Bruce E. Miller

The Inflammatory Response to Cardiopulmonary Bypass

Inflammation in cardiac surgical patients is produced by complex humoral and cellular interactions with numerous pathways including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators. Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction that can manifest as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and inflammation are also closely linked through networks of both humoral and cellular components including proteases of the clotting and fibrinolytic cascades, including tissue factor. Vascular endothelial cells also mediate inflammation and the cross talk between coagulation and inflammation. Novel antiinflammatory agents inhibit these processes by several mechanisms such as preventing proteolysis of the protease-activated receptor (aprotinin), inhibiting complement-mediated injury (pexelizumab), or inhibiting contact activation (kallikrein inhibitors). Surgery alone also activates specific hemostatic responses, activation of immune mechanisms, and inflammatory response mediated by the release of various cytokines and chemokines. Novel agents are under investigation to further improve outcomes in cardiac surgical patients.

Predicting and treating coagulopathies after cardiopulmonary bypass in children.

Coagulopathies in children after cardiopulmonary bypass (CPB) are complex.There are very limited data correlating coagulation tests with postoperative bleeding. We evaluated coagulation changes after CPB and after the administration of coagulation products to 75 children. Baseline coagulation tests were obtained and repeated after protamine administration, after transfusion of individual coagulation products, and on arrival in the intensive care unit (ICU). Regression analysis demonstrated no baseline coagulation test to predict postoperative chest tube drainage. Weight and duration of CPB were determined to be the only predictors of bleeding. Further analyses demonstrated that children <8 kg had more bleeding and required more coagulation products than children >8 kg. Postprotamine platelet count and fibrinogen level correlated independently with 24-h chest tube drainage in children <8 kg, whereas postprotamine platelet count and thrombelastographic values did so in patients weighing >8 kg. Platelet administration alone was found to restore effective hemostasis in many patients. With ongoing bleeding, cryoprecipitate improved coagulation parameters and limited blood loss. Fresh-frozen plasma administration after platelets worsened coagulation parameters and was associated with greater chest tube drainage and more coagulation product transfusions in the ICU. Objective data to guide post-CPB component therapy transfusion in children are suggested. Implications: Children <8 kg can be expected to have more severe coagulopathies, require more coagulation product transfusions, and bleed more after cardiopulmonary bypass. Correlations between coagulation tests and postoperative chest tube drainage are defined. Platelets and, if necessary, cryoprecipitate optimally restore hemostasis. Fresh-frozen plasma offers no benefits in correcting postcardiopulmonary bypass coagulopathies in children. (Anesth Analg 1997;85:1196-202)

Review articleThe inflammatory response to cardiopulmonary bypass

Inflammation in cardiac surgical patients is produced by complex humoral and cellular interactions with numerous pathways including activation, generation, or expression of thrombin, complement, cytokines, neutrophils, adhesion molecules, mast cells, and multiple inflammatory mediators. Because of the redundancy of the inflammatory cascades, profound amplification occurs to produce multiorgan system dysfunction that can manifest as coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and inflammation are also closely linked through networks of both humoral and cellular components including proteases of the clotting and fibrinolytic cascades, including tissue factor. Vascular endothelial cells also mediate inflammation and the cross talk between coagulation and inflammation. Novel antiinflammatory agents inhibit these processes by several mechanisms such as preventing proteolysis of the protease-activated receptor (aprotinin), inhibiting complement-mediated injury (pexelizumab), or inhibiting contact activation (kallikrein inhibitors). Surgery alone also activates specific hemostatic responses, activation of immune mechanisms, and inflammatory response mediated by the release of various cytokines and chemokines. Novel agents are under investigation to further improve outcomes in cardiac surgical patients.

Rapid evaluation of coagulopathies after cardiopulmonary bypass in children using modified thromboelastography.

Complex coagulopathies follow cardiopulmonary bypass (CPB) in children. However, objective laboratory data that can be acquired rapidly to guide their management are lacking. Because thromboelastography has proven useful in this regard, we evaluated the use of celite or tissue factor (TF) activation and heparinase modification of blood samples to allow rapid determination of thromboelastogram data in children younger than 2 yr undergoing CPB. Celite or TF activation shortened the initiation of clotting and, thus, the time required for the important thromboelastogram &agr; and maximum amplitude values to begin evolving. Although thromboelastogram &agr; and maximum amplitude values were increased with these activators, correlations persisted between platelet count or fibrinogen level and each of these values. The additional use of heparinase allowed thromboelastograms to be obtained during CPB with values not different from those obtained without heparinase after protamine administration. Therefore, celite- or TF-activated, heparinase-modified thromboelastograms begun during CPB allow objective data to be available by the conclusion of protamine administration to help restore hemostasis after CPB in children. Thromboelastography identified transient fibrinolysis during CPB in some children that resolved by the conclusion of protamine administration. Future investigations of the effectiveness of modified thromboelastography-guided coagulopathy management after CPB in children are needed. Implications Thromboelastography is useful in assessing the coagulopathies that follow cardiopulmonary bypass in children. Modifying blood samples with celite or tissue factor and heparinase allows thromboelastography begun before the termination of cardiopulmonary bypass to become a rapid point-of-care monitor to provide objective data for guiding blood component therapy to manage these coagulopathies.

The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery

BACKGROUND Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing. METHODS Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM. RESULTS The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively. CONCLUSIONS A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.

Functional Maturity of the Coagulation System in Children: An Evaluation Using Thrombelastography

There are quantitative deficiencies in the coagulation system for at least the first 6 mo of life.Clinical experience, however, does not indicate an increased risk of excessive bleeding during surgical procedures. Thrombelastography, a test providing a functional evaluation of coagulation, was used to assess the hemostatic system of pediatric patients under 2 yr of age. Thrombelastographic data were obtained from 237 healthy pediatric patients less than 2 yr of age undergoing elective noncardiac surgery. Five groups were distinguished: under 30 days, 1-3 mo, 3-6 mo, 6-12 mo, and 12-24 mo. Thrombelastography revealed no defects in coagulation when these groups were compared to each other or to adults, indicating a functionally intact hemostatic process even in neonates. Indeed, children less than 12 mo of age were found to initiate and develop clot faster than adults, with the coagulation process slowing to adult rates after 1 yr of age. In addition to defining functional integrity, our data represents a set of pediatric control thrombelastographic values that have not been previously reported and that may become important in understanding coagulation changes that accompany disease states and surgery in pediatric patients. (Anesth Analg 1997;84:745-8)

Hematologic and Economic Impact of Aprotinin in Reoperative Pediatric Cardiac Operations

BACKGROUND Aprotinin consistently reduces blood loss and transfusion requirements in adults during and after cardiac surgical procedures, but its effectiveness in children is debated. We evaluated the hemostatic and economic effects of aprotinin in children undergoing reoperative cardiac procedures with cardiopulmonary bypass. METHODS Control, low-dose aprotinin, and high-dose aprotinin groups were established with 15 children per group. Platelet counts, fibrinogen levels, and thromboelastographic values at baseline and after protamine sulfate administration, number of blood product transfusions, and 6-hour and 24-hour chest tube drainage were used to evaluate the effects of aprotinin on postbypass coagulopathies. Time needed for skin closure after protamine administration and lengths of stay in the intensive care unit and the hospital were recorded prospectively to determine the economic impact of aprotinin. RESULTS Coagulation tests performed after protamine administration rarely demonstrated fibrinolysis but did show significant decreases in platelet and fibrinogen levels and function. The thromboelastographic variables indicated a preservation of platelet function by aprotinin. Decreased blood product transfusions, shortened skin closure times, and shortened durations of intensive care unit and hospital stays were found in the aprotinin groups, most significantly in the high-dose group with a subsequent average reduction of nearly

Modified Fontan without use of cardiopulmonary bypass

3,000 in patient charges. CONCLUSIONS In children undergoing reoperative cardiac surgical procedures, aprotinin is effective in attenuating postbypass coagulopathies, decreasing blood product exposure, improving clinical outcome, and reducing patient charges.

Principles of hemostasis in children: models and maturation

BACKGROUND Direct cavopulmonary connection using an extracardiac conduit has a number of theoretical advantages in the staged management of children with single ventricular congenital heart defects. With appropriate planning, completion Fontan using an extracardiac connection may be accomplished without the use of cardiopulmonary bypass. METHODS From January 1995 to October 1997, 32 consecutive patients underwent completion Fontan using an extracardiac cavopulmonary connection. Twenty-one of these patients had completion Fontan without the use of cardiopulmonary bypass (No CPB group). Their postoperative outcome was retrospectively compared with a second group of 11 patients who underwent completion Fontan with an extracardiac conduit with the use of cardiopulmonary bypass. RESULTS There was no operative or hospital mortality in either group. Early postoperative hemodynamics appear to be significantly improved in the No CPB group. Transfusion of cryoprecipitate and platelets was significantly less in the group without the use of cardiopulmonary bypass (p = 0.026, p < 0.001, respectively). Review of the most recent 12 patients also demonstrated a substantially shorter extubation time and intensive care unit stay. The length of hospital stay was significantly shorter (p = 0.036). CONCLUSIONS Completion Fontan without the use of cardiopulmonary bypass results in improved immediate postoperative hemodynamics, and decreased use of blood and blood products. The most recent group appears to demonstrate a more rapid recovery time and shorter hospital stay (p = 0.036).

Fibrinogen in children undergoing cardiac surgery: is it effective?

Hemostasis is an active process regulating the formation and dissolution of fibrin clot to preserve vascular integrity. The different phases of hemostasis are coordinated so that effective clotting occurs only at the site of vascular injury while maintaining blood flow in other parts of the circulation. Procoagulant processes culminate in thrombin generation and fibrin clot formation to protect the vasculature against uncontrolled bleeding after injury. Conversely, anticoagulant processes limit clot extension to unaffected portions of the vasculature. Lastly, fibrinolysis is responsible for clot dissolution once tissue repair and regeneration permit the return of normal blood flow. A precise and delicate interplay exists among these processes to ensure normal hemostasis. The hemostatic system is incompletely developed at birth and matures throughout infancy. Both full‐term and preterm neonates are born with low levels of most procoagulant proteins including all the contact activation factors and vitamin K‐dependent factors. Similarly, levels of the major anticoagulant proteins are low at birth. Although often characterized as ‘immature’, the neonatal hemostatic system is nevertheless functionally balanced with no tendency toward coagulopathy or thrombosis. In this article, we will review the current models of hemostasis and the maturation of the hemostatic system. Our goal is to help clinicians gain a better understanding of the actions of procoagulant agents and of the disruptive effects of serious systemic illnesses on the precarious hemostatic balance of infants.