Substitution of ROTEM FIBTEM A5 for A10 in Trauma: An Observational Study Building a Case for More Rapid Analysis of Coagulopathy

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A. McCullough, Elizabeth Wake, Kerin Walters, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-97393/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jun, 2021 Read the published version in European Journal of Trauma and Emergency Surgery → Version 2 posted You are reading this latest preprint version Show more versions Abstract Purpose Rotational thromboelastometry (ROTEM®) allows guided blood product resuscitation to correct trauma induced coagulopathy in bleeding trauma patients. FIBTEM amplitude at 10 minutes (A10) has been widely used to identify hypofibrinogenaemia; locally a threshold of < 11 mm has guided fibrinogen replacement. Amplitude at 5 minutes (A5) carries an inherent time advantage. The primary aim was to explore the relationship between FIBTEM A5 and A10 in a trauma. Secondary aim was to investigate the use of A5 as a surrogate for A10 within a fibrinogen-replacement algorithm. Methods Retrospective observational cohort study of arrival ROTEM results from 1539 consecutive trauma patients at a Level 1 trauma centre in Australia. Consistency of agreement between FIBTEM A5 and A10 was assessed. A new fibrinogen replacement threshold was developed for A5 using the A5 – A10 bias; this was clinically compared to the existing A10 threshold. Results FIBTEM A5 displayed excellent consistency of agreement with A10. Intraclass correlation coefficient = 0.972 (95% confidence interval [CI] 0.969 – 0.974). Bias of A5 to A10 was -1.49 (95% CI 1.43 -1.56) mm. 19.34% patients met the original local threshold of A10 < 11 mm; 19.28% patients met the new, bias-adjusted threshold of A5 < 10 mm. Conclusions ROTEM FIBTEM A5 reliably predicts A10 in trauma. This further validates use of the A5 result over A10 allowing faster decision-making in time-critical resuscitation of trauma patients. A modification of -1 to the A10 threshold might be appropriate for use with the A5 value in trauma patients. Critical Care & Emergency Medicine ROTEM rotational thromboelastometry fibrinogen trauma haemorrhage coagulopathy resuscitation Figures Figure 1 Figure 2 Background Trauma is a major cause of mortality globally and estimated to cause 4.5 million deaths annually [1]. 25 - 50% of trauma deaths are due to exsanguination [2,3], and swift control of haemorrhage with replacement of blood products underpins the resuscitation of trauma patients. An alternative to standard, fixed-ratio major haemorrhage protocols involves targeted resuscitation guided by point-of-care viscoelastic haemostatic assays (VHAs) such as ROTEM (ROTEM®, Werfen, Barcelona, Spain) which identify deficient and dysfunctional coagulative components. This allows patient-specific administration of blood products to correct coagulopathy [4]. ROTEM FIBTEM assays assess the function of fibrinogen in clotting blood [5]. Low clot amplitude is indicative of hypofibrinogenaemia [6], and predictive of the need for massive transfusion [7]. In guided resuscitation algorithms this usually triggers fibrinogen replacement using fresh frozen plasma, cryoprecipitate or fibrinogen concentrate. The use of VHAs in trauma is a developing research field: observational data [8] and a single centre randomised control trial have suggested VHA might increase survival versus fixed-ratio blood product resuscitation [9]. On the contrary, VHA-augmented resuscitation did not improve outcomes when compared to resuscitation augmented by conventional laboratory clotting tests in the recent iTACTIC multicentre randomised control trial [10]. The European Task Force for Advanced Bleeding Care in Trauma advocated for the use of VHAs but did not recommend specific cutoff values to use; “more research is required... physicians should use their own judgement when developing local policies” [11]. Trauma services, including our own, have developed guidelines for fibrinogen replacement using FIBTEM amplitude at 10 minutes (A10) with a threshold for fibrinogen replacement of < 11 mm. Over time local practice moved to using A5 (amplitude at 5 minutes) as a surrogate for A10 values to guide resuscitation more rapidly (Additional File 1: current ROTEM-guided transfusion algorithm). This was performed without changing the threshold value of < 11 mm. The literature demonstrates that FIBTEM A5 may be better at predicting laboratory-based hypofibrinogenaemia than maximum clot formation (the maximum amplitude reached during a ROTEM assay) in large trials [6,12]. A5 thresholds of 9.5 mm and 10 mm respectively were shown to predict laboratory-based hypofibrinogenaemia with sensitivities (specificities) of 78% (70%) and 70% (76%). However, these studies did not present predictions of hypofibrinogenaemia based on A10 for comparison. The relationship between the two early FIBTEM variables has been inadequately studied. FIBTEM A5 and A10 have been shown to be highly correlated in multiple surgical settings [13–15] and EXTEM A5 and A10 to correlate strongly in the setting of trauma [16]. Yet data on the reliability, direction and magnitude of agreement between FIBTEM A5 and A10 are lacking. Clinically this relationship is important to understand for the development of more accurate guided resuscitation algorithms. Given that the clot has had five more minutes to strengthen between the FIBTEM A5 and A10 result, we hypothesised that A5 results reliably predict A10 values that are greater in magnitude. Thus A5 could be used to safely expedite the detection of and response to hypofibrinogenaemia. Objectives The primary objective was to explore the relationship between ROTEM FIBTEM A5 and A10 in a large cohort of trauma patients and in subsets of patients with massive haemorrhage and/or major trauma, as these are the patients for whom the benefits of more rapid ROTEM results might be most apparent. The secondary objectives were to assess the clinical relevance of the difference between A5 and A10 results when applied to our current local fibrinogen-replacement algorithm threshold of < 11 mm, and to compare these against a modified threshold for A5 developed by using the quantified relationship between FIBTEM A5 and A10 to modify the existing threshold. Methods Design and Setting This retrospective observational study is reported according to the STROBE Statement for observational studies [17]. The study setting was a 750-bed tertiary health service with a Level 1 Trauma Centre located in Southeast Queensland, Australia. The institution receives over 1500 trauma activations every year with an average of 300 being classed as major trauma (Injury Severity Score (ISS) ≥ 12)[18]. Participants Participants included patients of all ages that met the trauma call criteria (briefly: injury to more than one body region or injury involving chest or abdomen, and/or significant mechanism of injury; full criteria in Additional File 2) and received a ROTEM on presentation to the emergency department between April 2014 and December 2016. Patients who did not receive a ROTEM on presentation were excluded. Procedure Each ROTEM sample was collected as part of routine admission blood tests into a 3.5ml citrated Vacuette tube (Greiner Bio-One, Kremsmünster, Austria) and transported by hand from the Emergency Department to the Intensive Care Unit for analysis. A ROTEM Delta system was used to analyse samples. This is a semi-manual system that requires blood samples to be pipetted in multiple steps by trained operators. The system uses pin and cup technology with different reagent systems in each of the four channels [5]. In this study the FIBTEM assay was used (extrinsically activated with tissue factor, the platelet inhibitor cytochalasin D and 300ul of blood). ROTEM measurements were run for a minimum of ten minutes plus clotting time. This meant the minimum results were A5 and A10. Data Collection A Trauma Registry was maintained contemporaneously comprising demographic and clinical data including injury mechanism, injury severity score and mortality. This was supplemented by data from the electronic patient records including ROTEM results, baseline laboratory tests and blood product administration in the first 24 hours. Outcomes The primary outcome was consistency of agreement between pairs of FIBTEM A5 and A10 results in the whole cohort and by subgroup analyses of patients with massive transfusion (≥10 units packed red cells in 24 hours) and major trauma (ISS ≥12). Secondary outcomes included the measured bias (mean difference) between A5 and A10 pairs, and assessment of the clinical relevance of this difference by counting numbers of patients meeting fibrinogen-replacement threshold within our algorithm using the original A10 < 11 mm; current A5 < 11 mm; and a calculated new threshold for A5 (generated by applying the bias to the < 11 mm threshold). Statistical Methods Data were analysed using STATA (StataCorp, 2017, Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) and Microsoft Excel (Microsoft 2019, Version 1912 (Build 12325.20288)). ROTEM data were first screened and biologically implausible results and patients with missing data were excluded from the analysis. Descriptive data analysis was performed using counts and percentages for categorical data. Continuous data were described using median and interquartile range. For the primary outcome whole cohort FIBTEM A5 and A10 values were assessed for consistency of agreement using the intra-class correlation coefficient (ICC) based on a two-way mixed-effects model where the A5 and A10 tests were treated as fixed effects and the blood samples as random effects. Agreement was also assessed using a Bland-Altman plot which plots the mean of the two scores to the difference between scores and can identify systematic bias and heterogenous variation. Subgroup analyses were performed. In the first, participants were grouped by number of red cell transfusions in the first 24 hours (nil; one to three units; four to nine units; ten or more units). Ten or more units was selected as the last group as this traditionally represents massive transfusion. In a second analysis participants were grouped by Injury Severity Score (ISS; zero to seven, eight to eleven, twelve or more). The latter group represented major trauma [18]. For the secondary outcomes numbers of patients reaching ROTEM-guided threshold for fibrinogen replacement according to local fibrinogen replacement algorithm (FIBTEM amplitude < 11 mm) were counted using the A5 and A10 results to assess clinical relevance of any difference between A5 and A10 results. Based on the bias (mean difference) between the A5 and A10 results the threshold for fibrinogen replacement was modified for A5 values and the number of patients reaching this new threshold was counted. Numbers of patients who actually received fibrinogen were counted in each case for comparison. Ethics Ethics approval was obtained from the Gold Coast Hospital and Health Service Human Research Ethics Committee (HREC number blinded for peer review). Waived consent was granted as section 2.3 of the National Statement on Ethical Conduct in Human Research. Results Participants Over the three-year period between 20/1/14 to 30/12/16, 4495 patients met the trauma call criteria and 1539 patients had ROTEM FIBTEM performed. One patient’s data was removed due to implausible ROTEM results and 13 patients did not have an A10 value recorded. This left 1525 patients for the primary analysis (Fig1). Of the 1525 patients used for primary analysis, 1124 (73.70%) were male. All continuous variables displayed non-normal distributions. Median age was 37 years (interquartile range [IQR] 25 - 54). Blunt trauma comprised the main mechanism of injury, present in 1391 (91.21%) cases. 474 patients (31.08%) were classified as major trauma (ISS ≥ 12) and 123 (8.07%) received packed red cell transfusions in the first 24 hours from arrival. Further descriptive statistics can be found in Table 1. In the whole cohort, median (IQR) FIBTEM A5 values were 13 (10 – 16) mm and A10 values 14 (11 – 18) mm; laboratory-measured Clauss fibrinogen was 2.9 (2.5 – 3.4) g/l. ROTEM values for the subgroups are displayed in Table 2. N or Median % or IQR Total 1525 100 Age 37 25 – 54 Male 1124 73.70% Female 401 26.30% ISS 5 1 - 14 ISS ≥ 12 474 31.08% Died < 24 hr 12 0.79% Mechanism Blunt 1391 91.21% Penetrating 119 7.80% Burns 12 0.79% Immersion 3 0.20% PRBC transfusion in 24 hr 123 8.07% Massive transfusion (≥ 10 units PRC) 14 0.92% Initial Blood Results INR 1.0 1.0 - 1.1 INR > 1.3 47 3.08% pH 7.36 7.32 - 7.39 pH < 7.30 197 12.9% Base excess (mmol/l) 0.0 -1.8 - 1.4 Base excess 2.5 mmol/l 307 20.1% Table 1 : Descriptive statistics of cohort. Values given as a count with percentage of total or as median (interquartile range). IQR (interquartile range), ISS (injury severity score), PRC (packed red cell), INR (international normalised ratio) n A5 median (IQR) mm A10 median (IQR) mm Clauss Fibrinogen median (IQR) g/l Whole cohort 1525 13 (10 - 16) 14 (11 - 18) 2.9 (2.5 - 3.4) No PRC 1402 13 (10 - 16) 14 (12 - 18) 3.0 (2.6 - 3.5) 1 - 3 PRC 65 14 (10 - 19) 14 (11 - 21) 2.8 (2.3 - 3.3) 4 - 9 PRC 44 10 (6.8 - 13) 10.5 (7.8 - 13.3) 2.0 (1.5 - 2.6) ≥ 10 PRC 14 8.5 (5.3 - 12) 9.5 (6.3 - 14) 2.5 (1.2 - 2.9) ISS 0 - 8 846 13 (10 - 16) 14 (11 - 18) 2.9 (2.5 - 3.5) ISS 9 - 11 206 13 (10 - 16) 14 (11 - 17) 3.0 (2.5 - 3.4) ISS ≥ 12 473 13 (10 - 16) 14 (11 - 18) 2.9 (2.3 - 3.4) Table 2 : ROTEM FIBTEM and laboratory-measured Clauss Fibrinogen for the whole cohort and for sub-groups. Sub-groups by packed red cell transfusion quantity in the first 24 hours and by ISS. A5 (amplitude at 5 minutes), IQR (interquartile range), A10 (amplitude at 10 minutes), PRC (packed red cell units transfused in 24 hr), ISS (injury severity score) Primary Outcomes In the whole cohort A5 and A10 values had an ICC of 0.972 (95% CI 0.969 – 0.975). ICC values above 0.90 are considered to represent an excellent level of agreement [19]. ICCs reflecting excellent agreement levels were also observed in all sub-groups when broken down by numbers of PRC transfused in 24 hours or ISS (Table 3). Within the massive transfusion group (n = 15) the A5-A10 ICC was 0.987 (0.962 – 0.996). In patients with major trauma (n = 473) the A5 A10 ICC was 0.972 (0.966 – 0.976). Bland-Altman plots were also constructed to indicate agreement and plots for the whole cohort and the subgroups of massive haemorrhage and major trauma (Figure 2). 95% Confidence Intervals n ICC Lower CI Upper CI Whole cohort 1525 0.972 0.969 0.975 No transfusion 1402 0.970 0.966 0.973 1 - 3 PRCs 64 0.984 0.974 0.990 4 - 9 PRCs 44 0.992 0.985 0.995 ≥ 10 PRCs 15 0.988 0.963 0.996 ISS 0 - 9 846 0.973 0.969 0.976 ISS 9 - 11 206 0.969 0.959 0.976 ISS ≥ 12 473 0.972 0.966 0.976 Table 3: Intraclass correlation values and confidence intervals for A5 A10 comparison in sub-groups split by quantity of packed red cell transfusions in the first 24 hours and by Injury Severity Score. ICC (intraclass correlation), CI (95% confidence interval), PRC (packed red cells), ISS (Injury Severity Score) Secondary Outcomes From the whole cohort Bland-Altman plot the calculated bias (mean difference) between A10 and A5 values was observed to be 1.49 mm (95% CI 1.43 -1.56 mm) indicating the average A10 value was 1.49 mm greater than its counterpart A5 value. 295 (19.34%) patients met the original local ROTEM threshold (A10 < 11 mm) for fibrinogen replacement. 424 (27.80%) patients met the current ROTEM threshold (A5 < 11 mm) for fibrinogen replacement (see Additional File 1). A minority of patients in both groups actually received fibrinogen replacement (indicating that they had met the second clinical criterion of active bleeding): 45 (2.95% of total) and 51 (3.34% of total) patients respectively. The calculated new trial threshold for A5 (after subtracting the bias from the original A10 threshold of < 11 mm) was A5 < 10 mm (rounded to the nearest integer due to the precision of the ROTEM machine readouts). Using this new threshold 294 (19.28%) patients would have met the ROTEM criterion for fibrinogen replacement. Numbers of patients meeting these criteria are displayed in Table 4. Current Threshold Original Threshold New Threshold A5 < 11 mm A10 < 11 mm A5 < 10 mm Met ROTEM threshold 424 (27.80%) 295 (19.34%) 294 (19.28%) Fibrinogen replaced 51 (3.34%) 45 (2.95%) 47 (3.08%) Fibrinogen not replaced 373 (24.46%) 250 (16.39%) 247 (16.20%) Table 4 : Summary of numbers of patients from the whole cohort who would have met different ROTEM FIBTEM fibrinogen replacement thresholds and which of those patients actually received fibrinogen replacement. Current local guidelines recommend fibrinogen replacement when A5 < 11 mm AND there is a clinical assessment of significant bleeding. Discussion The study has demonstrated an excellent consistency of agreement of ROTEM FIBTEM A5 and A10, with an ICC (95% CI) of 0.972 (0.969 – 0.975) across a large cohort of trauma patients. This level of consistency of agreement was maintained within all subgroups analysed and importantly in the groups of major trauma (ISS ≥ 12) and massive transfusion (≥ 10 units PRCs in 24 hr). These sub-groups who are critically unwell are most likely to derive a treatment benefit from quicker identification and treatment of hypofibrinogenaemia during resuscitation and in which demonstrating reliability of FIBTEM A5 as a surrogate for A10 is most useful. Based on ROTEM results, locally published data demonstrate that teams can expect to deliver fibrinogen concentrate to such patients within 30 minutes or cryoprecipitate within 60 minutes [20,21]. Early ROTEM values (by virtue of being point-of-care) have shorter turnaround times than urgent laboratory coagulation studies; FIBTEM A5 has been measured to have a turnaround time of 12 minutes versus 37 minutes for Clauss fibrinogen [15]. The authors of this study are not aware of a study directly measuring turnaround time of A5 versus A10 results, but theoretically a five-minute difference would be expected. In severely bleeding patients, this potentially allows for identification and correction of coagulopathy earlier. It should be noted that multiple assays are often performed over the course of a resuscitation and this time benefit could be present at each stage. This study further supports the use of FIBTEM A5 over A10 as a rapid decision-making tool for targeted resuscitation of coagulopathy in trauma. To the authors’ knowledge the consistency of agreement and magnitude of differences between FIBTEM A5 and A10 has not been reported previously in the field of trauma. Strong correlations (albeit inappropriate Pearson or Spearman correlation [22]) have been demonstrated in elective surgery (cardiac and non-cardiac) studies [13–15]. Similarly, strong correlations have been observed in trauma between other related ROTEM values: FIBTEM A5 and MCF; A10 and MCF [23] and EXTEM A5 and A10 and MCF [16]. The intra-class correlation was used in this study (versus Pearson correlation) as it validly provides a more robust measure of consistency of agreement for the comparison of two diagnostic tests measuring the same clinical concept [24,25]. The findings demonstrate FIBTEM A10 had a bias of 1.49 mm from A5 (A10 result was on average 1.49 mm greater than its corresponding A5 result). This was in line with our hypothesis: a positive difference is to be expected as the blood clot has had five more minutes to strengthen between the A5 and A10 result. This bias was used to modify our existing fibrinogen replacement threshold with cautious success. Our institution’s protocol for fibrinogen replacement in trauma haemorrhage has two criteria: 1) clinical suspicion of significant ongoing haemorrhage and 2) ROTEM FIBTEM A5 < 11 mm (Additional File 1). The protocol was initially constructed as A10 < 11 mm as this was felt to better represent hypofibrinogenaemia at the time. Over time this was approximated to A5 < 11 mm to give a time-saving benefit. Our analyses identified that 27.8% patients (424 of 1525) met the current ROTEM threshold (A5 < 11 mm) for fibrinogen replacement. Use of the original threshold (A10 < 11 mm) would have resulted in 19.3% (295 of 1525) meeting criteria. Use of the A5 value with the original threshold for replacement therefore qualified an additional 129 patients (8.5%): this is a relative increase of 43.7%. Only a small minority of these extra patients (six) received fibrinogen replacement. The most likely reason for this is that for the majority there was no clinical suspicion of bleeding. Nonetheless, use of the current A5-based criterion might predispose to increased replacement of fibrinogen. Unnecessary replacement of fibrinogen with fibrinogen concentrate, cryoprecipitate or fresh frozen plasma is undesirable. There is a relatively unknown degree of risk of iatrogenic harm from the products themselves [26,27]; misinterpretation of a ‘step-wise’ algorithm could lead to failure to correct other abnormal variables; and all methods of replacement are financially costly [28]. Our modification of the A5 threshold resulted in 19.28% meeting the replacement criterion. This is noted to be almost exactly the same proportion as using the original threshold of A10 < 11 mm. In similar cohorts of trauma patients, Rourke et al [6] and Baksaas Aasen et al [12] found that FIBTEM A5 thresholds of 9.5 mm and 10 mm respectively were optimal for detecting laboratory Clauss hypofibrinogenaemia of <1.5 g/l and <2.0 g/l with sensitivities (specificities) of 78% (70%) and 70% (76%). The current study did not include receiver operating curve analysis comparing FIBTEM A5 to Clauss fibrinogen and so we cannot provide direct validity to these thresholds. These studies demonstrate that there is no consensus as to what level of hypofibrinogenaemia should trigger transfusion. However, it is likely that our threshold of FIBTEM A5 < 10 mm corresponds to Clauss hypofibrinogenaemia < 1.5 – 2.0 g/l. Further work is required to develop a consensus ROTEM FIBTEM threshold for replacement of fibrinogen in the context of trauma[11]. The authors acknowledge several limitations to the current study. Whilst it includes every patient who had a ROTEM on admission, not all trauma patients had a ROTEM. However, the likely bias in the study in this case would be towards including more severe trauma and this is the cohort of most clinical relevance. The particular viscoelastic haemostatic device used was ROTEM Delta. This is a multi-step, partially manual assay that was performed by clinicians in an emergency trauma setting. Whilst all users had training there are multiple stages where errors could occur. The fully automated ROTEM Sigma assay was not studied. Finally, the analyses of numbers of patients meeting different FIBTEM criteria for fibrinogen replacement were retrospective and theoretical: throughout the study period the clinical criterion used was the ‘current’ threshold of A5 < 11 mm. Conclusions This study provides further evidence to validate the use of ROTEM FIBTEM A5 in place of A10 in trauma. In a large cohort of trauma patients FIBTEM A5 has excellent agreement with A10 and this is preserved in the subgroups of major trauma and massive transfusion. There is a small difference in magnitude between A5 and A10 results in the same patient and interchangeable use of values is inadvisable as it might identify quite different numbers of patients as deficient in fibrinogen. Our findings back previous work suggesting a FIBTEM A5 threshold of < 10 mm may be appropriate for targeted fibrinogen replacement when used in the context of traumatic haemorrhage. Useful future work might involve receiver operating curve analyses of ROTEM FIBTEM A5 versus A10 in the same cohort of patients and similar work with EXTEM values to guide platelet transfusion. List of Abbreviations ROTEM – rotational thromboelastometry; A5 – amplitude at five minutes; A10 – amplitude at ten minutes; MCF – maximum clot firmness; TIC – trauma-induced coagulopathy; DCR – damage control resuscitation; ICC – intra-class correlation; ISS – injury severity score; PRC – packed red cells; INR - international normalised ratio; IQ - interquartile Declarations Authors contributions: AB consolidated the databases and wrote the manuscript. JM ran the statistical analyses. KW, EW, DH, EC, AC collected the primary data. DC facilitated the running of the study and data collection. JW led the study. All authors read and reviewed the manuscript prior to submission. Acknowledgements: Dr Ian Hughes: Office for Research Governance and Development, Gold Coast Health Funding: The authors declare no external funding sources. Competing interests: The authors (Alexander Blayney, James P.A. McCullough, Elizabeth Wake, Kerin Walters, Don Campbell, Debbie Ho, Erick Chan, Aashish Chalasani and James Winearls) declare that they have no conflict of interest. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Authors contributions: AB consolidated the databases and wrote the manuscript. JM ran the statistical analyses. KW, EW, DH, EC, AC collected the primary data. DC facilitated the running of the study and data collection. JW led the study. All authors read and reviewed the manuscript prior to submission. 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Wikkelsø A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Møller AM, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev [Internet]. John Wiley & Sons, Ltd; 2013 [cited 2020 Jun 15]; Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008864.pub2/abstract Jensen NHL, Stensballe J, Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review. Acta Anaesthesiol Scand. 2016;60:1033–42. Curry N, Rourke C, Davenport R, Stanworth S, Brohi K. Fibrinogen replacement in trauma haemorrhage. Scand J Trauma Resusc Emerg Med. 2014;22:A5. Supplementary Files AdditionalFile1.pdf PDF of the local current ROTEM transfusion algorithm for critical bleeding. See “Step 2” (interpretation of FIBTEM for fibrinogen replacement). It should be noted that the exact wording of the algorithm differs slightly to that used in the report: The algorithm uses ≤ 10 mm as a threshold; this is expressed as < 11 mm in the report to facilitate direct comparison to the literature. As the outputs from the ROTEM are expressed as integers, the interpretation of these two thresholds is identical. AdditionalFile2.pdf PDF of the Trauma criteria used to define patients for our cohort. The local service operates a two tier trauma activation protocol: “Alert” and “Respond”. For the purposes of this study, patients meeting criteria for either tier were included in our trauma cohort. Cite Share Download PDF Status: Published Journal Publication published 16 Jun, 2021 Read the published version in European Journal of Trauma and Emergency Surgery → Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-97393","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Original research","associatedPublications":[],"authors":[{"id":4060903,"identity":"bbc591b8-791b-464a-a1d6-e48330e3b22e","order_by":0,"name":"Alexander Blayney","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIiWNgGAWjYDACdgYGZoYCMJPxMZhiZm4A0xK4tDCDkAGEacwAYjEzEq+FTRqshYGAFv5m5mPSBQZ2idvZe8yqCyr+RPO3A7X8qGBInNmAXYvEYbZk4xkGyYk7e86Y3Z5xxiB3xmHGBsaeMwyJs3E57DCP4WMeA+bEDTdyzG7zthnkNgC1MDO2MSTOw6FD/jD/h8M8BvWJG+6/MSsGaZlPSIvBYR5GoC2HgbbwmDGDtGyAacHlMMPDbMZAvxw33nAmrVia54xx7kagloM9ZySMcXlf7njzM+mCimrZDccPb/zMUyGXO+/84YMPflTYyM44gMv/EODYwMBhAOcdwBORcGAPTDoPCKoaBaNgFIyCkQkA219aFnEEHKcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1969-1027","institution":"Gold Coast Health","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Blayney","suffix":""},{"id":4060904,"identity":"c88ab24a-05bc-4cc2-a665-ff5d82a26c1d","order_by":1,"name":"James P. A. McCullough","email":"","orcid":"","institution":"Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"James","middleName":"P. A.","lastName":"McCullough","suffix":""},{"id":4060905,"identity":"dd02608a-fa34-4971-b92f-327da7575285","order_by":2,"name":"Elizabeth Wake","email":"","orcid":"","institution":"Trauma Service, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"","lastName":"Wake","suffix":""},{"id":4060906,"identity":"19740753-5337-43e0-bf70-aeb5bf28e579","order_by":3,"name":"Kerin Walters","email":"","orcid":"","institution":"Intensive Care Unit, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kerin","middleName":"","lastName":"Walters","suffix":""},{"id":4060907,"identity":"40fa10e2-918c-4d0d-91fe-d346e33b30ca","order_by":4,"name":"Don Campbell","email":"","orcid":"","institution":"Trauma Service, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Don","middleName":"","lastName":"Campbell","suffix":""},{"id":4060908,"identity":"ca63b7f4-adb6-4107-80be-85fa81387aea","order_by":5,"name":"Debbie Ho","email":"","orcid":"","institution":"Intensive Care Unit, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Debbie","middleName":"","lastName":"Ho","suffix":""},{"id":4060909,"identity":"62f233bd-4ae0-4f3f-85f0-b7027074e6a7","order_by":6,"name":"Erick Chan","email":"","orcid":"","institution":"Intensive Care Unit, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Erick","middleName":"","lastName":"Chan","suffix":""},{"id":4060910,"identity":"ec031337-90bd-4aa5-aa1f-3c300e027a81","order_by":7,"name":"Aashish Chalasani","email":"","orcid":"","institution":"Intensive Care Unit, Gold Coast University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aashish","middleName":"","lastName":"Chalasani","suffix":""},{"id":4060911,"identity":"e6201bd7-6935-485f-bf9b-8e2b12f59d9d","order_by":8,"name":"James Winearls","email":"","orcid":"","institution":"Intensive Care Unit, Gold Coast University Hospital; Intensive Care Unit, St Andrews War Memorial Hospital; University of Queensland; Monash University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Winearls","suffix":""}],"badges":[],"createdAt":"2020-10-23 17:30:58","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-97393/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-97393/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00068-021-01652-w","type":"published","date":"2021-06-16T11:20:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":5843121,"identity":"10e74cb5-9f6d-4689-9183-af4ecd8c0a67","added_by":"auto","created_at":"2021-02-10 21:48:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37703,"visible":true,"origin":"","legend":"Flow chart representing patients included in primary analysis, exclusions and reasons for exclusions","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-97393/v2/0b01b700848d77e658d44ef7.jpg"},{"id":5843122,"identity":"1a6501af-976a-4a78-b0a7-a8e0d6c28dcc","added_by":"auto","created_at":"2021-02-10 21:48:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53988,"visible":true,"origin":"","legend":"Bland-Altman density plots demonstrating level of agreement between FIBTEM A5 and A10. Plots demonstrate the distribution of the means of pairs of A5 and A10 against the difference between their values, for the whole cohort and subgroups of massive transfusion (≥ 10 units of packed red cells transfused in 24 hours) and major trauma (Injury Severity Score ≥ 12). Bolder colour indicates a greater density of points. SD (standard deviation)","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-97393/v2/e6596ff319b15397138d4c1f.jpg"},{"id":20183464,"identity":"bee1e722-9937-4b96-8d05-4a681bc7bc47","added_by":"auto","created_at":"2022-04-11 11:20:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":470368,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-97393/v2/520550ad-7ca3-4033-b3ce-75535da8c0a0.pdf"},{"id":5843274,"identity":"b5b82799-859d-44e2-b8a9-f5821501bf01","added_by":"auto","created_at":"2021-02-10 21:51:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2147379,"visible":true,"origin":"","legend":"PDF of the local current ROTEM transfusion algorithm for critical bleeding. See “Step 2” (interpretation of FIBTEM for fibrinogen replacement). It should be noted that the exact wording of the algorithm differs slightly to that used in the report: The algorithm uses ≤ 10 mm as a threshold; this is expressed as \u003c 11 mm in the report to facilitate direct comparison to the literature. As the outputs from the ROTEM are expressed as integers, the interpretation of these two thresholds is identical.","description":"","filename":"AdditionalFile1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-97393/v2/b4ec7b441f566328932760d8.pdf"},{"id":5843124,"identity":"247c72cd-7932-495b-8d66-5d3ae67b6807","added_by":"auto","created_at":"2021-02-10 21:48:54","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":325168,"visible":true,"origin":"","legend":"PDF of the Trauma criteria used to define patients for our cohort. The local service operates a two tier trauma activation protocol: “Alert” and “Respond”. For the purposes of this study, patients meeting criteria for either tier were included in our trauma cohort.","description":"","filename":"AdditionalFile2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-97393/v2/1808e3463c7a1e0d5d822c55.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSubstitution of ROTEM FIBTEM A5 for A10 in Trauma: An Observational Study Building a Case for More Rapid Analysis of Coagulopathy\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eTrauma is a major cause of mortality globally and estimated to cause 4.5 million deaths annually [1].\u0026nbsp; 25 - 50% of trauma deaths are due to exsanguination [2,3], and swift control of haemorrhage with replacement of blood products underpins the resuscitation of trauma patients. An alternative to standard, fixed-ratio major haemorrhage protocols involves targeted resuscitation guided by point-of-care viscoelastic haemostatic assays (VHAs) such as ROTEM (ROTEM\u0026reg;, Werfen, Barcelona, Spain) which identify deficient and dysfunctional coagulative components. This allows patient-specific administration of blood products to correct coagulopathy [4]. ROTEM FIBTEM assays assess the function of fibrinogen in clotting blood [5].\u0026nbsp; Low clot amplitude is indicative of hypofibrinogenaemia [6], and predictive of the need for massive transfusion [7]. In guided resuscitation algorithms this usually triggers fibrinogen replacement using fresh frozen plasma, cryoprecipitate or fibrinogen concentrate.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe use of VHAs in trauma is a developing research field: observational data [8] and a single centre randomised control trial have suggested VHA might increase survival versus fixed-ratio blood product resuscitation [9]. On the contrary, VHA-augmented resuscitation did not improve outcomes when compared to resuscitation augmented by conventional laboratory clotting tests in the recent iTACTIC multicentre randomised control trial [10]. The European Task Force for Advanced Bleeding Care in Trauma advocated for the use of VHAs but did not recommend specific cutoff values to use; \u0026ldquo;more research is required... physicians should use their own judgement when developing local policies\u0026rdquo; [11].\u003c/p\u003e\n\u003cp\u003eTrauma services, including our own, have developed guidelines for fibrinogen replacement using FIBTEM amplitude at 10 minutes (A10) with a threshold for fibrinogen replacement of \u0026lt; 11 mm. Over time local practice moved to using A5 (amplitude at 5 minutes) as a surrogate for A10 values to guide resuscitation more rapidly (Additional File 1: current ROTEM-guided transfusion algorithm).\u0026nbsp; This was performed without changing the threshold value of \u0026lt; 11 mm.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe literature demonstrates that FIBTEM A5 may be better at predicting laboratory-based hypofibrinogenaemia than maximum clot formation (the maximum amplitude reached during a ROTEM assay) in large trials [6,12]. A5 thresholds of 9.5 mm and 10 mm respectively were shown to predict laboratory-based hypofibrinogenaemia with sensitivities (specificities) of 78% (70%) and 70% (76%).\u0026nbsp; However, these studies did not present predictions of hypofibrinogenaemia based on A10 for comparison. The relationship between the two early FIBTEM variables has been inadequately studied. \u0026nbsp;FIBTEM A5 and A10 have been shown to be highly correlated in multiple surgical settings [13\u0026ndash;15] and EXTEM A5 and A10 to correlate strongly in the setting of trauma [16]. \u0026nbsp;Yet data on the reliability, direction and magnitude of agreement between FIBTEM A5 and A10 are lacking. \u0026nbsp;Clinically this relationship is important to understand for the development of more accurate guided resuscitation algorithms.\u0026nbsp; \u0026nbsp;Given that the clot has had five more minutes to strengthen between the FIBTEM A5 and A10 result, we hypothesised that A5 results reliably predict A10 values that are greater in magnitude. Thus A5 could be used to safely expedite the detection of and response to hypofibrinogenaemia.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary objective was to explore the relationship between ROTEM FIBTEM A5 and A10 in a large cohort of trauma patients and in subsets of patients with massive haemorrhage and/or major trauma, as these are the patients for whom the benefits of more rapid ROTEM results might be most apparent.\u0026nbsp; The secondary objectives were to assess the clinical relevance of the difference between A5 and A10 results when applied to our current local fibrinogen-replacement algorithm threshold of \u0026lt; 11 mm, and to compare these against a modified threshold for A5 developed by using the quantified relationship between FIBTEM A5 and A10 to modify the existing threshold.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eDesign and Setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study is reported according to the STROBE Statement for observational studies [17]. The study setting was a 750-bed tertiary health service with a Level 1 Trauma Centre located in Southeast Queensland, Australia. The institution receives over 1500 trauma activations every year with an average of 300 being classed as major trauma (Injury Severity Score (ISS) \u0026ge; 12)[18].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants included patients of all ages that met the trauma call criteria (briefly: injury to more than one body region or injury involving chest or abdomen, and/or significant mechanism of injury; full criteria in Additional File 2) and received a ROTEM on presentation to the emergency department between April 2014 and December 2016. Patients who did not receive a ROTEM on presentation were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach ROTEM sample was collected as part of routine admission blood tests into a 3.5ml citrated Vacuette tube (Greiner Bio-One, Kremsm\u0026uuml;nster, Austria) and transported by hand from the Emergency Department to the Intensive Care Unit for analysis. A ROTEM Delta system was used to analyse samples. This is a semi-manual system that requires blood samples to be pipetted in multiple steps by trained operators. The system uses pin and cup technology with different reagent systems in each of the four channels [5]. In this study the FIBTEM assay was used (extrinsically activated with tissue factor, the platelet inhibitor cytochalasin D and 300ul of blood). ROTEM measurements were run for a minimum of ten minutes plus clotting time. This meant the minimum results were A5 and A10. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA Trauma Registry was maintained contemporaneously comprising demographic and clinical data including injury mechanism, injury severity score and mortality.\u0026nbsp; This was supplemented by data from the electronic patient records including ROTEM results, baseline laboratory tests and\u003c/p\u003e\n\u003cp\u003eblood product administration in the first 24 hours.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome was consistency of agreement between pairs of FIBTEM A5 and A10 results in the whole cohort and by subgroup analyses of patients with massive transfusion (\u0026ge;10 units packed red cells in 24 hours) and major trauma (ISS \u0026ge;12). \u0026nbsp;Secondary outcomes included the measured bias (mean difference) between A5 and A10 pairs, and assessment of the clinical relevance of this difference by counting numbers of patients meeting fibrinogen-replacement threshold within our algorithm using the original A10 \u0026lt; 11 mm; current A5 \u0026lt; 11 mm; and a calculated new threshold for A5 (generated by applying the bias to the \u0026lt; 11 mm threshold).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were analysed using STATA (StataCorp, 2017, Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) and Microsoft Excel (Microsoft 2019, Version 1912 (Build 12325.20288)).\u0026nbsp; ROTEM data were first screened and biologically implausible results and patients with missing data were excluded from the analysis. Descriptive data analysis was performed using counts and percentages for categorical data.\u0026nbsp; Continuous data were described using median and interquartile range.\u003c/p\u003e\n\u003cp\u003eFor the primary outcome whole cohort FIBTEM A5 and A10 values were assessed for consistency of agreement using the intra-class correlation coefficient (ICC) based on a two-way mixed-effects model where the A5 and A10 tests were treated as fixed effects and the blood samples as random effects.\u0026nbsp; \u0026nbsp;\u0026nbsp;Agreement was also assessed using a Bland-Altman plot which plots the mean of the two scores to the difference between scores and can identify systematic bias and heterogenous variation.\u003c/p\u003e\n\u003cp\u003eSubgroup analyses were performed. In the first, participants were grouped by number of red cell transfusions in the first 24 hours (nil; one to three units; four to nine units; ten or more units).\u0026nbsp; Ten or more units was selected as the last group as this traditionally represents massive transfusion.\u0026nbsp; In a second analysis participants were grouped by Injury Severity Score (ISS; zero to seven, eight to eleven, twelve or more).\u0026nbsp; The latter group represented major trauma [18].\u003c/p\u003e\n\u003cp\u003eFor the secondary outcomes numbers of patients reaching ROTEM-guided threshold for fibrinogen replacement according to local fibrinogen replacement algorithm (FIBTEM amplitude \u0026lt; 11 mm) were counted using the A5 and A10 results to assess clinical relevance of any difference between A5 and A10 results.\u003c/p\u003e\n\u003cp\u003eBased on the bias (mean difference) between the A5 and A10 results the threshold for fibrinogen replacement was modified for A5 values and the number of patients reaching this new threshold was counted. Numbers of patients who actually received fibrinogen were counted in each case for comparison.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained from the Gold Coast Hospital and Health Service Human Research Ethics Committee (HREC number blinded for peer review). Waived consent was granted as section 2.3 of the National Statement on Ethical Conduct in Human Research.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cu\u003eParticipants\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eOver the three-year period between 20/1/14 to 30/12/16, 4495 patients met the trauma call criteria and 1539 patients had ROTEM FIBTEM performed. One patient\u0026rsquo;s data was removed due to implausible ROTEM results and 13 patients did not have an A10 value recorded. This left 1525 patients for the primary analysis (Fig1).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf the 1525 patients used for primary analysis, 1124 (73.70%) were male. All continuous variables displayed non-normal distributions. Median age was 37 years (interquartile range [IQR] 25 - 54). Blunt trauma comprised the main mechanism of injury, present in 1391 (91.21%) cases.\u0026nbsp; 474 patients (31.08%) were classified as major trauma (ISS \u0026ge; 12) and 123 (8.07%) received packed red cell transfusions in the first 24 hours from arrival. Further descriptive statistics can be found in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the whole cohort, median (IQR) FIBTEM A5 values were 13 (10 \u0026ndash; 16) mm and A10 values 14 (11 \u0026ndash; 18) mm; laboratory-measured Clauss fibrinogen was 2.9 (2.5 \u0026ndash; 3.4) g/l.\u0026nbsp; ROTEM values for the subgroups are displayed in Table 2.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e\u003cstrong\u003eN or Median\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003e% or IQR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e\u003cstrong\u003e1525\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003e100\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e25 \u0026ndash; 54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e1124\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e73.70%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e401\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e26.30%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eISS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e1 - 14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; ISS \u0026ge; 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e474\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e31.08%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eDied \u0026lt; 24 hr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0.79%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"350\"\u003e\n\u003cp\u003e\u003cstrong\u003eMechanism\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Blunt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e1391\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e91.21%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Penetrating\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e119\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e7.80%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Burns\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0.79%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Immersion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0.20%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003ePRBC transfusion in 24 hr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e123\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e8.07%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eMassive transfusion (\u0026ge; 10 units PRC)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0.92%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u003cstrong\u003eInitial Blood Results\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eINR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e1.0 - 1.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; INR \u0026gt; 1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e3.08%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003epH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e7.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e7.32 - 7.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; pH \u0026lt; 7.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e197\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e12.9%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eBase excess (mmol/l)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e0.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e-1.8 - 1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Base excess \u0026lt; -2.0 mmol/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e262\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e17.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003eLactate (mmol/l)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e1.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e1.2 - 2.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"242\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Lactate \u0026gt; 2.5 mmol/l\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"108\"\u003e\n\u003cp\u003e307\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e20.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr /\u003eTable 1\u003c/strong\u003e: Descriptive statistics of cohort. Values given as a count with percentage of total or as median (interquartile range).\u0026nbsp; IQR (interquartile range), ISS (injury severity score), PRC (packed red cell), INR (international normalised ratio)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" width=\"661\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 48px;\"\u003e\n\u003ctd style=\"height: 48px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"57\"\u003e\n\u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"132\"\u003e\n\u003cp\u003e\u003cstrong\u003eA5 median (IQR) mm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003eA10 median (IQR) mm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"236\"\u003e\n\u003cp\u003e\u003cstrong\u003eClauss Fibrinogen median (IQR) g/l\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eWhole cohort\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e1525\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e13 (10 - 16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e14 (11 - 18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e2.9 (2.5 - 3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo PRC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e1402\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e13 (10 - 16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e14 (12 - 18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e3.0 (2.6 - 3.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e1 - 3 PRC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e14 (10 - 19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e14 (11 - 21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e2.8 (2.3 - 3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 - 9 PRC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e10 (6.8 - 13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e10.5 (7.8 - 13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e2.0 (1.5 - 2.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e 10 PRC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e8.5 (5.3 - 12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e9.5 (6.3 - 14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e2.5 (1.2 - 2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS 0 - 8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e846\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e13 (10 - 16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e14 (11 - 18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e2.9 (2.5 - 3.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS 9 - 11\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"57\"\u003e\n\u003cp\u003e206\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"132\"\u003e\n\u003cp\u003e13 (10 - 16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e14 (11 - 17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"236\"\u003e\n\u003cp\u003e3.0 (2.5 - 3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35.9062px;\"\u003e\n\u003ctd style=\"height: 35.9062px;\" width=\"113\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS \u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e 12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.9062px;\" width=\"57\"\u003e\n\u003cp\u003e473\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.9062px;\" width=\"132\"\u003e\n\u003cp\u003e13 (10 - 16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.9062px;\" width=\"123\"\u003e\n\u003cp\u003e14 (11 - 18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35.9062px;\" width=\"236\"\u003e\n\u003cp\u003e2.9 (2.3 - 3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr /\u003eTable 2\u003c/strong\u003e: ROTEM FIBTEM and laboratory-measured Clauss Fibrinogen for the whole cohort and for sub-groups. Sub-groups by packed red cell transfusion quantity in the first 24 hours and by ISS.\u0026nbsp; A5 (amplitude at 5 minutes), IQR (interquartile range), A10 (amplitude at 10 minutes), PRC (packed red cell units transfused in 24 hr), ISS (injury severity score)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePrimary Outcomes\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn the whole cohort A5 and A10 values had an ICC of 0.972 (95% CI 0.969 \u0026ndash; 0.975).\u0026nbsp; ICC values above 0.90 are considered to represent an excellent level of agreement [19].\u003c/p\u003e\n\u003cp\u003eICCs reflecting excellent agreement levels were also observed in all sub-groups when broken down by numbers of PRC transfused in 24 hours or ISS (Table 3).\u0026nbsp; Within the massive transfusion group (n = 15) the A5-A10 ICC was 0.987 (0.962 \u0026ndash; 0.996). In patients with major trauma (n = 473) the A5 A10 ICC was 0.972 (0.966 \u0026ndash; 0.976).\u003c/p\u003e\n\u003cp\u003eBland-Altman plots were also constructed to indicate agreement and plots for the whole cohort and the subgroups of massive haemorrhage and major trauma (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" width=\"431\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"151\"\u003e\n\u003cp\u003e\u003cstrong\u003e95% Confidence Intervals\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e\u003cstrong\u003eICC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e\u003cstrong\u003eLower CI \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u003cstrong\u003eUpper CI\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eWhole cohort\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e1525\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.972\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.969\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.975\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo transfusion\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e1402\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.970\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.966\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.973\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003e1 - 3 PRCs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.984\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.974\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.990\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 - 9 PRCs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.992\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.985\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.995\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e \u003cstrong\u003e10 PRCs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.988\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.963\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.996\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS\u0026nbsp; 0 - 9 \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e846\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.973\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.969\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.976\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS\u0026nbsp; 9 - 11\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e206\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.969\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.959\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.976\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eISS \u003c/strong\u003e\u003cstrong\u003e\u0026ge;\u003c/strong\u003e\u003cstrong\u003e 12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"100\"\u003e\n\u003cp\u003e473\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.972\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"70\"\u003e\n\u003cp\u003e0.966\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e0.976\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr /\u003eTable 3:\u003c/strong\u003e Intraclass correlation values and confidence intervals for A5 A10 comparison in sub-groups split by quantity of packed red cell transfusions in the first 24 hours and by Injury Severity Score. ICC (intraclass correlation), CI (95% confidence interval), PRC (packed red cells), ISS (Injury Severity Score)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSecondary Outcomes\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eFrom the whole cohort Bland-Altman plot the calculated bias (mean difference) between A10 and A5 values was observed to be 1.49 mm (95% CI 1.43 -1.56 mm) indicating the average A10 value was 1.49 mm greater than its counterpart A5 value.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e295 (19.34%) patients met the original local ROTEM threshold (A10 \u0026lt; 11 mm) for fibrinogen replacement. 424 (27.80%) patients met the current ROTEM threshold (A5 \u0026lt; 11 mm) for fibrinogen replacement (see Additional File 1). A minority of patients in both groups actually received fibrinogen replacement (indicating that they had met the second clinical criterion of active bleeding): 45 (2.95% of total) and 51 (3.34% of total) patients respectively.\u003c/p\u003e\n\u003cp\u003eThe calculated new trial threshold for A5 (after subtracting the bias from the original A10 threshold of \u0026lt; 11 mm) was A5 \u0026lt; 10 mm (rounded to the nearest integer due to the precision of the ROTEM machine readouts).\u0026nbsp; Using this new threshold 294 (19.28%) patients would have met the ROTEM criterion for fibrinogen replacement. \u0026nbsp;Numbers of patients meeting these criteria are displayed in Table 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Threshold\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal Threshold\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eNew Threshold\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003eA5 \u0026lt; 11 mm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003eA10 \u0026lt; 11 mm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003eA5 \u0026lt; 10 mm\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eMet ROTEM threshold\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e424 (27.80%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e295 (19.34%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e294 (19.28%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eFibrinogen replaced\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e51 (3.34%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e45 (2.95%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e47 (3.08%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e\u003cstrong\u003eFibrinogen not replaced\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e373 (24.46%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e250 (16.39%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"156\"\u003e\n\u003cp\u003e247 (16.20%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr /\u003eTable 4\u003c/strong\u003e: Summary of numbers of patients from the whole cohort who would have met different ROTEM FIBTEM fibrinogen replacement thresholds and which of those patients actually received fibrinogen replacement.\u0026nbsp; Current local guidelines recommend fibrinogen replacement when A5 \u0026lt; 11 mm AND there is a clinical assessment of significant bleeding.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study has demonstrated an excellent consistency of agreement of ROTEM FIBTEM A5 and A10, with an ICC (95% CI) of 0.972 (0.969 \u0026ndash; 0.975) across a large cohort of trauma patients.\u0026nbsp; This level of consistency of agreement was maintained within all subgroups analysed and importantly in the groups of major trauma (ISS \u0026ge; 12) and massive transfusion (\u0026ge; 10 units PRCs in 24 hr). These sub-groups who are critically unwell are most likely to derive a treatment benefit from quicker identification and treatment of hypofibrinogenaemia during resuscitation and in which demonstrating reliability of FIBTEM A5 as a surrogate for A10 is most useful.\u0026nbsp; Based on ROTEM results, locally published data demonstrate that teams can expect to deliver fibrinogen concentrate to such patients within 30 minutes or cryoprecipitate within 60 minutes [20,21]. Early ROTEM values (by virtue of being point-of-care) have shorter turnaround times than urgent laboratory coagulation studies; FIBTEM A5 has been measured to have a turnaround time of 12 minutes versus 37 minutes for Clauss fibrinogen [15]. The authors of this study are not aware of a study directly measuring turnaround time of A5 versus A10 results, but theoretically a five-minute difference would be expected. In severely bleeding patients, this potentially allows for identification and correction of coagulopathy earlier.\u0026nbsp; It should be noted that multiple assays are often performed over the course of a resuscitation and this time benefit could be present at each stage.\u0026nbsp; This study further supports the use of FIBTEM A5 over A10 as a rapid decision-making tool for targeted resuscitation of coagulopathy in trauma.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo the authors\u0026rsquo; knowledge the consistency of agreement and magnitude of differences between FIBTEM A5 and A10 has not been reported previously in the field of trauma.\u0026nbsp; Strong\u0026nbsp; correlations (albeit inappropriate Pearson or Spearman correlation [22]) have been demonstrated in elective surgery (cardiac and non-cardiac) studies [13\u0026ndash;15]. Similarly, strong correlations have been observed in trauma between other related ROTEM values: FIBTEM A5 and MCF; A10 and MCF [23] and EXTEM A5 and A10 and MCF [16]. The intra-class correlation was used in this study (versus Pearson correlation) as it validly provides a more robust measure of consistency of agreement for the comparison of two diagnostic tests measuring the same clinical concept [24,25].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe findings demonstrate FIBTEM A10 had a bias of 1.49 mm from A5 (A10 result was on average 1.49 mm greater than its corresponding A5 result).\u0026nbsp; This was in line with our hypothesis: a positive difference is to be expected as the blood clot has had five more minutes to strengthen between the A5 and A10 result. This bias was used to modify our existing fibrinogen replacement threshold with cautious success. \u0026nbsp;Our institution\u0026rsquo;s protocol for fibrinogen replacement in trauma haemorrhage has two criteria: 1) clinical suspicion of significant ongoing haemorrhage and 2) ROTEM FIBTEM A5 \u0026lt; 11 mm (Additional File 1).\u0026nbsp; The protocol was initially constructed as A10 \u0026lt; 11 mm as this was felt to better represent hypofibrinogenaemia at the time.\u0026nbsp; Over time this was approximated to A5 \u0026lt; 11 mm to give a time-saving benefit.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur analyses identified that 27.8% patients (424 of 1525) met the current ROTEM threshold (A5 \u0026lt; 11 mm) for fibrinogen replacement.\u0026nbsp; Use of the original threshold (A10 \u0026lt; 11 mm) would have resulted in 19.3% \u0026nbsp;(295 of 1525) meeting criteria.\u0026nbsp; Use of the A5 value with the original threshold for replacement therefore qualified an additional 129 patients (8.5%): this is a relative increase of 43.7%.\u0026nbsp; Only a small minority of these extra patients (six) received fibrinogen replacement.\u0026nbsp; The most likely reason for this is that for the majority there was no clinical suspicion of bleeding.\u0026nbsp; Nonetheless, use of the current A5-based criterion might predispose to increased replacement of fibrinogen.\u0026nbsp; Unnecessary replacement of fibrinogen with fibrinogen concentrate, cryoprecipitate or fresh frozen plasma is undesirable.\u0026nbsp; There is a relatively unknown degree of risk of iatrogenic harm from the products themselves [26,27]; misinterpretation of a \u0026lsquo;step-wise\u0026rsquo; algorithm could lead to failure to correct other abnormal variables; and all methods of replacement are financially costly [28].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur modification of the A5 threshold resulted in 19.28% meeting the replacement criterion.\u0026nbsp; This is noted to be almost exactly the same proportion as using the original threshold of A10 \u0026lt; 11 mm.\u0026nbsp; In similar cohorts of trauma patients, Rourke et al [6] and Baksaas Aasen et al [12] found that FIBTEM A5 thresholds of 9.5 mm and 10 mm respectively were optimal for detecting laboratory Clauss hypofibrinogenaemia of \u0026lt;1.5 g/l and \u0026lt;2.0 g/l with sensitivities (specificities) of 78% (70%) and 70% (76%). The current study did not include receiver operating curve analysis comparing FIBTEM A5 to Clauss fibrinogen and so we cannot provide direct validity to these thresholds. These studies demonstrate that there is no consensus as to what level of hypofibrinogenaemia should trigger transfusion. However, it is likely that our threshold of FIBTEM A5 \u0026lt; 10 mm corresponds to Clauss hypofibrinogenaemia \u0026lt; 1.5 \u0026ndash; 2.0 g/l. Further work is required to develop a consensus ROTEM FIBTEM threshold for replacement of fibrinogen in the context of trauma[11].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge several limitations to the current study.\u0026nbsp; Whilst it includes every patient who had a ROTEM on admission, not all trauma patients had a ROTEM.\u0026nbsp; However, the likely bias in the study in this case would be towards including more severe trauma and this is the cohort of most clinical relevance.\u0026nbsp; The particular viscoelastic haemostatic device used was ROTEM Delta. This is a multi-step, partially manual assay that was performed by clinicians in an emergency trauma setting. Whilst all users had training there are multiple stages where errors could occur.\u0026nbsp; The fully automated ROTEM Sigma assay was not studied.\u0026nbsp; Finally, the analyses of numbers of patients meeting different FIBTEM criteria for fibrinogen replacement were retrospective and theoretical: throughout the study period the clinical criterion used was the \u0026lsquo;current\u0026rsquo; threshold of A5 \u0026lt; 11 mm.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study provides further evidence to validate the use of ROTEM FIBTEM A5 in place of A10 in trauma. \u0026nbsp;In a large cohort of trauma patients FIBTEM A5 has excellent agreement with A10 and this is preserved in the subgroups of major trauma and massive transfusion. There is a small difference in magnitude between A5 and A10 results in the same patient and interchangeable use of values is inadvisable as it might identify quite different numbers of patients as deficient in fibrinogen. Our findings back previous work suggesting a FIBTEM A5 threshold of \u0026lt; 10 mm may be appropriate for targeted fibrinogen replacement when used in the context of traumatic haemorrhage.\u0026nbsp; Useful future work might involve receiver operating curve analyses of ROTEM FIBTEM A5 versus A10 in the same cohort of patients and similar work with EXTEM values to guide platelet transfusion.\u003c/p\u003e"},{"header":"List of Abbreviations","content":"\u003cp\u003eROTEM \u0026ndash; rotational thromboelastometry; A5 \u0026ndash; amplitude at five minutes; A10 \u0026ndash; amplitude at ten minutes; MCF \u0026ndash; maximum clot firmness; TIC \u0026ndash; trauma-induced coagulopathy; DCR \u0026ndash; damage control resuscitation; ICC \u0026ndash; intra-class correlation; ISS \u0026ndash; injury severity score; PRC \u0026ndash; packed red cells; INR - international normalised ratio; IQ - interquartile\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAB consolidated the databases and wrote the manuscript. JM ran the statistical analyses. KW, EW, DH, EC, AC collected the primary data. DC facilitated the running of the study and data collection. JW led the study.\u0026nbsp; All authors read and reviewed the manuscript prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Ian Hughes: Office for Research Governance and Development, Gold Coast Health\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no external funding sources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors (Alexander Blayney, James P.A. McCullough, Elizabeth Wake, Kerin Walters, Don Campbell, Debbie Ho, Erick Chan, Aashish Chalasani and James Winearls) declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAB consolidated the databases and wrote the manuscript. JM ran the statistical analyses. KW, EW, DH, EC, AC collected the primary data. DC facilitated the running of the study and data collection. JW led the study.\u0026nbsp; All authors read and reviewed the manuscript prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics / consent:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed according to the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Ethics approval was obtained from the Gold Coast Hospital and Health Service Human Research Ethics Committee on the 26\u003csup\u003eth\u003c/sup\u003e March 2014 (HREC/14/QGC/17). Waived consent was granted as section 2.3 of the National Statement on Ethical Conduct in Human Research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRoth GA, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980\u0026ndash;2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392:1736\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eS\u0026oslash;reide K, Kr\u0026uuml;ger AJ, V\u0026aring;rdal AL, Ellingsen CL, S\u0026oslash;reide E, Lossius HM. Epidemiology and Contemporary Patterns of Trauma Deaths: Changing Place, Similar Pace, Older Face. World J Surg. 2007;31:2092\u0026ndash;103.\u003c/li\u003e\n\u003cli\u003eCole E, Weaver A, Gall L, West A, Nevin D, Tallach R, et al. A Decade of Damage Control Resuscitation: New Transfusion Practice, New Survivors, New Directions. Ann Surg. 2019;\u003c/li\u003e\n\u003cli\u003eWinearls J, Mitra B, Reade MC. Haemotherapy algorithm for the management of trauma-induced coagulopathy: an Australian perspective. Curr Opin Anesthesiol. 2017;30:265\u0026ndash;276.\u003c/li\u003e\n\u003cli\u003eWhiting D, DiNardo JA. TEG and ROTEM: Technology and clinical applications. Am J Hematol. 2014;89:228\u0026ndash;32.\u003c/li\u003e\n\u003cli\u003eRourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eHagemo JS, Christiaans SC, Stanworth SJ, Brohi K, Johansson PI, Goslings JC, et al. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care. 2015;19:97.\u003c/li\u003e\n\u003cli\u003eTapia NM, Chang A, Norman M, Welsh F, Scott B, Wall MJ, et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74:378\u0026ndash;85; discussion 385-386.\u003c/li\u003e\n\u003cli\u003eGonzalez E, Moore EE, Moore HB, Chapman MP, Chin TL, Ghasabyan A, et al. Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy. Ann Surg. 2016;263:1051\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eBaksaas-Aasen K, Gall LS, Stensballe J, Juffermans NP, Curry N, Maegele M, et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med. 2021;47:49\u0026ndash;59.\u003c/li\u003e\n\u003cli\u003eSpahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98.\u003c/li\u003e\n\u003cli\u003eBaksaas-Aasen K, Dieren SV, Balvers K, Juffermans N, N\u0026aelig;ss P, Rourke C, et al. Data-driven Development of ROTEM and TEG Algorithms for the Management of Trauma Hemorrhage: A Prospective Observational Multicenter Study. Ann Surg. 2019;270:1178\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eG\u0026ouml;rlinger K, Dirkmann D, Solomon C, Hanke AA. Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. BJA Br J Anaesth. Oxford Academic; 2013;110:222\u0026ndash;30.\u003c/li\u003e\n\u003cli\u003eDirkmann D, G\u0026ouml;rlinger K, Dusse F, Kottenberg E, Peters J. Early thromboelastometric variables reliably predict maximum clot firmness in patients undergoing cardiac surgery: a step towards earlier decision making. Acta Anaesthesiol Scand. 2013;57:594\u0026ndash;603.\u003c/li\u003e\n\u003cli\u003eOlde Engberink RHG, Kuiper GJAJM, Wetzels RJH, Nelemans PJ, Lance MD, Beckers EAM, et al. Rapid and Correct Prediction of Thrombocytopenia and Hypofibrinogenemia With Rotational Thromboelastometry in Cardiac Surgery. J Cardiothorac Vasc Anesth. 2014;28:210\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eKelly JM, Rizoli S, Veigas P, Hollands S, Min A. Using rotational thromboelastometry clot firmness at 5 minutes (ROTEM\u0026reg; EXTEM A5) to predict massive transfusion and in-hospital mortality in trauma: a retrospective analysis of 1146 patients. Anaesthesia. 2018;73:1103\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eElm E von, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. PLOS Med. Public Library of Science; 2007;4:e296.\u003c/li\u003e\n\u003cli\u003ePalmer CS, Gabbe BJ, Cameron PA. Defining major trauma using the 2008 Abbreviated Injury Scale. Injury. 2016;47:109\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003ePortney LG, Watkins MP. Foundations of clinical research: applications to practice. Third. Upper Saddle River, NJ: Pearson/Prentice Hall; 2000.\u003c/li\u003e\n\u003cli\u003eSeebold JA, Campbell D, Wake E, Walters K, Ho D, Chan E, et al. Targeted fibrinogen concentrate use in severe traumatic haemorrhage. Crit Care Resusc. The Australasian Medical Publishing Company; 2019;21:171.\u003c/li\u003e\n\u003cli\u003eHo D, Chan E, Campbell D, Wake E, Walters K, Bulmer AC, et al. Targeted cryoprecipitate transfusion in severe traumatic haemorrhage. Injury [Internet]. 2020 [cited 2020 Jul 1]; Available from: http://www.sciencedirect.com/science/article/pii/S0020138320304721\u003c/li\u003e\n\u003cli\u003eMartin Bland J, Altman DouglasG. STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT. The Lancet. 1986;327:307\u0026ndash;10.\u003c/li\u003e\n\u003cli\u003eMeyer ASP, Meyer MAS, S\u0026oslash;rensen AM, Rasmussen LS, Hansen MB, Holcomb JB, et al. Thrombelastography and rotational thromboelastometry early amplitudes in 182 trauma patients with clinical suspicion of severe injury. J Trauma Acute Care Surg. 2014;76:682\u0026ndash;690.\u003c/li\u003e\n\u003cli\u003eMcGraw KO, Wong SP. Forming inferences about some intraclass correlation coefficients. Psychol Methods. US: American Psychological Association; 1996;1:30\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003eSchuck P. Assessing reproducibility for interval data in health-related quality of life questionnaires: Which coefficient should be used? Qual Life Res. 2004;13:571\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eWikkels\u0026oslash; A, Lunde J, Johansen M, Stensballe J, Wetterslev J, M\u0026oslash;ller AM, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev [Internet]. John Wiley \u0026amp; Sons, Ltd; 2013 [cited 2020 Jun 15]; Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008864.pub2/abstract\u003c/li\u003e\n\u003cli\u003eJensen NHL, Stensballe J, Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review. Acta Anaesthesiol Scand. 2016;60:1033\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eCurry N, Rourke C, Davenport R, Stanworth S, Brohi K. Fibrinogen replacement in trauma haemorrhage. Scand J Trauma Resusc Emerg Med. 2014;22:A5.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ROTEM, rotational thromboelastometry, fibrinogen, trauma, haemorrhage, coagulopathy, resuscitation ","lastPublishedDoi":"10.21203/rs.3.rs-97393/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-97393/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose \u003c/strong\u003eRotational thromboelastometry (ROTEM®) allows guided blood product resuscitation to correct trauma induced coagulopathy in bleeding trauma patients.\u0026nbsp;FIBTEM amplitude at 10 minutes (A10) has been widely used to identify hypofibrinogenaemia; locally a threshold of \u0026lt; 11 mm has guided fibrinogen replacement. Amplitude at 5 minutes (A5) carries an inherent time advantage.\u0026nbsp;The primary aim was to explore the relationship between FIBTEM A5 and A10 in a trauma.\u0026nbsp;Secondary aim was to investigate the use of A5 as a surrogate for A10 within a fibrinogen-replacement algorithm.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eRetrospective observational cohort study of arrival ROTEM results from 1539 consecutive trauma patients at a Level 1 trauma centre in Australia. Consistency of agreement between FIBTEM A5 and A10 was assessed.\u0026nbsp;A new fibrinogen replacement threshold was developed for A5 using the A5 – A10 bias; this was clinically compared to the existing A10 threshold.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eFIBTEM A5 displayed excellent consistency of agreement with A10. Intraclass correlation coefficient = 0.972 (95% confidence interval [CI] 0.969 – 0.974). Bias of A5 to A10 was -1.49 (95% CI 1.43 -1.56) mm. 19.34% patients met the original local threshold of A10 \u0026lt; 11 mm; 19.28% patients met the new, bias-adjusted threshold of A5 \u0026lt; 10 mm.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eROTEM FIBTEM A5 reliably predicts A10 in trauma. This further validates use of the A5 result over A10 allowing faster decision-making in time-critical resuscitation of trauma patients. A modification of -1 to the A10 threshold might be appropriate for use with the A5 value in trauma patients.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Substitution of ROTEM FIBTEM A5 for A10 in Trauma: An Observational Study Building a Case for More Rapid Analysis of Coagulopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2021-02-10 21:48:52","doi":"10.21203/rs.3.rs-97393/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-10-28 22:46:30","doi":"10.21203/rs.3.rs-97393/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e251c079-cb88-42b9-b7e9-f48995c8626a","owner":[],"postedDate":"February 10th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":916221,"name":"Critical Care \u0026 Emergency Medicine"}],"tags":[],"updatedAt":"2022-04-11T11:20:22+00:00","versionOfRecord":{"articleIdentity":"rs-97393","link":"https://doi.org/10.1007/s00068-021-01652-w","journal":{"identity":"european-journal-of-trauma-and-emergency-surgery","isVorOnly":false,"title":"European Journal of Trauma and Emergency Surgery"},"publishedOn":"2021-06-16 11:20:22","publishedOnDateReadable":"June 16th, 2021"},"versionCreatedAt":"2021-02-10 21:48:52","video":"","vorDoi":"10.1007/s00068-021-01652-w","vorDoiUrl":"https://doi.org/10.1007/s00068-021-01652-w","workflowStages":[]},"version":"v2","identity":"rs-97393","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-97393","identity":"rs-97393","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}