HHE Sponsored supplement: Managing perioperative bleed - Page 20

blood loss, whereas all other factors seem to be less affected by haemodilution and blood loss; 11 this has been observed in both adult and paediatric perioperative settings. 1 Fibrinogen plays several key roles in the maintenance of haemostasis. 12,13 Fibrinogen acts by crosslinking platelets via glycoprotein IIb–IIIa receptors, which builds the surface for the following haemostatic process, and is the key substrate for activated thrombin, which converts it to fibrin, the key component of the mechanically stable clot. It is well known that acquired hypofibrinogenaemia seems to be the leading determinant in dilutional coagulopathy in adults and children. 1,14–18 Plasma and cryoprecipitate are alternative sources of fibrinogen. Cryoprecipitate contains higher concentrations of fibrinogen than plasma, but was withdrawn from several European countries because of the risk of immunologic reactions and potential transmission of infectious agents. It should be acknowledged that recommended doses for plasma of 10–15ml/kg might not be adequate to achieve a clinically meaningful improvement in haemostatic potential. 11 Fibrinogen activity can be assessed by the Clauss assay, and current recommendations emphasise a trigger level of 150–200mg/dl for initiating fibrinogen substitution therapy in a bleeding patient. 19 Ideally, functional fibrinogen activity can be assessed reliably and much faster using the ROTEM ® or TEG ® . As such, fibrinogen substitution can be initiated if maximum clot firmness (MCF) at 10 minutes (A10) is ≤ 7mm, which approximates to a Clauss assay of ≤ 150 mg/dl. 3 Clinical studies in adults have demonstrated a beneficial role for intraoperative substitution with human fibrinogen concentrate to treat hypofibrinogenaemia 20–25 with a very good safety profile. 26,27 A randomised clinical trial in children who underwent major craniofacial surgery has demonstrated that early intraoperative fibrinogen substitution at a dose of 30mg/kg using a threshold of ROTEM ® FIBTEM MCF <13mm has led to a significant and clinically relevant reduction of transfused red blood cell concentrates compared with a lower threshold of a FIBTEM MCF <8mm. 10 Although blood loss was still considerable, neither transfusion of plasma nor platelet was necessary. At the same time, earlier substitution with fibrinogen decreased calculated blood loss from a median of 156.9% to 89.7%. No postoperative RBC transfusion in any child was necessary, which is in sharp contrast to published data for children who underwent major craniofacial surgeries, where postoperative transfusion occurred relatively frequently (26–40%). Notably, this management was not linked to a significant increase in total costs for transfused allogeneic blood products and coagulation factors thus offering an economically equivalent approach to coagulation management. 28 Data from a randomised clinical trial in children undergoing cardiac surgery showed that fibrinogen concentrate was as efficient and safe as transfusion of cryoprecipitate in the management of bleeding after cardiopulmonary bypass weaning. 29 In the same setting, a retrospective Prompt and timely identification of the underlying coagulopathy and, consequently, individualised treatment of depleted factors are the mainstay of a modern and advanced coagulation management data analysis in children who underwent cardiopulmonary bypass surgery revealed a significant reduction in transfusion requirements for cryoprecipitate and fresh frozen plasma, if fibrinogen concentrate at a dose of 70mg/kg was given in the rewarming phase. 30 A meta-analysis of 14 randomised clinical trials in adult and paediatric cardiosurgical patients demonstrated that all-cause mortality was lower in the fibrinogen concentrate group, and bleeding and transfusion requirements were significantly lower versus placebo or a comparator group. 31 There were no differences in the rates of thrombotic events and myocardial infarction. Analysis of our own data showed that a dose of 30mg/kg can increase FIBTEM clot firmness approximately 3mm, which may be insufficient in most cases of more severe bleeding conditions with acquired hypofibrinogenaemia. Thus, a dose of 50mg/kg has become standard in our hospital, which is likely to increase the FIBTEM MCF at least 5mm. In summary, fibrinogen concentrate is highly efficient in treating acquired hypofibrinogenaemia, offers a good safety profile, is almost immediately available, can be stored at room temperature, can be timely and reliably guided by viscoelastic testing, and can be administered in a very short time. Prothrombin complex concentrate Prothrombin complex concentrates (PCCs) are licensed for rapid reversal of low vitamin K-dependent coagulation factor levels due to vitamin K antagonists in the setting of active bleeding and for urgent prophylaxis of bleeding. Besides that, PCC is frequently used in adult patients to correct coagulopathy with low vitamin K-dependent coagulation factor levels and perioperative bleeding. 32,33 However, data on its off-label use in children are very limited. Analysis of a 5-year retrospective case series in patients aged from 0–16 years has demonstrated favourable efficacy and safety of PCCs. 34 In that study, 11 patients were treated for vitamin K antagonist-related reversal of high international normalised ratio (INR), two children were treated for elevated INR not related to vitamin K antagonist use, and for intractable bleeding post-cardiopulmonary bypass surgery in three children. However, total sample size was small, and dosing regimen was not based on evidence- based data. One thrombotic event was documented, but true contribution to PCC was unclear. Data from ex vivo supplemention of PCC to blood samples obtained from neonates after cardiopulmonary bypass showed that even a very low dose of 4.7–14U/kg was sufficient to enhance lag time, the peak amount, and the rate of thrombin generation. 35 A case report has described the effective use of PCC in a newborn suffering from spontaneous intracranial bleeding, and who did not receive vitamin K supplementation at birth. 36 As a result, there is little evidence on the safety and efficacy of PCC in children. However, for treatment of severe bleeding episodes, where plasma is unavailable as a source of coagulation factors, or where there is a risk of hypervolaemia due to large amounts of plasma, use of PCC might offer a useful approach. 20 HHE 2018 | hospitalhealthcare.com