HPE CSL Managing Perioperative Bleeding handbook - Page 20

Paediatrics
20
1 , 14 – 18 coagulopathy in adults and children .
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 Cryoprecipitate contains higher concentrations of fibrinogen than plasma , but was withdrawn from several European countries because of the risk of immunologic reactions and potential transmission of infectious agents .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 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
“ 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 ”
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 postcardiopulmonary 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 .
Factor FXIII concentrate Factor XIII represents another major contributor in achieving clot stability by cross-linking fibrin monomers , and preventing clot lysis by covalent binding of α 2
-plasmin inhibitor to fibrin molecules . Although congenital FXIII deficiency is a very rare bleeding disorder , there are clinical data proving that acquired FXIII deficiency can be observed frequently during major paediatric surgery . 37 , 38 In the latter study , FXIII levels decreased to minimal levels of activity of 33 % ( 15 – 61 %), which has been determined to be the lower threshold in adults to initiate FXIII supplementation . 3
hospitalpharmacyeurope . com
Paediatrics 20 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 hospitalpharmacyeurope.com 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 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 “Prompt and timely identification of the underlying coagulopathy and, consequently, individualised treatment of ѕѽ)ɔѡх䁽)ɸ)مձѥ)ӊt)ѡɽѥٕ́彍ɑ)ɍѥ)ͥ́ȁݸф͡ݕѡ)͔ɕ͔% Q4)Ёɵ́ɽ᥵ѕ͵ݡ)䁉ՙЁЁ͕́ɔ)͕ٕɔѥ́ݥѠեɕ)ɥQ̰͔(́хɐ)хݡ́Ѽɕ͔ѡ)% Q45 ЁЀյ)%յ䰁ɥɅє)䁕Ёɕѥեɕ)ɥ́ͅ)ɽ́Ёѕ䁅م)ѽɕЁɽѕɅɔ)ѥ䁅ɕ䁝ե)٥͍ѥѕѥ)ѕɕٕ͡Ёѥ)AɽѡɽɅє)AɽѡɽɅѕ(A ̤ɔ͕ȁɅɕٕͅ)܁٥х,Ёձѥ)ѽȁٕ́ՔѼ٥х,х)ѡ͕ѥѥٔ)ɝЁɽ居́) ͥ́ѡаA ́ɕՕѱ͕)ձЁѥ́ѼɕЁձѡ)ݥѠ܁٥х,)ձѥѽȁٕ́)ɥɅѥٔȰ́!ݕٕȰф)͔́ɕɔٕ)ѕͥ́Ե啅ȁɕɽѥٔ)͔͕ɥ́ѥ́ɽÊL)啅́́ɅѕٽɅ)䁅ͅ䁽A ̸Ё%ѡ)Ց䰀āѥ́ݕɔɕѕȁ٥х),хеɕѕɕٕͅ)ѕɹѥɵ͕Ʌѥ%9Hݼ)ɕݕɔɕѕȁمѕ%9H)ЁɕѕѼ٥х,хЁ͔)ȁɅхд)ɑձ䁉́ɝ䁥ѡɕ)ɕ!ݕٕȰѽхͥͅ锁݅)͵ͥɕ݅́Ё͕)٥͕ф=ѡɽѥ)ٕЁ݅́յѕЁՔ)ɥѥѼA ݅́չȸф)ɽ٥ټѥA Ѽ)́ͅхɽѕ)ѕȁɑձ䁉́͡ݕ)ѡЁٕٕ䁱܁͔иߊLT)݅́ՙЁѼѥѡ)չаѡɅєѡɽ)Ʌѥԁ͔ɕЁ͍́ɥ)ѡѥ͔ٔA ݉ɸ)ՙɥɽх́ɅɅ)ݡЁɕٔ٥х),хѥЁѠ)́ɕձаѡɔ́ѱ٥)ѡͅ䁅䁽A ɕ)!ݕٕȰȁɕѵЁ͕ٕɔ)ͽ̰ݡɔ͵́չم)ͽɍձѥѽ̰ȁݡɔ)ѡɔ́ɥͬٽՔѼ)ɝչ́͵͔A )Ёȁ͕հɽ)ѽȁa%%$Ʌє)ѽȁa%%$ɕɕ͕́ѡȁ)ɥѽȁ٥Ёх䁉)ɽ̵ɥ̰)ɕٕѥЁͥ́䁍مЁ):ĀȀ͵ѽȁѼɥ)ձ̸ѡ՝хa%%$)䁥ٕ́ɅɔͽɑȰ)ѡɔɔфɽ٥ѡ)եɕa%%$䁍͕ٕ)ɕՕѱ䁑ɥȁɥ)ɝ一ܰ%ѡѕȁՑ䰁a%%$)ٕ́ɕ͕Ѽٕ́)ѥ٥䁽̔׊LĔݡ́)ѕɵѼѡݕȁѡɕ͡)ձ́Ѽѥєa%%$хѥ