aminocaproic acid produced a significant reduction in postoperative blood loss compared with placebo (median loss, 438 mL, 538 mL, and 700 mL, respectively). Transfusion of red cells was similar in all three groups. Nonetheless, the percentage of patients receiving hemostatic blood products was significantly decreased in the epsilon-aminocaproic acid group compared with the placebo group (20% versus 43%; p = 0.03). Both tranexamic acid and epsilon-aminocaproic acid significantly decreased total exposure to allogeneic blood products compared with placebo (p = 0.01 and p = 0.05, respectively), and this reduction was clinically important (median exposure, 2, 2, and 7.5 units, respectively). Fibrinolysis was inhibited significantly in both treatment groups. CONCLUSIONS: We conclude that either high-dose tranexamic acid or epsilon-aminocaproic acid effectively reduces transfusions in patients undergoing primary, elective myocardial revascularization.

Factors predictive of oxygen consumption during the immediate postoperative period in open heart surgery.

BACKGROUND: Postoperative oxygen consumption (VO2) is critical during the recovery period that follows open heart surgery and depends on patient characteristics and surgical factors. OBJECTIVE: To explore the surgical and patient-related factors that may influence VO2 during the early postoperative period. DESIGN: Prospective study. SETTING: Postoperative intensive care unit. PATIENTS: Study participants were 50 consecutive patients undergoing elective open heart surgery. There were 39 men and 11 women, with a mean age of 58+/-10 years. MEASUREMENTS AND MAIN RESULTS: VO2, oxygen extraction and arterial lactate were measured 1, 4, 12 and 24 h postoperatively. VO2 increased significantly during the first 12 h and stabilized thereafter. Oxygen extraction remained stable through the first 24 h. Covariance analysis on repeated measures showed that the extracorporeal circulatory period (P<0.01), age (P<0.01), body temperature (P<0.05) and use of noradrenalin (P<0.05) were predictive factors influencing postoperative VO2. Although arterial lactate increased significantly during the first 12 h period, no correlation with VO2 was found. However, covariance analysis showed that female sex, patient age (older than 65 years) and bypass period were positive correlating factors for the increase in arterial lactate. CONCLUSIONS: Patient VO2 need is decreased early after open heart surgery and returns to normal after 12 h. Surgical and patient-specific factors are responsible for these changes. Arterial lactate measurements were not found to be reliable indexes of VO2 need during this period.

The oculocardiac reflex in strabismus surgery.

During strabismus surgery on 81 extraocular muscles in 49 children the cardiac response to calibrated traction on each of the muscles operated on was studied through the use of a microdisplacement transducer and the tachometer of a cardiac monitor. There was no significant difference in the frequency of induction of the oculocardiac reflex between the medial rectus and the other muscles or between the two eyes. However, quick traction provoked a reflex in 87% of instances, whereas progressive traction did so in only 51% of instances, a significant difference (p less than 0.05). Thus, because the oculocardiac reflex is frequent during strabismus surgery, cardiac monitoring during the operation and minimal, gentle manipulation of the extraocular muscles are important.

[Erythrocyte transfusions: an evidence-based approach]. / La transfusion érythrocytaire : une approche basée sur les données probantes.

Few randomized controlled studies, the only trial design where causality can be established between an intervention and the benefits or harms thereof, have been published on the benefits and risks of a restrictive vs a liberal transfusion strategy. We review the 19 controlled studies on erythrocyte transfusion thresholds published since the eighties. These studies suggest that, overall, morbidity (including cardiac morbidity) and mortality, along with hemodynamic, respiratory and oxygen transport variables, are similar when a restrictive transfusion strategy (transfusion threshold between 7 and 8 g/dL) or a liberal strategy (transfusion threshold of 10 g/dL) are used. In fact, a restrictive strategy can even be associated with a number of benefits. The relevance of a higher transfusion threshold in view of avoiding morbidity in patients presenting a cardiovascular risk is unlikely, at least uncertain. Finally, anaemia has little or no impact on functional recovery and on quality of life, whether in the immediate or late postoperative period. It is clear that a restrictive strategy is associated with a reduced exposure to red cell transfusions, allowing a reduction in transfusion-related adverse events. Thus, all red cell transfusions must be tailored to the patient's needs, at the time the need prevails. In conclusion, most recommendations on transfusion practice are limited by the lack of evidence-based data and reveal our ignorance on the topic. High quality clinical trials in different patient populations must become available in order to determine optimal transfusion practices. Since then, a restrictive strategy aiming for a moderately anaemic threshold (7-8 g/dL) is appropriate under most circumstances.

The coagulopathy of massive transfusion.

Recently, the Groupe d'Intérêt en Hémostase Périopératoire reviewed the pathophysiology of coagulopathy in massively transfused, adult and previously haemostatically competent patients in both elective surgical and trauma settings. In this article, we focus on our main observations. First, in most cases, the onset and severity of coagulopathy associated with massive transfusion differs depending on whether haemorrhage occurs as a result of trauma or elective surgery. In trauma patients, tissue trauma is uncontrolled, the interval between haemorrhage and treatment can vary widely, hypovolemia, shock and hypothermia are frequent, and coagulopathy is often related to the development of disseminated intravascular coagulation. Monitoring of haemostasis occurs late, when coagulopathy is installed, and treatment can be very difficult. In elective surgery patients, the situation remains controlled and, in most cases, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. Monitoring of haemostasis is ongoing and treatment is usually much simpler. Second, blood products have changed over time and this has affected the management of the bleeding patient. Contrary to the recommendations of studies published at a time when whole blood was readily available, the first line of treatment (at least in elective surgery patients) ought to be with fresh-frozen plasma to correct decreased levels of coagulation factors. The role of recombinant activated factor VII to treat bleeding that cannot be controlled by conventional measures remains to be clarified. Coagulopathy associated with massive transfusion remains an important clinical problem. Treatment strategies must be adapted to the context and to the blood products available. Nevertheless, the level of evidence supporting specific treatment options is low and more studies are required to guide our management of massively transfused patients.

Pharmacological strategies for blood conservation in cardiac surgery: erythropoietin and antifibrinolytics.

PURPOSE: We review the clinically important benefits of the two principal pharmacological strategies, erythropoietin (EPO) and antifibrinolytics (aprotinin and lysine analogues), to decrease transfusion of allogeneic blood products (ABP) during and after cardiac surgery. SOURCE: Articles were selected from an ongoing review of the literature, with special attention to meta-analyses dealing with EPO and/or antifibrinolytics and cardiac surgery. PRINCIPAL FINDINGS: The few studies available include a number of patients insufficient to allow definitive conclusions on the benefits of EPO in cardiac surgery. Further studies are required to determine the optimal dose of EPO and to compare its cost-effectiveness with other blood sparing strategies in this context. Both aprotinin and lysine analogues effectively decrease ABP transfusions and the incidence of re-thoracotomy. In addition, high-dose aprotinin reduces cerebrovascular morbidity and mortality after cardiopulmonary bypass. Several mechanisms have been put forward to explain these beneficial effects, some of which could well be common to all antifibrinolytics. The clinical benefits of aprotinin's unique anti-inflammatory effect are not entirely clear but the finding that it reduces the incidence of stroke and death is certainly a major argument in favor of its utilization. Yet, we have to ensure that aprotinin's benefits are not offset by side-effects such as allergy. CONCLUSIONS: We still need large scale studies to definitely confirm the benefits and exclude the deleterious effects of these drugs on outcomes other than ABP requirements. At present, aprotinin is the only agent that has been shown to reduce the risk of cerebrovascular accident and mortality after cardiac surgery in adults.

Inotropic support of the heart that fails to successfully wean from cardiopulmonary bypass: the Montreal Heart Institute experience.

The selection of an appropriate therapeutic regimen, especially in patients with preexisting cardiac dysfunction prior to surgery, is a crucial element for successful separation from cardiopulmonary bypass (CPB). At the present time there are no definitive studies to determine which treatment modality, or combination of treatments, is optimal in this patient population. A brief review of the literature is presented to answer the following questions: (1) Should inotropic support be administered in anticipation of failure to wean from CPB? and (2) Which inotrope or combination of drugs is best? There is no evidence at present that the prophylactic administration of inotropes to assist separation from CPB may result in damaging effects to the myocardium in humans. Inasmuch as tachycardia is avoided and coronary perfusion pressure is maintained within the normal range, prophylactic inotropes may be of benefit to patients with preexisting myocardial dysfunction during weaning from CPB by allowing a smoother separation and a shorter time on CPB. While no specific drug has been proven superior, the use of phosphodiesterase inhibitors as part of the regimen to provide inotropic support in these patients may exert a beneficial effect on myocardial ischemia and reperfusion injury. Prophylactic support of the circulation during separation from CPB, especially with phosphodiesterase inhibitors, may be indicated in this specific patient population as part of the strategy to ensure maximal preservation of myocardial function.

Natural and synthetic antifibrinolytics in adult cardiac surgery: efficacy, effectiveness and efficiency.

Epsilon-aminocaproic acid and tranexamic acid, two synthetic antifibrinolytics, and aprotinin, an antifibrinolytic derived from bovine lung, are used to reduce excessive bleeding and transfusion of homologous blood products (HBP) after cardiac surgery. This review analyzes the studies on the utilization of antifibrinolytics in adult cardiac surgery according to the epidemiological concepts of efficacy, effectiveness and efficiency. A majority of published studies confirm the efficacy of antifibrinolytics administered prophylactically to reduce postoperative bleeding and transfusion of HBP. More studies are needed, however, to compare antifibrinolytics and determine if any one is superior to the others. Despite their demonstrated efficacy, antifibrinolytics are only one of the options available to diminish the use of HBP. Other blood-saving techniques, surgical expertise, temperature during cardiopulmonary bypass and respect of established transfusion guidelines may modify the effectiveness of antifibrinolytics to the point where antifibrinolytics may not be necessary. At this time, insufficient data have been published to perform a cost vs benefit analysis of the use of antifibrinolytics. This complex analysis takes into account not only direct costs (cost of the drug and of blood products), but also the ensuing effects of treatment such as: length of stay in the operating room, in the intensive care unit and in the hospital; need for surgical re-exploration; treatment of transfusion or drug-related complications, etc. In particular, the risk of thrombotic complications associated with antifibrinolytics is the subject of an ongoing, unresolved controversy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Intestinal distention during elective abdominal surgery: should nitrous oxide be banished?]. / La distension intestinale pendant la chirurgie abdominale élective: doit-on bannir le protoxyde d'azote?

High concentrations (70-80 per cent) of nitrous oxide (N2O) have been shown to cause distension of gas-containing distensible structures such as the intestines and are, for this reason, avoided by some during elective abdominal operations on the GI tract. We undertook this study to determine if N2O was responsible of a measurable change in intestinal diameter or of clinical difficulty in closing the abdomen in patients undergoing elective intestinal surgery of intermediate duration. Twenty patients scheduled for elective abdominal surgery were studied. Premedication and induction were identical in all patients. Maintenance of anesthesia in Group I was with enflurane in air/oxygen, and fentanyl. Patients in Group II received enflurane in N2O/oxygen, and fentanyl. FIO2 was 0.4 in both groups and monitored neuromuscular blockade with pancuronium was kept optimal throughout the operation. The surgeon was blinded as to the random distribution of patients to either group. Girth measurements at the level of the umbilicus were recorded before induction and after surgery. The circumferences of the terminal ileum and of the transverse colon were measured at the beginning and at the end of surgery. The surgeon was asked to rate the difficulty in closing the abdomen as 0 = none, 1 = slight, 2 = moderate, 3 = severe, 4 = impossible. Data were analysed using Student's paired t test, unpaired t test and Fisher's exact test. P less than 0.05 was considered statistically significant. There was no significant difference between groups in age, sex distribution, weight and duration of surgery (approximately 90 minutes in both groups).(ABSTRACT TRUNCATED AT 250 WORDS)