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Use of Coagulation Point-of-Care Tests in the Management of Anticoagulation and Bleeding in Pediatric Cardiac Surgery: A Systematic Review

Bianchi, Paolo MD*; Beccaris, Camilla MD; Norbert, Martina BSc; Dunlop, Bradley BSc; Ranucci, Marco MD, FESC§

Author Information
doi: 10.1213/ANE.0000000000004563

Abstract

See Article, p 1591

Management of bleeding and coagulopathy are central features in the treatment of neonates and children undergoing cardiac surgery. Age-specific differences in the hemostatic system have been described. From birth to adulthood, there is an increase in the concentration of both the vitamin K–dependent clotting factors (factor II, factor VII, factor IX, and factor X) and contact factors (factor XI and factor XII). Natural anticoagulants are reduced1 as a result of decreased hepatic synthesis and accelerated clearance.2 This model is known in the literature as “developmental hemostasis.”3

In cardiac surgery, the scenario is made more complex by several factors. Unique cardiac anatomy, degree of cyanosis, and/or intracardiac mixing can alter anemia tolerance and bleeding risk in each patient. Moreover, surgery and cardiopulmonary bypass (CPB) both activate the inflammatory response that triggers the activation of the coagulation system. Finally, the degree of hemodilution is influenced by the composition of the CPB prime and has a central role in this complex picture.4

Blood transfusions are often necessary. However, they are associated with pulmonary complications, prolonged mechanical ventilation, and length of stay.5–7 Reduced priming volumes, ultrafiltration, antifibrinolytics, and cell saving have now been introduced at many institutions. Using these measures, centers report not only decreased blood transfusions but also improved clinical outcomes.8 In addition to the clinical benefits, these measures have been shown to be cost-effective.9

Point-of-care hemostatic tests have been broadly adopted in adult patients having cardiac surgery. Studies have shown that therapeutic algorithms10 including point-of-care tests (POCTs) are effective in reducing transfusion requirements and major bleeding following CPB.11 The use of POCTs in the pediatric field, however, is still debated and there is significant interinstitutional variability in their use. This review aims to summarize the literature concerning POCTs in pediatric cardiac surgery.

METHODS

In accordance with the guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA]), our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 25 September 2018 (registration ID: CRD42018105709).

Eligibility Criteria

We included randomized controlled trials (RCTs), including cluster RCT, controlled (nonrandomized) clinical trials (CCTs), prospective and retrospective comparative cohort studies, case–control or non–case–control studies.

We included studies examining the pediatric population (<18 years old) undergoing cardiac surgery in which the coagulation profile was assessed with POCTs. No temporal limits were used.

Articles were excluded if they (1) did not focus on pediatric patients undergoing cardiac surgery or (2) did not involve at least one of the following:

  • Heparin Monitoring Systems: activated clotting time (ACT), Hepcon Hemostasis Management System HMS, Medtronic Inc, Minneapolis, MN
  • Thromboelastography (TEG; Haemonetics Corporation, Braintree, MA)
  • Thromboelastometry (ROTEM; Tem International GmbH, Munich, Germany)
  • Platelet function tests: PFA 100 Siemens Healthcare Diagnostics, Tarrytown, NY; Multiplate Aggregometry Roche Diagnostics, Basel, Switzerland; CPA Impact R, Diamed, Cresier, Switzerland; Verify now Accriva Diagnostics, San Diego, CA)

Search Strategy

Three electronic databases (PubMed/Medline, Embase, and the Cochrane Controlled Clinical Trials register) were searched with the following keywords: cardiopulmonary bypass, point of care, pediatric cardiac surgery, children, neonates, infants, ACT, thromboelastography, thromboelastometry, TEG, ROTEM, blood management, coagulation, fresh-frozen plasma (FFP), blood, platelets, congenital heart surgery, fibrinogen, multiplate, aggregometry, platelet count. The last search was performed on January 31, 2019.

RESULTS

Selection Process

Table 1. - Heparin Effect Monitoring: ACT-Based Point-of-Care Tests
ACT-Based POCTs Journal, Year Numerosity (and Age) Test Used Main Result
Andrew et al12 Thromb Haemost, 1993 20 patients Hemochron and Hemotech ACT Great variability of result using the 2 different tests. Hemochron results systematically higher
D’Errico et al13 J Cardiothorac Vasc Anesth, 1996 99 patients (neonates to adults) Hemochron ACT Younger patient (<5 y) requires higher heparin dosage to reach target ACT. No difference after heparin neutralization with protamine. Higher heparin concentration required for preschool patients (<5 y)
Martindale et al14 J Cardiothorac Vasc Anesth, 1996 58 patients (0–18 y) Hepcon and Hemochron ACT No difference in baseline ACT. Hepcon measures significantly lower after heparin administration. Hemochron is also a better indicator of heparin neutralization. Not investigated. Authors suggest an individual approach considering age and hemodilution
Gruenwald et al15 Perfusion, 2000 51 patients (<1 y) Hepcon ACT Lack of correlation between Hepcon ACT and the gold standard plasma antifactor Xa activity assay. This was probably due to hemodilution
Codispoti et al16 Ann Thorac Surg, 2001 26 patients (3–6 y) ACT and Hepcon (HMS) Patients in the individualized HMS group patients needed higher doses of heparin and reduced amounts of protamine. Reduced blood loss and transfusion requirement in the HMS group
Guzzetta et al17 Anesth Analg, 2008 25 patients (<6 mo) Hepcon (HMS) A heparin concentration-based heparin management protocol resulted in higher, more constant heparin concentrations during CPB than a standard weight-based protocol
Guzzetta et al18 Anesth Analg, 2010 44 patients (<6 mo) Hemochron, Hepcon (HMS), i-STAT Poor correlation between ACT measures and antifactor Xa heparin concentration. HMS able to estimate heparin concentration and prevent individual variability
Gruenwald et al19 J Am Coll Cardiol, 2010 90 patients (<1 y) ACT and Hepcon (HMS) HMS cannot be used with the conventional “adult” protocol in patients <1 y old. A modified, “pediatric,” protocol is useful in the heparin management
Gautam et al20 Pediatr Anesth, 2013 100 patients (1 mo–5 y) ACT and thromboelastography Heparin reversal monitoring with ACT can be misleading. ACT assays do not show coagulation impairment due to protamine overdose
Willems et al21 J Cardiothorac Vasc Anesth, 2016 173 patients (0–16 y) ACT and thromboelastometry Poor agreement showed by ACT and ROTEM in the detection of residual heparinization
Abbreviations: ACT, activated clotting time; CPB, cardiopulmonary bypass; HMS, heparin monitoring system.

Table 2. - Use of Viscoelastic Point-of-Care Tests
Viscoelastic POCTs Journal, Year Numerosity (Age) Test Used Main Result
Martin et al22 Int J Clin Monit Comput, 1991 22 patients (0–16 y) TEG TEG was able to predict postoperative bleeding. Prolonged K phase and diminished MA phase in bleeders
Miller et al23 Anesth Analg, 1997 75 patients (0–6 y) TEG Postoperative TEG α and MA correlated independently with chest tube drainage
Williams et al24 J Cardiothorac Vasc Anesth, 1998 278 patients (0–10 y) TEG TEG is able to detect fibrinolysis. This did not influence postoperative blood loss
Williams et al25 J Cardiothorac Vasc Anesth, 1999 494 patients (0–16 y) TEG Postoperative TEG MA was associated with postoperative bleeding
Miller et al26 Anesth Analg, 2000 85 patients (<2 y) TEG Celite and tissue factor can be used as activators to get a quick response
Oliver et al27 Ann Thorac Surg, 2003 56 patients (<15 mo) TEG In a cohort of patients receiving albumin or FFP in the CPB priming, TEG can detect hemodilution. Study not powered to detect association between TEG and postoperative bleeding
Osthaus et al28 Blood Coagul Fibrinolysis, 2008 51 patients (<1 y) ROTEM (INTEM, EXTEM, FIBTEM) CHD patients show preoperative impaired clot formation. This is more pronounced in cyanotic patients. Parameters showing clot formation (CFT, MCF) are significantly deranged in every test used
Moganasundram et al29 Anesth Analg, 2010 50 patients (0–5 y) TEG TEG MA is able to detect a platelet and/or fibrinogen decrease. Good correlation between TEG MA and postoperative bleeding. Fibrinolysis can be present but is not associated with bleeding. Addition of heparinase to TEG showed to consistently detect residual heparin activity. Patients receiving higher doses of protamine showed longer postprotamine clot initiation times
Cui et al30 Artif Organs, 2010 31 patients (0–6 y) TEG Patients randomized to receive TEG-driven postoperative bleeding management had less transfusions and shorter mechanical ventilation
Tirosh-Wagner et al31 Pediatr Blood Cancer, 2011 15 patients (1 mo–10 y) ROTEM (EXTEM) ROTEM showed a significant prolongation of CT and decreased MCF postoperatively associated with increased bleeding
Romlin et al32 Anesth Analg, 2011 110 patients (0–15 y) ROTEM (INTEM, FIBTEM, HEPTEM) Patients randomized to receive a ROTEM-driven bleeding management showed a reduced transfusion requirement without any increased postoperative bleeding
Niebler et al33 World J Pediatr Congenit Heart Surg, 2012 60 patients (<13 y) TEG Postoperative TEG abnormalities present in bleeders and nonbleeders. Successful bleeding treatment when TEG driven. Authors highlight risk for overtreatment
Gautam et al20 Pediatr Anesth, 2013 100 patients (1 mo–5 y) TEG TEG shows a prolongation in R time as an effect of protamine overdosing
Lee et al34 Yonsei Med J, 2013 123 patients (0–16 y) ROTEM (INTEM, EXTEM, FIBTEM) Patients receiving FFP in the priming showed a reduction in the postoperative ROTEM derangements (A10, CFT, MCF). These were not associated with a significant difference in postoperative bleeding
Pekelharing et al35 Int Jnl Lab Hem, 2014 107 patients (0–16 y) TEG No correlation between TEG and postoperative bleeding after the arrival in PICU
Faraoni et al36 J Cardiothorac Surg, 2014 182 patients (0–12 y) ROTEM (EXTEM, FIBTEM) FFP added in the pump priming effective in increasing fibrinogen concentration. This is detectable using EXTEM and FIBTEM MCF
Faraoni et al37 Eur J Anaesthesiol, 2014 156 patients (0–4 y) ROTEM (EXTEM, INTEM, HEPTEM, FIBTEM) Post protamine INTEM CFT and FIBTEM MCF are related with postoperative bleeding (MCF <3 mm) underlying the central role played by fibrinogen in this population
Galas et al38 J Thorac Cardiovasc Surg, 2014 63 patients (0–5 y) ROTEM (INTEM, EXTEM, FIBTEM) Fibrinogen concentrate and cryoprecipitate used for fibrinogen supplementation. FIBTEM (MCF) could effectively detect fibrinogen implementation
Faraoni et al39 Pediatr Anesth, 2015 49 patients (<3 mo) ROTEM (EXTEM) Post bypass ROTEM assays can be used to assess the amplification and the propagation phases of the coagulation
Perez-Ferrer et al40 Br J Anaesth, 2015 4762 ROTEM (<18 y) ROTEM (EXTEM, INTEM, HEPTEM, FIBTEM, APTEM) Strong correlation between early values of clot amplitude (A5, A10, A15) and MCF. Early ROTEM parameters can therefore be used for an early directed hemostatic therapy
Nakayama et al41 Br J Anaesth, 2015 78 patients (<24 mo) ROTEM (EXTEM, INTEM, HEPTEM, FIBTEM, APTEM) EXTEM-A10 and FIBTEM A-10 related to the total amount of chest tube drainage. Moreover, implementation of intraoperative ROTEM-guided transfusion algorithm reduced postoperative bleeding and blood transfusion.
Faraoni et al42 Eur J Anaesthesiol, 2015 191 patients (1 mo–5 y) ROTEM (EXTEM, FIBTEM, HEPTEM) Authors described a ROTEM-based algorithm to guide hemostatic therapy. Notably, this should be used just in bleeding patients to avoid overtreatment
Kane et al43 J Surg Res, 2016 150 patients (0–18 y) TEG TEG-based bleeding treatment is associated with reduction in platelet and cryoprecipitate transfusions. TEG was also cost-effective
Vida et al44 Artif Organs, 2016 81 patients (<16 y) ROTEM (INTEM, EXTEM, FIBTEM) Preoperative abnormalities in CHD patients. In cyanotic patients, there is an inverse linear correlation between Sao 2 and the propagation phase (CFT). Linear correlation between Sao 2 and clot firmness (MCF)
Rizza et al45 Paediatr Anaesth, 2017 63 patients (<24 mo) TEG No difference in TEG between cyanotic and noncyanotic patients before, during, and after surgery. Good correlation between platelets and fibrinogen with TEG MA
Gautam et al46 Paediatr Anaesth, 2017 105 patients (0–5 y) Functional fibrinogen TEG Functional fibrinogen shows a linear correlation with plasma fibrinogen levels (Claus) both before and after CPB
Laskine-Holland et al47 Anesth Analg, 2017 320 patients (0–12 y) ROTEM (INTEM, EXTEM, FIBTEM) On unadjusted analysis, cyanotic patients showed a decreased clot firmness compared with noncyanotic children
Spiezia et al48 Thromb Res, 2017 83 patients
(1 mo–14 y)
ROTEM (INTEM, EXTEM, FIBTEM) No preoperative test was able to predict postoperative bleeding. Postoperative CT (EXTEM) and MCF (INTEM, EXTEM) significantly deranged in bleeders
Faraoni et al49 J Cardiothorac Vasc Anesth, 2017 138 patients (0–5 mo) TEG AND ROTEM (EXTEM, FIBTEM) Association between transfusion of blood products (without intraoperative clotting monitoring) and increased incidence of thrombotic complications. TEG MA, EXTEM, and FIBTEM MCF predictive postoperative thrombosis
Bianchi et al50 Br J Anaesth, 2017 73 patients (0–10 mo) ROTEM (EXTEM, FIBTEM) Patients randomized to receive FFP in the CPB priming showed a significant increase in FIBTEM and EXTEM MCF (intraoperative and postoperative). This was associated with a reduction in bleeding
Fang et al51 J Cardiothorac Vasc Anesth, 2018 1498 patients (0 adults) TEG and ACT Patients showing hypercoagulable state (reduced K value) show a decreased response to heparin (weak relationship)
Ranucci et al52 Perfusion, 2019 77 patients (0–6 mo) ROTEM (EXTEM, FIBTEM) After protamine, negative association between MCF at EXTEM and chest drain blood loss and severe bleeding
Abbreviations: CFT, clot formation time; CHD, congenital heart disease; CPB, cardiopulmonary bypass; CT, clotting time; FFP, fresh-frozen plasma; MA, maximum amplitude; MCF, maximum clot firmness; PICU, pediatric intensive care unit; POCT, point-of-care test; ROTEM, thromboelastometry; Sao2, arterial oxygen saturation; TEG, thromboelastography.

Table 3. - Point-of-Care Tests Assessing Platelet Function in Pediatric Cardiac Surgery
Platelet Function POCTs Journal, Year Numerosity (Age) Test Used Main Result
Tirosh-Wagner et al31 Pediatr Blood Cancer, 2011 15 patients (1 mo–10 y) CPA CPA, used before and after CPB, did not serve as a prognostic tool for predicting bleeding risk
Ranucci et al53 Minerva Anestesiol, 2012 22 patients (0–3 y) Multiplate Platelet function in this cohort demonstrates a variable pattern and no association with postoperative bleeding
Bønding Andreasen et al54 Paediatr Anaesth, 2014 40 patients (0–15 y) Multiplate In this cohort, duration of CPB was associated with both decreased platelet count and function, whereas hypothermia correlated with a reduced platelet function, independently of platelet count
Romlin BS et al55 Br J Anaesth, 2014 57 patients (0–7.5 y) Multiplate Platelet count and platelet aggregation are markedly reduced during and after pediatric cardiac surgery. The recovery in aggregation is faster than in platelet count. Intraoperative platelet dysfunction is associated with increased transfusion requirements
Zubair et al56 Interact Cardiovasc Thorac Surg, 2015 658 patients (0–18 y) PFA-100 Prolonged preoperative closure time is significantly associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre. No significant association with postoperative bleeding
Romlin et al57 Br J Anaesth, 2016 57 patients (0–7.5 y) ROTEM (HEPTEM and Multiplate) ROTEM (CFT, MCF) identified platelet dysfunction on CPB but not after surgery. ROTEM cannot be used specifically for platelet dysfunction
Abbreviations: CFT, clot formation time; CPA, cone and platelet analyzer; CPB, cardiopulmonary bypass; MCF, maximum clot firmness; POCT, point-of-care test; ROTEM, thromboelastometry; TEG, thromboelastography.

The initial search resulted in 80 articles meeting inclusion criteria. Thirty-three articles were discarded because they were not pediatric focused or did not contain data about one of the included POCTs. These results were divided into 3 major groups based on the POCT used (total 47 studies): (1) ACT-based instruments (10 studies), (2) viscoelastic tests (32 studies), and (3) platelet function tests (6 studies). One study utilizing more than 1 ACT and TEG was considered in both groups. These are presented in Tables 1–3 accordingly.

DISCUSSION

Heparin Monitoring Systems

Anticoagulation may be monitored by measuring either the heparin effect or the heparin concentration. ACT, the test commonly used to monitor the heparin effect, is initiated by contact activation, which can be altered in neonates and infants. Therefore, baseline ACT values can be prolonged in these patients. ACT can also be affected by other factors during CPB, including hemodilution, thrombocytopenia, and hypothermia.12 The importance of these factors varies widely with age. Nonetheless, the “standard” CPB dose of 300 U/kg heparin seems to be safe in patients over 5 years. However, patients <5 years may need a dose closer to 500 U/kg to initiate CPB.13

ACT determination through different methods (Hepcon and Hemochron) showed a poor correlation with heparin concentration.14,15 Nevertheless, a reduction in heparin concentration during bypass might be followed by an increase in ACT that can be misinterpreted as having adequate heparin levels.18

When compared with ACT, Hepcon Heparin Monitoring System (HMS, a heparin dose-response test using an automated/computerized system), showed more reliable results in an ex vivo model.13

Several studies showed how Hepcon HMS16–18 consistently suggested higher doses of heparin administration leading to a more stable heparin concentration with an associated, probably beneficial, reduced thrombin generation. Heparin concentrations measured using Hepcon HMS also demonstrated strong agreement with antifactor Xa plasma heparin concentrations.18 This correlation has been studied in the adult cardiac population and found to be excellent.58,59

Another device, HMS Plus (Hepcon HMS Plus), a system providing both ACT and whole blood heparin concentration, was shown to underestimate heparin concentration. A tailored approach, taking account of age and weight, improved the heparin management with HMS Plus.19 Anticoagulation in pediatrics is a complex scenario where none of the devices seem completely reliable in determining a blood heparin concentration. When clinicians require a more precise monitoring of anticoagulation, direct heparin level concentration (available as a laboratory test) should be considered. Future studies should, therefore, investigate a wider use of heparin dose-response tests (Hepcon) or develop new point-of-care anti-Xa level tests.

Monitoring of Heparin Reversal

“Heparin rebound” is a residual heparin effect known to occur sometime after initial heparin neutralization with protamine.60,61 Heparin neutralization, assessed with ACT, did not show age-related differences in pediatric patients.13 It is generally accepted that the ACT can correctly detect protamine-driven heparin neutralization.14,15,18 However, Hepcon HMS-driven individualized heparin management showed a more patient-tailored approach, capable of reducing the amount of protamine needed.15

ACT cannot detect protamine overdosing. Viscoelastic tests, on the other hand, may suggest it via significantly longer post-protamine clot initiation times.20,21,29 Interestingly, patients whose baseline TEG shows a hypercoagulable state have a decreased heparin response.51

Association Between Viscoelastic Tests and Bleeding

TEG is a viscoelastic test on whole blood that examines the entire hemostatic pathway from clot initiation to fibrinolysis. In children, celite and tissue factor can both be used as “activators” for a quicker response.26 Moreover, in adults,62 heparinase can be used to neutralize heparin, allowing TEG tracings to be obtained before CPB termination. This may assist in recognizing specific deficiencies and plan the post-CPB coagulopathy management. The thromboelastometry system is a variant of the traditional TEG. It uses a combination of 5 assays to characterize the coagulation profile of a citrated whole blood sample. Data from a retrospective study39 showed how dynamic thromboelastometry parameters could be used to estimate the amplification and the propagation phases during the coagulation process in children undergoing cardiac surgery. As in TEG, early values of clot amplitudes (A5, A10, A15) are useful parameters to guide goal-directed hemostatic therapy.40

A publication from 199122 initially described a relationship between altered intraoperative TEG results (reduced K and maximum amplitude [MA] phase) and postoperative bleeding. Accordingly, postoperative TEG MA showed a good association with bleeding in later studies.23,25,29 Similarly, in thromboelastometry, the most significant association has been found between parameters of maximum clot firmness (MCF) and bleeding.31,41,42,48 This is not surprising because both parameters describe interactions between platelets and fibrinogen which is crucial in clot formation and stability. Although a single study concluded that neither TEG nor conventional laboratory tests showed correlation with postoperative bleeding,35 a strong limitation of this study might have been that testing was performed only in the intensive care unit (ICU) and after treatment of the acute bleeding phase. Preoperative standard tests and TEG parameters, conversely, are not predictors of postoperative bleeding.23,45

Viscoelastic Tests in Cyanotic Patients

Cyanosis is a well-known risk factor for perioperative coagulation imbalance in children with congenital heart disease (CHD) that can result in increased risks of both thrombotic and bleeding diatheses coagulopathy.4 The underlying mechanism is not completely understood. Possible explanations are a deficiency in coagulation factor synthesis due to systemic hypoxia or to the presence of a subclinical activation of the coagulation cascade leading to an abnormal consumption of platelets and clotting factors. Rheological factors may also influence the coagulation system. Polycythemia causes hyperviscosity and increases platelet activation in response to high shear stress and chronic nonpulsatile blood flow in palliated circulations is associated with endothelial dysfunction.63

TEG and thromboelastometry show conflicting results regarding viscoelastic tests in cyanotic patients. TEG did not show significant differences between cyanotic and acyanotic patients. Moreover, no standard preoperative test or TEG parameter in cyanotic patients was a strong predictor of postoperative bleeding after 12 hours.45 Preoperative thromboelastometry, on the other hand, detected coagulation derangements associated with cyanosis.28,44,47 An inverse linear correlation between oxygen saturation and the propagation phase (ROTEM clot formation time [CFT]) together with a direct linear correlation between saturation and MCF (ROTEM MCF) has been described.28 Cyanosis was also found to be an independent predictor of intrinsically increased MCF after adjusting for hematocrit, sex, and platelet count.47 Authors have suggested that this characteristic should be accounted for when treating patients with CHD because it could be a risk factor of postoperative thrombosis. It is interesting, however, that postoperative ROTEM has not shown differences between cyanotic and noncyanotic patients.31 It is likely that cyanosis does not represent the primary cause for hemostatic abnormalities.

TEG and Fibrinolysis

Two studies investigated hyperfibrinolysis showing similar results.24,29 Fibrinolysis was detected in 3% of children pre-CPB, 16% during CPB, and 3% postbypass. In both studies, fibrinolysis did not show any correlation with postoperative bleeding.

Viscoelastic Tests and Fibrinogen

Gautam et al46 showed the correlation between functional fibrinogen (TEG) and plasma fibrinogen levels (Clauss) both before and after CPB. In a randomized pilot study,38 ROTEM was used to assess the response to fibrinogen administration. Patients were allocated, in case of hypofibrinogenemia, to receive fibrinogen concentrate or cryoprecipitate after CPB. In both arms, FIBTEM MCF increased, showing it to be a reliable tool for fibrinogen concentration monitoring.

ROTEM has been extensively used to investigate the role of plasma fibrinogen concentration and the possible trigger point for fibrinogen supplementation.37,50,52 Fibrinogen concentration <150 mg·dL−1 or FIBTEM MCF <3 mm predicted excessive blood loss.37 Accordingly, in the Albumin vs Plasma for PaEdiAtric pRiming (APPEAR) study,50 ROTEM showed a significant increase in FIBTEM MCF and EXTEM related to higher fibrinogen concentration. This was associated with a significant reduction in bleeding. In an extended population,52 the same group recently confirmed the association between low post protamine FIBTEM MCF and postoperative bleeding. The best cutoff value was identified at a fibrinogen level of 150 mg·dL−1, consistent with the previous study from Faraoni et al.37

Viscoelastic Tests and CPB Priming

Many cardiac centers utilize various preemptive techniques to reduce the impact of coagulation derangement caused by CPB. FFP had a protective effect on the clot initiation time on TEG in patients <4 years old.29 In another study, hemodilution was well detected with TEG by R time, α angle, and MA derangement.27 When used in patients at higher risk of hemodilution (lower weight), use of FFP determined an increase in fibrinogen concentration detectable using EXTEM and FIBTEM MCF.34,36,50

Algorithms Involving Viscoelastic Tests

Viscoelastic tests have now been successfully included in clinical algorithms. However, TEG abnormalities can be present in both bleeding and nonbleeding patients, potentially leading to unnecessary treatments.33 Despite this risk, introduction of TEG into clinical practice has several positive effects as shown by a study conducted in China.30 Patients treated using TEG received fewer transfusions and shorter mechanical ventilation. Two more studies32,41 showed how a thromboelastometry-driven bleeding treatment markedly reduced transfusion requirement. This resulted in a half-day reduction in pediatric intensive care unit (PICU) stay as a consequence of reduced chest drainage.41 A perioperative TEG-driven algorithm for bleeding management has been tested in a heterogeneous population (0–18 years).43 This was shown to reduce platelets and cryoprecipitate transfusion in a cost-effective manner.

At present, data in literature are too weak to define POCTs as the “gold standard” for the treatment of perioperative bleeding. However, they certainly show promise to be useful tools to guide transfusions and, as such, should be available in every pediatric cardiac center.

Transfusions can expose pediatric patients to thrombotic risks as shown in a prospective observational study published by Faraoni et al.49 The authors found an association between transfusions and thrombotic complications, with 9% of the transfused patients developing thrombotic complications. The authors concluded that patients who developed thrombotic complications might have been overtreated with allogeneic blood product transfusions. Specifically, patients receiving a combination of platelets, cryoprecipitate, and rFVIIa had a higher risk of thrombotic complications. An MCF >22 mm on FIBTEM was the best predictor for thrombotic complications.

Overall, the benefits of viscoelastic testing seem to be maximized only when combined with a structured transfusion algorithm.

Platelet Function Test

Impaired platelet function is a poorly understood risk factor for severe bleeding in adult cardiac surgery.64–67 After CPB, there is a disruption of factors specific to platelets, which normally bind von Willebrand factor to elicit platelet aggregation.68–70 In children, besides this qualitative dysfunction, there is often a quantitative reduction in platelet concentration induced by hemodilution. Viscoelastic tests may not reflect impaired platelet function. Other factors, such as fibrinogen and factor XIII, can affect their parameters. Moreover, impaired platelet function and hypofibrinogenemia often occur simultaneously during and after CPB. More specific POCTs for platelet function have been developed in adults but are rarely used in the pediatric clinical setting. These include platelet aggregometry (Multiplate), and platelet function analyzer (PFA-100, Verify now, CPA).

Multiplate testing has demonstrated a significant decrease in platelet function immediately after coming off bypass that persists into the first postoperative day.53–55 The duration of CPB was associated with both a decreased platelet count and reduction in platelet function. Moderate to deep hypothermia during CPB was recognized as a risk factor for decreased platelet function, whereas cyanosis or previous heart surgery caused no further changes in platelet function following CPB. Platelet function measurement with Multiplate has been compared with a viscoelastic test (ROTEM HEPTEM) in children.57 Thromboelastometry parameters of CFT and MCF suggested platelet dysfunction while on CPB, but not after surgery. As mentioned above, however, these variables are not specific for platelet function.

A different test, PFA-100, provides a quantitative, rapid in vitro method to assess primary platelet-related hemostasis. Using this test, Zubair et al56 found an association between low preoperative platelet function and increased blood product transfusions. This, however, was not associated with a significant increase in postoperative bleeding. The use of a third POCT (cone and platelet analyzer [CPA]) was used in a small study.31 No correlation between the results obtained with this test and postoperative bleeding or transfusions was found.

CONCLUSIONS

In the clinical setting of adults undergoing cardiac surgery, the use of coagulation POCTs on bleeding patients is recommended in many guidelines.10,71 However, clinicians dealing with the pediatric population vary in applying medical knowledge based on adult experiences. These risks are even more pronounced in the field of hemostasis and cardiac surgery, due to several peculiarities typical of this environment.3

In the setting of heparin effect monitoring, this is monitored in pediatric patients without specific differences with respect to the adults. However, in pediatrics, ACT does not seem to be acceptably reliable, especially once on CPB. The hemodilution encountered, together with temperature variation, makes ACT reliability much lower than commonly believed.18

As highlighted by Gruenwald et al,19 we need devices and protocols appropriately validated in children. Anticoagulation during CPB is not limited to the need to avoid clot formation within the CPB circuit, but to achieve the best possible control of CPB-related inflammatory effects.72 Moreover, increased thrombin generation may lead to severe bleeding.73 Because of all these aspects, a higher, rather than lower, heparin concentration might be suggested in future when more evidence will be available.

As for adults, the overall positive predictive value of POCTs for excessive bleeding remains low, and therefore these tests should not guide specific interventions in nonbleeding patients to avoid a potential overtreatment. Published data on viscoelastic tests are generally in favor of their use in pediatric cardiac surgery patients with or at high risk of bleeding. However, a formal meta-analysis is impossible, given the wide heterogeneity of the patients and tests studied.

It should be underscored that not all the potential bleeding mechanisms are explored by these tests. Primary hemostasis defects (ie, congenital or acquired von Willebrand disease) are not detected. Another interesting aspect is the strict synergism between platelets and fibrinogen, which, just like bricks and cement, concur in building an adequately strong clot. Viscoelastic tests can describe this aspect through the MCF. Although POCTs can extract the fibrinogen component, they are not able to detect the role of the platelet in the clot strength. To fill this gap, further studies should involve TEG platelet mapping which has not been tested in pediatric cardiac surgery and might be practical for centers using TEG. Other platelet function tests probably need a more extensive investigation and might demonstrate interesting results in the future.

The main limitation of this review is probably related to the limited amount of studies present in the literature. They also target different age groups presenting different algorithms with results which are difficult to compare.

What seems clearly defined is the necessity of an early goal-directed hemostatic therapy, as advocated by Faraoni.74 Ongoing bleeding triggers a detrimental cascade with consumption of factors, platelets, and fibrinogen which, at some point, becomes difficult to correct despite aggressive transfusions. For this reason, the use of quick and reliable tests (POCTs) in combination with a POCT-based bleeding management algorithm seems reasonable according to the present evidence.

DISCLOSURES

Name: Paolo Bianchi, MD.

Contribution: This author helped set the inclusion criteria, literature search, analyze the results, and write the manuscript; and read, provided feedback, and approved the final manuscript.

Conflicts of Interest: P. Bianchi is the guarantor of the review.

Name: Camilla Beccaris, MD.

Contribution: This author helped analyze the results and draft the manuscript and read, provided feedback, and approved the final manuscript.

Conflicts of Interest: None.

Name: Martina Norbert, BSc.

Contribution: This author helped in setting the inclusion criteria and literature search.

Conflicts of Interest: None.

Name: Bradley Dunlop, BSc.

Contribution: This author helped in setting the inclusion criteria and literature search and read, provided feedback, and approved the final manuscript.

Conflicts of Interest: None.

Name: Marco Ranucci, MD, FESC.

Contribution: This author helped analyze the results and draft the manuscript and read, provided feedback, and approved the final manuscript.

Conflicts of Interest: M. Ranucci received grants from Roche Diagnostics, Research grants, and speaker’s fees from CSL Behring and Hemosonics. Speaker’s fees also from Haemonetics, Medtronic, Livanova, and Edwards Lifesciences.

This manuscript was handled by: Roman M. Sniecinski, MD.

FOOTNOTES

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