A feasibility study for a multi-centre randomised controlled trial evaluating the effects of early administration of cryoprecipitate in major traumatic haemorrhage
Injury is a leading cause of death and disability worldwide. Around 5400 people die inEngland every year and many thousands more are left severely disabled. The costs ofmajor trauma to the NHS are up to £0.4 billion/year with lost economic output in the UKfrom death and disability up to £3.7 billion (2007 prices; National Audit Office).Uncontrolled haemorrhage is the primary cause of death in 40% of cases (Sauaia et al1995). Transfusion therapy is an integral part of treatment for major blood loss. A globalsurvey of blood usage in 2007 reported that trauma accounted for 10% of all red blood celland 27% of fresh frozen plasma (FFP) use (Cobain et al 2007). Blood for transfusion is ascarce costly resource associated with risks.Our group has completed systematic reviews appraising the management of majorbleeding in trauma focusing on transfusion therapy (Curry et al 2011) and the use offibrinogen concentrate (FgC) (Meyer et al 2011) and cryoprecipitate (NIHR PGfAR 2008:Traumatic Coagulopathy & Massive Transfusion: Improving Outcomes & Saving Blood).Common findings were: (1) dearth of RCT evidence in relation to the effects of transfusionpractices on coagulopathy and patient outcomes; (2) studies of early plasma/bloodcomponentregimens were observational and open to bias. No RCTs have evaluated theuse of FgC or cryoprecipitate in trauma and there is a very limited evidence base to definesafe and effective levels of fibrinogen in any patient group with acquiredhypofibrinogenaemia.Major changes are taking place in transfusion management for trauma with an emphasison early transfusion of higher doses of blood components (Spinella & Holcomb 2009).This practice aims to arrest bleeding by targeting clotting abnormalities that oftenaccompany traumatic bleeding. Fibrinogen is probably the most important protein incoagulation for it is the final point of the coagulation cascade being converted to insolublefibrin strands and also is the ligand for platelet aggregation thereby acting as the bridgefor stable clot formation. If levels of fibrinogen fall then patients have reduced ability toform clots and bleed for longer. Indeed it has been shown that fibrinogen is one of theearliest coagulation proteins to fall in major bleeding (Hiippala 1998) and adequate timelyreplacement of fibrinogen is hypothesised to result in improved haemorrhage control.The current source of fibrinogen in the UK is cryoprecipitate and there are few data todemonstrate its efficacy as a source of fibrinogen. A recent UK study auditingcryoprecipitate use reported that trauma was the second highest clinical user accountingfor 10% of the total number of units transfused (personal communication Stanworth2012). In addition data from our observational ACIT study show that approximately 10% ofall recruited patients receive cryoprecipitate within the first 12 hours of hospital admission.There are no RCT data to confirm that the new aggressive transfusion protocols result inimproved outcomes. Therefore it is important that robust trial data are collected on theeffectiveness of early fibrinogen replacement in massive haemorrhage.Early clinical data suggest fibrinogen supplementation improves outcomes. Lowerfibrinogen levels prior to cardiac surgery (Karlsson et al 2008) or obstetric haemorrhage(=2g/L) (Charbit et al 2007) have been reported to predict worse bleeding outcomes. Intrauma two observational cohort studies have reported reduction of mortality in patientsreceiving higher fibrinogen content during massive transfusion therapy (Stinger et al 2008Dente et al 2009) and in one of these studies this reduction (from 36 to 17%) wasassociated with higher post transfusion fibrinogen values (3.2g/L vs. 2.6g/L p=0.01)(Dente et al 2009).Data from our observational study have demonstrated that for trauma patients withbleeding Clauss fibrinogen levels can be maintained throughout bleeding if transfusiontherapy includes the use of fibrinogen containing blood components (FFP plateletscryoprecipitate) (figure A) (unpublished data). Figure A compares fibrinogen blood levelsduring active bleeding between two groups of patients all of whom received at least 4units of red blood cells (n = 103). The black bars denote the average fibrinogen level inpatients who received no exogenous source of fibrinogen (n= 39) compared to a group(n= 64) which received at least one fibrinogen containing blood component. The mediantime from admission to hospital until transfusion of cryoprecipitate in this group of patientswas 103 minutes (IQR: 78-134 min) using the standard massive haemorrhage protocolwhere cryoprecipitate is given most commonly at the end of transfusion pack 2 (seeAppendix A). We envisage that we will be able to achieve a cryoprecipitate transfusiontime of less than 90 minutes in the intervention arm in at least 90% of the participants inthis group. This is because we will be pro-actively administering cryoprecipitate in theintervention arm and our observational data demonstrate that the median time fromadmission to transfusion of FFP (a blood component that is pro-actively given for traumaand takes a similar number of minutes to defrost as cryoprecipitate) is 40 minutes (IQR:20-65 min) (n= 75). We will ensure that the biomedical scientists who work in blood bankare called immediately after randomisation of a participant to the intervention arm. Thecryoprecipitate takes 17 minutes to be defrosted and the research team will ensure that itis delivered to the participant and transfused at the earliest opportunity.Figure A demonstrates that the use of fibrinogen containing blood components maintainsClauss fibrinogen levels but these values do not increase above baseline admissionlevels. Non-coagulopathic trauma patients have a fibrinogen value at admission of 2.4g/Land coagulopathic patients have a level of 1.6g/L and regression modelling analysessuggested that low admission fibrinogen levels were an independent predictor of 24 hourand 28 day mortality (unpublished data). It is therefore possible that early cryoprecipitatetransfusion may supplement fibrinogen levels and maintain a higher baseline value offibrinogen during the bleeding episode.Further ex vivo data from our group assessing the effect of FgC and cryoprecipitate oncoagulopathic blood samples has informed the dose for this trial. These data demonstrate that addition of 4g FgC results in an increase in ROTEM clot strength values and ROTEMFIBTEM values which might indicate clinical efficacy and this approximately equates to 2pools of cryoprecipitate. The specifications for cryoprecipitate provided by NHS Blood andTransplant are that 75% of all tested units must contain >140mg fibrinogen and theapproximate mean fibrinogen content of each 5 unit pool is 2.0-2.3g. A typical adult doseis two five-donor pools (equivalent to 10 single donor units) and therefore contains avariable amount of fibrinogen between 4.0 4.6g (NHS Blood & Transplant 2010). Wehave reported on the value of ROTEM analysis to rapidly evaluate coagulopathy(Davenport et al 2011) and a recent publication has also reported that ROTEM FIBTEMparameters (FIBTEM A10) have a high predictive value for massive transfusion in traumapatients (Schochl et al 2011).Cryoprecipitate has been used for over 40 years in the UK as a standard treatment for lowfibrinogen levels in patients with major blood loss. Risks from cryoprecipitate transfusionare small but include those common to all blood components (i.e. infection transfusionassociated acute lung injury and transfusion associated circulatory overload). NHSBT datafrom the year 2010/2011 show that 22623 pools of cryoprecipitate were issued in Englandand for the year 2010 1464 transfusion incidents were reported to the nationalhaemovigilance body but only 1 adverse event was related to cryoprecipitate (an episodeof transfusion associated dyspnoea) (SHOT 2010). A specific theoretical but as yetunknown risk from cryoprecipitate transfusion is that of thrombo-embolic disease whichmight occur due to an elevation in fibrinogen levels. There are no reported data examiningthis risk and although it is probable that the risks are small this study will collect safetydata up to 3 months following randomisation.
|PI Name||Wood - PR|
|Sponsor||NHS Blood and Transplant|
|Proposed End Date||23/10/2013|
|Study Run through CRF?||No|
|Recruitment so far||0|