Nina A. Guzzetta

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.

Ultrasoft microgels displaying emergent platelet-like behaviours

Efforts to create platelet-like structures for the augmentation of haemostasis have focused solely on recapitulating aspects of platelet adhesion; more complex platelet behaviours such as clot contraction are assumed to be inaccessible to synthetic systems. Here, we report the creation of fully synthetic platelet-like particles (PLPs) that augment clotting in vitro under physiological flow conditions and achieve wound-triggered haemostasis and decreased bleeding times in vivo in a traumatic injury model. PLPs were synthesized by combining highly deformable microgel particles with molecular-recognition motifs identified through directed evolution. In vitro and in silico analyses demonstrate that PLPs actively collapse fibrin networks, an emergent behaviour that mimics in vivo clot contraction. Mechanistically, clot collapse is intimately linked to the unique deformability and affinity of PLPs for fibrin fibres, as evidenced by dissipative particle dynamics simulations. Our findings should inform the future design of a broader class of dynamic, biosynthetic composite materials.

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

Principles of hemostasis in children: models and maturation

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.

Benefits and risks of red blood cell transfusion in pediatric patients undergoing cardiac surgery

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.

Fibrinogen in children undergoing cardiac surgery: is it effective?

As the number of neonates and young infants undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) increases, red blood cell (RBC) transfusion will continue to be an integral part of the practice of pediatric cardiac anesthesiology. The decision of when to transfuse RBCs to these patients is complex and influenced by multiple factors such as size, presence of cyanotic heart disease, complexity of the surgical procedure, and the hemostatic alterations induced by CPB. The known benefits of RBC transfusion include an increase in the oxygen‐carrying capacity of blood, improved tissue oxygenation, and improved hemostasis. Unfortunately, there is no minimum hemoglobin level that serves as a transfusion trigger for all pediatric patients undergoing cardiac surgery. Physiologic signs such as tachycardia, hypotension, low mixed venous oxygen saturation and increased oxygen extraction ratios can provide objective evidence of the need to augment a given hemoglobin level. Nevertheless, the benefits of RBC transfusion must be balanced against its risks and, in recent years, RBC transfusion has been subjected to intense scrutiny. The adverse consequences of RBC transfusion include the transmission of infectious diseases and immune‐mediated and nonimmune‐mediated complications. Advances in donor selection, infectious disease testing of donated blood, use of leukocyte reduction and irradiation of blood in defined situations have improved the safety of the blood supply in terms of infection transmission. However, a growing number of prospective randomized clinical trials are finding an association between RBC transfusion and an increased risk of morbidity and mortality even with the use of leuko‐reduced blood. Thus, it is becoming increasingly important that the decision to transfuse RBCs be made with a thorough understanding of the benefit‐to‐risk ratio. This review addresses the benefits and risks of RBC transfusion, pertinent data acquired in the setting of congenital cardiac surgery and techniques designed to minimize the need for RBC transfusion.

The impact of aprotinin on postoperative renal dysfunction in neonates undergoing cardiopulmonary bypass: a retrospective analysis.

There is speculation based on laboratory tests and biochemical data regarding the functional integrity of the fibrinogen in young children. Recent investigations in adults have demonstrated that their fibrinogen level correlates with the thromboelastogram maximum amplitude (MA) after modification with a glycoprotein IIb/IIIa receptor blocker that uncouples platelet-fibrinogen interactions. We postulate that if the fibrinogen of young children is functionally intact then their fibrinogen levels should also correlate with modified thromboelastogram MA values as they do in adults. We compared modified and unmodified thromboelastogram variables of 250 children <2 yr old undergoing cardiac surgery with their fibrinogen levels and platelet counts. Five age groups were distinguished to determine if and when correlations become significant (<1 mo, 1–3 mo, 3–6 mo, 6–12 mo, and 12–24 mo). Fibrinogen levels correlated with modified thromboelastogram MAs only in the 12–24 mo group. In this 12–24 mo age group other correlations between fibrinogen levels and thromboelastogram variables influenced by fibrinogen also became significant, as did correlations noted in adults between platelet counts and thromboelastogram variables. We conclude that the fibrinogen of children <12 mo old with congenital heart disease is qualitatively dysfunctional.

A Comparison of Heparin Management Strategies in Infants Undergoing Cardiopulmonary Bypass

BACKGROUND: Recent concern about the safety of aprotinin administration to adults has led to its suspension from worldwide markets. However, few studies have examined its safety in pediatric patients. Studies in children evaluating aprotinin’s safety have been hindered by the heterogeneity of pediatric patients and the inconsistency of clinical protocols. In this investigation, we retrospectively reviewed 200 neonatal cardiac surgical cases performed at our institution to examine the safety of aprotinin, focusing on postoperative renal dysfunction, using a consistent aprotinin dosing protocol. METHODS: Two-hundred consecutive neonates scheduled for palliative or corrective congenital cardiac surgery requiring cardiopulmonary bypass (CPB) from January 1, 2005 through February 28, 2007 were included in this retrospective investigation. Preoperative, intraoperative and postoperative data were collected and analyzed. Markers of safety included 72-h postoperative renal dysfunction, need for dialysis (peritoneal or hemodialysis), thrombosis and in-hospital mortality. RESULTS: Neonates were divided into those who received aprotinin (aprotinin group; n = 156) and those who did not (no aprotinin group; n = 44). Twenty-four and 72-h postoperative serum creatinine levels were significantly greater than baseline levels in both groups. The degree of change in creatinine levels was highly significant and similar between the two groups. A larger percentage of neonates in the aprotinin group developed renal dysfunction, although this difference was not statistically significant. Stepwise logistic regression, assessing the impact on renal dysfunction of all variables that indicated significance between neonates who did or did not receive aprotinin and between neonates who did or did not develop renal dysfunction, identified CPB time and age as significant predictors of postoperative renal dysfunction. All neonates who developed postoperative renal dysfunction had a CPB time of more than 100 min regardless of the use of aprotinin. Additionally, using this subset, similar percentages of renal dysfunction occurred in both groups. A second multivariable regression analysis to simultaneously account for the predictors of CPB time, age and aprotinin administration found CPB time to be the only significant predictor of renal dysfunction. Incidences of postoperative dialysis, postoperative thrombosis and in-hospital mortality were not statistically significantly different between the aprotinin and the no aprotinin groups. CONCLUSION: The occurrence of postoperative renal dysfunction in neonates was more significantly predicted by the duration of CPB than by the intraoperative administration of aprotinin. CPB times of more than 100 min appeared to be a critical marker for the development of postoperative renal dysfunction. Randomized prospective trials are needed to confirm the validity of our retrospective findings.

Review of the off-label use of recombinant activated factor VII in pediatric cardiac surgery patients.

BACKGROUND:Recent investigations in adult patients have suggested that a heparin concentration-based anticoagulation protocol for heparin administration during cardiopulmonary bypass (CPB) significantly reduced hemostatic activation when compared with standard weight-based heparin doses. Reductions in hemostatic activation during CPB could be particularly beneficial in pediatric patients in whom CPB-related coagulation issues are complex and influenced by many variables. However, information regarding heparin levels during CPB and their correlation to hemostatic activation is lacking in children. In this investigation, we compared a patient-specific heparin concentration-based heparin management protocol with a standard weight-based protocol in infants <6-mo-of-age. The efficacy of these two protocols was assessed by comparisons of heparin concentration, levels of biochemical markers of hemostatic activation, and clinical outcome. METHODS:Twenty-five infants <6-mo-old scheduled for primary, elective repair of a congenital heart defect were enrolled in this study. Patients were randomized to receive either 400 U/kg of heparin (control group) or a patient-specific heparin dose calculated by the Hepcon Hemostasis Management System Plus (Hepcon HMS; Medtronic, Minneapolis, MN; intervention group). Heparin concentrations were compared between the two groups at predetermined intervals. Blood samples for biochemical markers of hemostatic activation were collected before and after CPB, and measurements of clinical outcome were recorded. RESULTS:Infants in the intervention group received a larger total heparin dose than infants in the control group. Heparin concentrations after the initial heparin dose and 30 min into CPB were similar between groups; however, at the start of rewarming and at the termination of CPB, infants in the intervention group had significantly higher heparin concentrations than infants in the control group. Infants in the intervention group also generated less F1.2 and consumed less factor VIII than infants in the control group. Clinically, however, infants in the intervention group received one more donor exposure from the administration of blood products post-CPB. CONCLUSION:A heparin concentration-based heparin management protocol in infants <6-mo-old resulted in higher, more constant heparin concentrations during CPB than a standard weight-based protocol. Furthermore, higher heparin concentrations were associated with greater suppression of hemostatic activation, as measured by less generation of thrombin and less consumption of factor VIII. Our findings demonstrate that use of a patient-specific heparin concentration-based protocol for heparin administration during CPB in infants may attenuate hemostatic activation. However, further research is needed to determine if this protocol has clinically beneficial hemostatic effects.

Excessive postoperative bleeding and outcomes in neonates undergoing cardiopulmonary bypass.

In recent years the off-label use of recombinant activated factor VII (rFVIIa) has markedly increased, particularly in pediatric cardiac surgery patients, and practitioners differ widely in their usage of the drug. In 2009, the Congenital Cardiac Anesthesia Society (CCAS) assembled a task force to review the literature on rFVIIa administration to pediatric cardiac surgery patients. The goal of the CCAS Task Force was to assess current practices and make recommendations about rFVIIa therapy to enhance quality of care, improve patient outcomes, reduce costs, and develop future research. In this review we summarized the important topics on current administration of rFVIIa to pediatric cardiac surgery patients including indications for use, efficacy, safety, dosing, and monitoring.All pediatric and pertinent adult literature regarding the administration of rFVIIa to cardiac surgical patients and published since 2000 were selected and studied. Of the 40 pediatric publications reviewed for this report, only 1 was a prospective randomized controlled trial thus making determinations of efficacy difficult. There is no substantive evidence to support the efficacy of rFVIIa as prophylactic or routine therapy during pediatric cardiac surgery. It may prove reasonable as rescue therapy because current observational evidence suggests that potential benefits of rFVIIa for this indication might outweigh the risks. Rescue therapy is appropriate for bleeding that is massive, potentially life-threatening, and refractory to conventional therapy. Nevertheless, extreme caution is advised when considering the administration of rFVIIa to patients who are at risk for thromboembolic complications because rates for clinical and subclinical thrombosis secondary to rFVIIa therapy are unknown at this time.This review is designed to aid practitioners in deciding when and how to administer rFVIIa to pediatric cardiac surgery patients; it is not intended to determine standard-of-care or practice guidelines. There are insufficient data to make evidence-based recommendations. Randomized controlled trials are needed to assess the efficacy of rFVIIa as prophylactic, routine, or rescue therapy and to determine the drugs safety profile particularly with regard to thrombosis. The CCAS rFVIIa Task Force will continue to monitor the literature, gather data, and make updates as more information becomes available.