David Faraoni

Randomized controlled trials vs. observational studies: why not just live together?

Randomized controlled trials (RCTs) are considered the gold standard for clinical research, thus having a high impact on clinical guidelines and our daily patients’ care. However, various treatment strategies which we consider “evidence based” have never been subject to a prospective RCT, as we would rate it unethical to withheld an established treatment to individuals in an placebo controlled trial.In a recent BMC Anesthesiology publication, Trentino et al. analyzed the usefulness of observational studies in assessing benefit and risk of different transfusion strategies. The authors nicely reviewed and summarized similarities and differences, advantages and limitations, between different study types frequently used in transfusion medicine. In this interesting article, the authors conclude, that ‘when comparing the results of observational studies with RCTs assessing transfusion outcomes, it is important that one consider not only the study method, but also the key elements of the study design’. Thus, in this commentary we now discuss the pro’s and con’s of different study types, even irrespective of transfusion medicine.

Use of factor concentrates for the management of perioperative bleeding: guidance from the SSC of the ISTH

Perioperative bleeding is a common complication following major surgery. Despite surgical measures to minimize bleeding, patients develop acquired hemostatic defects due to multiple factors that include hemorrhagic loss, consumption, dilution of coagulation factors and platelets, hypothermia, acidosis, and activation of fibrinolytic and inflammatory pathways. Therapeutic approaches for restoring haemostasis include allogeneic blood product administration. This article is protected by copyright. All rights reserved.

Relationship Between Transfusion of Blood Products and the Incidence of Thrombotic Complications in Neonates and Infants Undergoing Cardiac Surgery

OBJECTIVES The authors hypothesized that transfusion of blood products in neonates and infants undergoing high-risk cardiac surgery in the absence of intraoperative coagulation monitoring increases the risk of thrombotic complications. DESIGN Prospective observational study. SETTING Neonates and infants undergoing cardiac surgery at a tertiary pediatric center. PARTICIPANTS Neonates weighing >2.5 kg and infants ≤12 months of age undergoing elective cardiac surgery with cardiopulmonary bypass were included in this prospective observational study. INTERVENTION None. MEASUREMENTS AND RESULTS Demographic data, surgical characteristics, transfusion data, and coagulation parameters (thromboelastography and thromboelastometry) were collected. Logistic regression analysis was performed to identify potential determinants of postoperative thrombotic complications. Among the 138 neonates and infants included in the study, 12 (9%) developed a postoperative thrombotic complication. Unadjusted logistic regression analysis confirmed that the number and volume of blood products transfused were associated significantly with the increased incidence of thrombotic complication (odds ratio: 2.78, 95% confidence interval: 1.30-5.94, p = 0.008). This association persisted after adjustment for patients age, the need for deep hypothermic cardiac arrest, and bypass time (odds ratio: 2.23, 95% confidence interval: 1.02-4.87, p = 0.044). The number of blood products transfused was associated with a significant increase in parameters of clot amplitudes measured at cardiac intensive care unit admission, while no difference was reported when measured after the administration of protamine. CONCLUSIONS This prospective observational study reports a significant association between transfusion of blood products in neonates and young infants undergoing cardiac surgery and an increased incidence of thrombotic complications in the absence of intraoperative coagulation monitoring.

Elevated preoperative von Willebrand Factor is associated with perioperative thrombosis in infants and neonates with congenital heart disease

Essentials Perioperative thrombosis is a major cause of morbidity and mortality in congenital heart disease. Neonates and infants undergoing repair of congenital heart lesions were prospectively followed. Elevated von Willebrand factor (VWF) to ADAMTS‐13 activity ratios typified the postoperative period. Thrombosis was associated with preoperative VWF activity and cryoprecipitate transfusion

Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution:

We read with great interest the case reported by Dr. Hassen and colleagues describing the management of severe bleeding associated with bivalirudin in a patient with acute heparin-induced thrombocytopenia (HIT) undergoing emergent complex cardiac surgery.1 Acute renal failure serves as an explanation for the persisting anticoagulant effect observed in this case as, in dialysis patients, the half-life of bivalirudin can be prolonged up to 3.5 hours.2 Uncontrollable diffuse bleeding is a challenging scenario for cardiac surgical teams. In this case report, Hassan et al. used a multimodal approach to manage haemorrhage, which also included the administration of 4-factor prothrombin complex concentrate (PCC) containing heparin. Based on this single-case experience, the authors suggested an algorithm for the management of patients with comparable clinical conditions. Although the long-term course of the patient was fortunately uneventful, the management strategy promoted by the authors should be interpreted with caution. It is well accepted that even small amounts of heparin may trigger HIT reactions. Refaai et al. reported a case of HIT-associated venous thromboembolism and cerebral venous thrombosis as the consequence of heparin ‘flushes’.3 As thrombin plays a pivotal role in HITassociated thromboembolism (TE), it can be speculated that high intraoperative concentrations of bivalirudin may have prevented/attenuated any potential manifestations of HIT that could have been induced by the heparin contained in the PCC. However, a not rare phenomenon known as ‘late onset HIT’ has also been described in the case published by Refaai et al., meaning that HIT can occur even days following heparin exposure.3 In addition, the administration of PCC itself may be considered as a risk factor for TE complications. The halflife of the pro-coagulant factors contained in the PCC ranges from approximately 6 hours for factor VII to more than 10 days for factor II, while it is approximately 2 days for the antithrombotic proteins C and S.4 The safety profile of these powerful drugs has only been assessed in small randomized or retrospective trials, most of them for the reversal of vitamin k antagonist (VKA) therapy (only approved indication).5 The incidence of TE reported in the prospective studies for VKA reversal was approximately 4%.5 However, incidences as high as 20% have been reported following the administration of PCC for major bleeding outside the context of VKA reversal.6 Considering the absence of safety data in bleeding patients and the risk of ‘delayed onset HIT’, the administration of heparin-containing PCC should not be recommended for bleeding management in patients treated with bivalirudin. Viewing the dilemma of currently available approaches in cases of diffuse microvascular bleeding in patients treated with bivalirudin, we prefer to cautiously tamponade the thorax, leave the chest open (which also prevents the bleeding associated with the placement of sternal wires during anticoagulation) and start continuous haemofiltration immediately after intensive care unit admission. Using such a strategy, the chest can usually be closed within 24 hours when laboratory parameters have normalized and diffuse bleeding has stopped. The underlying risk for preoperative TE complications is not increased. As outlined by Dr. Hassan et al., our experience with bivalirudin anticoagulation during cardiac surgery and, Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution

The Pediatric Cardiac Anesthesia Handbook

The Pediatric Cardiac Anesthesia Handbook (first edition), by Drs. V.G. Nasr and J.A. DiNardo, is a comprehensive handbook that provides a concise overview of perioperative management of pediatric patients undergoing cardiac surgery. Published by two renowned experts in pediatric cardiac anesthesia from Boston Children’s Hospital (Boston, Massachusetts), this handbook fills an important gap in the medical literature as a complement to the comprehensive textbook specifically dedicated to pediatric cardiac anesthesia. The involvement of just two authors contributes to a uniform style, smooth flow, and minimal repetition that is not often seen in multi-authored texts. This handbook reviews the pathophysiology and management strategies of the most common congenital heart diseases (CHDs) and provides the readers with expert advice for addressing challenging clinical situations. Its portable format makes it a convenient reference source that can be brought into the operating room. Throughout the book, readers are provided with informative tables and figures illustrating key points. It includes 33 chapters, with part I (seven chapters, 66 pages) reviewing the basics of CHD and pediatric cardiac anesthesia and part II (25 chapters, 176 pages) discussing the perioperative management of the most common cardiac lesions. Chapter 1 briefly reviews embryology and cardiovascular development, and Chapter 2 summarizes the pathophysiology of congenital heart disease, intraand extra-cardiac shunts, and the physiology of pulmonary vascular resistance and its potential for manipulation. Comprehensive schematic representations are included in this chapter that clearly show the pathophysiology of CHD. Chapter 3 briefly reviews the preoperative evaluation of the patient and the medications commonly used in children with CHD. In Chapters 4 and 5, the authors discuss intraoperative monitoring and the indications for it, as well as interpretation of cardiac catheterization data. Chapters 6 and 7 briefly review the use of cardiopulmonary bypass and other mechanical support devices. Important information is provided here regarding management of extracorporeal support devices, considerations for anticoagulation, and potential complications. The following chapters (8–33) are dedicated to perioperative management of specific cardiac lesions, including patent ductus arteriosus, aortopulmonary window, coarctation of the aorta, atrial septal defect, ventricular septal defect, atrioventricular canal defects, double-outlet right ventricle, truncus arteriosus, total anomalous pulmonary venous return, left ventricular outflow tract obstruction, mitral valve disease, pulmonary atresia with intact ventricular septum, tetralogy of Fallot, tetralogy of Fallot with pulmonary atresia, tetralogy of Fallot with absent pulmonary valve, transposition of the great arteries, single-ventricle lesions, hypoplastic left heart syndrome, interrupted arctic arch, vascular rings, tricuspid atresia, heart transplantation, heart–lung and lung transplantation, anomalous origin of the left coronary artery from the pulmonary artery, heterotaxy, and the Ebstein anomaly. Each of these chapters includes a brief introduction, followed by a description of the anatomy and physiology of each cardiac lesion with accompanying informative illustrations and tables. The authors then V. Chin, MD D. Faraoni, MD, PhD, FCCP, FAHA (&) Division of Cardiac Anesthesia, Department of Anesthesia and Pain Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada e-mail: david.faraoni@sickkids.ca

Management of antiplatelet therapy in patients undergoing elective invasive procedures: Proposals from the French Working Group on perioperative hemostasis (GIHP) and the French Study Group on thrombosis and hemostasis (GFHT). In collaboration with the French Society for Anesthesia and Intensive Care (SFAR).

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT) in collaboration with the French Society for Anaesthesia and Intensive Care Medicine (SFAR) drafted up-to-date proposals for the management of antiplatelet therapy in patients undergoing elective invasive procedures. The proposals were discussed and validated by a vote; all proposals but one could be assigned with a high strength. The management of antiplatelet therapy is based on their indication and the procedure. The risk of bleeding related to the procedure can be divided into high, moderate and low categories depending on the possibility of performing the procedure in patients receiving antiplatelet agents (none, monotherapy and dual antiplatelet therapy respectively). If discontinuation of antiplatelet therapy is indicated before the procedure, a last intake of aspirin, clopidogrel, ticagrelor and prasugrel 3, 5, 5 and 7 days before surgery respectively is proposed. The thrombotic risk associated with discontinuation should be assessed according to each specific indication of antiplatelet therapy and is higher for patients receiving dual therapy for coronary artery disease (with further refinements based on a few well-accepted items) than for those receiving monotherapy for cardiovascular prevention, for secondary stroke prevention or for lower extremity arterial disease. These proposals also address the issue of the potential role of platelet functional tests and consider management of antiplatelet therapy for regional anaesthesia, including central neuraxial anaesthesia and peripheral nerve blocks, and for coronary artery surgery.

Position of the French Working Group on Perioperative Haemostasis (GIHP) on viscoelastic tests: What role for which indication in bleeding situations?

PURPOSE Viscoelastic tests (VETs), thromboelastography (TEG®) and thromboelastometry (ROTEM®) are global tests of coagulation performed on whole blood. They evaluate the mechanical strength of a clot as it builds and develops after coagulation itself. The time required to obtain haemostasis results remains a major problem for clinicians dealing with bleeding, although some teams have developed a rapid laboratory response strategy. Indeed, the value of rapid point-of-care diagnostic devices such as VETs has increased over the years. However, VETs are not standardised and there are few recommendations from the learned societies regarding their use. In 2014, the recommendations of the International Society of Thrombosis and Haemostasis (ISTH) only concerned haemophilia. The French Working Group on Perioperative haemostasis (GIHP) therefore proposes to summarise knowledge on the clinical use of these techniques in the setting of emergency and perioperative medicine. METHODS A review of the literature. PRINCIPAL FINDINGS The role of the VETs seems established in the management of severe trauma and in cardiac surgery, both adult and paediatric. In other situations, their role remains to be defined: hepatic transplantation, postpartum haemorrhage, and non-cardiac surgery. They must be part of the global management of haemostasis based on algorithms defined in each centre and for each population of patients. Their position at the bedside or in the laboratory is a matter of discussion between clinicians and biologists. CONCLUSION VETs must be included in algorithms. In consultation with the biology laboratory, these devices should be situated according to the way each centre functions.

Incidence and predictors of massive bleeding in children undergoing liver transplantation: A single-center retrospective analysis

Liver transplantation represents a major surgery involving a highly vascular organ. Reports defining the scope of bleeding in pediatric liver transplants are few.

Preoperative Thromboelastographic Profile of Patients with Congenital Heart Disease: Association of Hypercoagulability and Decreased Heparin Response

OBJECTIVE To describe the demographic and thromboelastographic characteristics of patients with congenital heart disease presenting with decreased heparin response before cardiac surgery. DESIGN Retrospective, observational study. SETTING Single institution, tertiary, academic, university hospital. PARTICIPANTS The study comprised 496 pediatric and adult patients undergoing cardiac surgery for congenital heart disease. INTERVENTIONS Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS Data on preoperative thromboelastography (TEG), demographics, and response to heparin were collected retrospectively. Logistic regression analysis was used to study the association between TEG and response to heparin. Decreased heparin response (defined as activated clotting time <480 s initial bolus of 300 U/kg heparin) was observed in 23.6% of patients presenting for surgery. Age distribution and preoperative coagulation profiles were similar for both nonresponders and responders to heparin. Preoperatively, nonresponders demonstrated all thromboelastrographic characteristics consistent with a hypercoagulable profile (shorter reaction time, K value, wider angle, and maximum amplitude). Univariate logistic regression identified all TEG variables significantly associated with decreased heparin response. After adjustment for age, procedure type, and the presence of cyanosis, a multivariate logistic regression model identified the TEG variable K (≤1.3 min) as being significantly associated with decreased heparin response (odds ratio 3.7; confidence interval 2.3-5.8; p < 0.0001). CONCLUSIONS Decreased response to heparin before cardiac surgery in patients with congenital heart disease is associated with preoperative hypercoagulability identified using a viscoelastic test. Additional studies are needed to better understand the etiology of decreased heparin response and potential clinical strategies to improve anticoagulation management.