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Perioperative Monitoring of Coagulation in Neonates and Children Undergoing Cardiac Surgery

David Faraoni, MD, PhD
Boston Children’s Hospital
Boston, MA

Helen Holtby, MBBS, FRCPC
The Hospital for Sick Children
Toronto, ON

Introduction
Monitoring of coagulation during cardiopulmonary bypass (CPB) is an exercise in guesswork, physiologic complexity, and team behavior. Firstly, monitoring efforts are designed to rule out the (rare) possibility that the patient presents with a pre-existing disorder. Secondly (prior to and during CPB), the monitoring purportedly informs us that appropriate doses of unfractionated heparin have been given to the patient so that coagulation does NOT occur. Finally, hopefully, monitoring helps manage the postoperative bleeding and coagulopathy that frequently ensues, especially in neonates and young infants.  We see as a routine, laboratory testing (PTT, INR, platelet count) preoperatively, some form of activated clotting time (ACT) measurement intra-operatively, and an increased supplementation with visco-elastic point of care tests.  All these measurements have limitations, and the developmental biology of the coagulation system means that normal values and function change during the first six months of life.1 Additionally, very few studies address the human factors at play in both the causation and treatment of bleeding.

Preoperative monitoring
Standard coagulation assays (i.e. PTT or INR) have been misused for a long time for the diagnosis of congenital and acquired coagulopathies. This has been extensively discussed, and the benefit of systematic testing is weak (or absent).  However, these assays are still routinely ordered.2–4  Routine testing with conventional assays is also uninformative for many reasons, including a high rate of false negatives in the presence of von Willebrand disease (the most prevalent congenital disease) and a high rate of false positives in the presence of abnormalities that do not increase the bleeding risk (e.g. factor XII deficiency).5

The development of viscoelastic test has not significantly improved the predictive value of preoperative coagulation monitoring thus far.6 To summarize: in children undergoing cardiac surgery, the probability that preoperative testing will identify a congenital disorder that could significantly increase the bleeding risk and change perioperative management, is extremely low. A careful history may be at least as useful, is less expensive, and does not need a venipuncture, which is certainly advantageous from the child’s perspective.

Intraoperative monitoring
The monitoring of heparin-induced anticoagulation during CPB is of critical importance. Inadequate anticoagulation may lead to ineffective suppression of thrombin generation and may result in dramatic thrombotic complications. It can also contribute to postoperative bleeding.7 While ACT measurement remains the standard for intraoperative (or perioperative) monitoring of heparin based anticoagulation, this whole blood assay is influenced by many different factors. Several studies have shown a poor correlation between ACT values and plasma heparin concentrations in children and adults undergoing CPB. In addition, hypothermia, hemodilution, and decreased platelet count and function observed during CPB contribute to the prolongation of ACT to ‘targeted’ values while heparin levels may be inadequate. The same is true after the administration of protamine, when any underlying coagulopathy can falsely mimic residual heparinization, leading to inappropriate doses of protamine, which may worsen the coagulopathy and certainly does not address the underlying issue. Anti-factor Xa assay (which is the “gold standard” for heparin dosing) has been used to monitor heparin anticoagulation in critical care areas, including patients on mechanical support.8 Anti-Xa results are directly correlated to heparin levels, but it takes longer to do than an ACT, is more expensive, and is not readily available at all centers; hence the reliance on ACT and bedside tests, despite their limitations.

Postoperative monitoring
Standard coagulation tests were neither designed to monitor perioperative coagulopathy nor to guide the administration of hemostatic agents in bleeding situations.9 As it usually takes 30–45 minutes to obtain the results from standard coagulation assays, they provide limited historical information in the context of acute bleeding. In addition, standard laboratory tests are performed on platelet poor plasma and do not allow for a global assessment of clot formation, giving no information about clot firmness and clot lysis.

The development of new viscoelastic point-of-care assays [i.e. thromboelastography (TEG®) and thromboelastometry (ROTEM®)] allows for a rapid detection of coagulopathy and goal-oriented therapeutic approach. These whole-blood viscoelastic assays are now recommended by both the European Society of Anesthesiology10 and the American Society of Anesthesiology11 to monitor perioperative coagulopathy and guide the administration of hemostatic agents. Viscoelastic tests offer advantages compared to standard coagulation assays. Different authors reported that clot amplitudes measured at 5 or 10 minutes after the clotting time predict a decrease in maximal clot amplitudes. This confirmed that these parameters allow for early, goal-directed hemostatic therapy in bleeding children.12

In a recent study, Ortmann et al. observed that the results from viscoelastic coagulation tests at the end of CPB produce clinically comparable results to the same test after reversal of heparin.13 This suggests that on-bypass testing with viscoelastic assays is a useful tool for early planning of coagulation management, specifically with regard to the need for fibrinogen and platelets, the two major substrates for clot formation. The fibrinogen function/level is assessed by fibrinogen function assays (i.e. fib-tem® on ROTEM®, TEG® Fibrinogen Assay), and the platelet count is assessed by the difference between amplitudes obtained on the global assays (i.e. ex-tem® on ROTEM®, Kaolin-activated TEG®) and the fibrinogen function assays.14
However, viscoelastic tests, like standard coagulation assays, do not predict coagulopathy and bleeding in cardiac surgery. Different prospective and retrospective studies have shown that the use of algorithm-based approaches using viscoelastic tests may decrease postoperative bleeding and the incidence of blood product transfusion in patients undergoing cardiac surgery.15–17

In a recent study of adults undergoing cardiac surgery, Karkouti et al. reported that the use of a simple ROTEM-guided algorithm in bleeding patients significantly reduced the incidence of red blood cell, plasma, and platelet transfusions.16 This study emphasized the significant change in the behavior of the care team in the operating room. In children undergoing cardiac surgery, Romlin et al. compared the use of a ROTEM-guided algorithm with a standard approach based on routine coagulation assays.18 The use of a ROTEM-guided algorithm was associated with a significant reduction in the incidence of red blood cell and plasma transfusion but was associated with more platelets and fibrinogen concentrate administration.

More recently, Nakayama et al. reported their two-step study.19 A retrospective analysis assessed the ROTEM variables to design a specific algorithm. In the prospective part, the authors randomized children to be treated either using the ROTEM-guided algorithm or a conventional approach.  The use of the ROTEM-guided algorithm significantly increased the volume of intra-operative plasma and platelet transfusion, while postoperative transfusions were significantly decreased.  Overall transfusions were not decreased by the use of this ROTEM-guided algorithm, but this study confirmed that viscoelastic tests allow for a rapid intra-operative detection of coagulopathy, a better intra-operative treatment, and less transfusion in the cardiac ICU.  

Conclusion
Perioperative management of coagulopathy and bleeding in neonates and children undergoing cardiac surgery is complex and multifactorial. Although standard coagulation assays remain widely used to assess coagulopathy, these tests provide very limited information. Viscoelastic assays are increasingly used and recommended for guiding the administration of hemostatic agents in adults and children undergoing cardiac surgery.  Thus far there is no evidence of improved patient outcomes with the use of either standard coagulation or viscoelastic assays.  Algorithm-based approaches improve transfusion practice and can decrease bleeding.  This reflects a change in both behavior and culture in treating teams. The role of surgeons and the individual beliefs of anesthesiologists regarding the use of blood products are powerful confounders for studies.  These factors, as well as the complexities of the pediatric population, make robust reproducible research very difficult.  That does not mean it is not essential. The increased interest and acceptance of algorithm-based approaches will be very helpful in enabling real improvements in patient care by allowing us to design studies with meaningful outcomes, thus demonstrating effective monitoring and interventions. 

References

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