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Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial
Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, Gruber G, Schmid S, Friesenecker B, Lorenz IH, et al
The Lancet. Haematology. 2017;4((6):):e258-e271.. e258
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Abstract
BACKGROUND Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure. METHODS This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635. FINDINGS Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25.34 [95% CI 5.47-240.03], p<0.0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3.04 [0.95-10.87], p=0.042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1.92 [95% CI 0.78-4.86], p=0.15). INTERPRETATION Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP. FUNDING None.
Clinical Commentary
What is known?
The management of major trauma haemorrhage has changed significantly over the last two decades, and the use of haemostatic resuscitation (the transfusion of red cells and FFP early and in high ratio to mitigate/treat clotting abnormalities that arise from severe trauma haemorrhage) is now standard practice. There are attendant risks from the transfusion of blood components (TRALI, TACO, increased rates of multiple organ failure (MOF) in trauma) and the potential to use clotting factor concentrates (CFCs) such as prothrombin complex concentrate, factor XIII and fibrinogen in place of FFP may confer advantages.
What did this paper set out to examine?
The RETIC study was a single centre, open-label, RCT evaluating the effects of FFP vs. coagulation factor concentrates (CFCs) as treatment for major bleeding after injury in adult trauma patients (age 18 80). The primary endpoint was the development of MOF during ICU stay, as defined by the SOFA score. Secondary endpoints were numerous and included transfusion use, changes to clotting parameters, thromboembolic complications and mortality. The study was designed to detect a difference in MOF between groups notably the publication did not specify the difference expected and 292 patients were required for 80% power.
What did they show?
The study recruited 100 patients (48 FFP and 52 CFC) between March 2012 Feb 2016. Six patients were later excluded. 44FFP and 50 CFC patients were analysed. The baseline characteristics in each arm were balanced. The study was terminated early for safety 52% patients in FFP arm required rescue therapy (double dose therapy followed by switching to the other treatment to stop the bleeding) compared to 4% CFC group (OR: 25.34 [95% CI 5.47 240.03], p < 0.0001). Additionally more FFP patients received massive transfusion; OR 3.04 [0.95 10.87], p = 0.042.
Primary endpoint results were provided using a modified ITT population (patients randomised but did not complete therapy were removed). The study showed no significant difference in MOF between arms: 66% FFP arm vs. 50% CFC arm; OR 1.92 [95%CI 0.78 4.86], p = 0.15. Post-hoc logistic regression analysis showed a significant difference in MOF development in the FFP arm for patients who had higher injury severity and worse brain injury; OR 3.13 [1.19-8.88], p = 0.025. The CFC patients were more likely to have coagulopathy reversed OR 25.34 [5.47-240.03], p <0.0001. (Defined by: FIBTEM A10 >8mm, EXTEM CT < 78 secs and no clinical bleeding). Seven patients died 5 CFC and 2 FFP, most due to severe brain injury and no patient died from exsanguination.
What are the implications for practice and for future work?
Overall, given these limitations, there will be debate about the implications of this trial for practice. The findings regarding reversal of coagulopathy are intriging there is a clear agreement between reversal of coagulopathy i.e. a FIBTEM A10 >8mm, and an EXTEM CT < 78 secs and reduced bleeding. This is the first time, in an RCT setting, that improved ROTEM parameters have been linked to clinical reduction of bleeding and these findings are important. One particular area for further research might be to validate whether the ROTEM parameters are effective thresholds for bleeding treatment and importantly linking the thresholds with hard clinical outcomes such as mortality or significant reduction in transfusion therapy.
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Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy in adult trauma patients with bleeding
Hunt H, Stanworth S, Curry N, Woolley T, Cooper C, UkoumunneO, Zhelev Z, Hyde C
Cochrane Database of Systematic Reviews. 2015;((2):):CD010438.
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Abstract
BACKGROUND Trauma-induced coagulopathy (TIC) is a disorder of the blood clotting process that occurs soon after trauma injury. A diagnosis of TIC on admission is associated with increased mortality rates, increased burdens of transfusion, greater risks of complications and longer stays in critical care. Current diagnostic testing follows local hospital processes and normally involves conventional coagulation tests including prothrombin time ratio/international normalized ratio (PTr/INR), activated partial prothrombin time and full blood count. In some centres, thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are standard tests, but in the UK they are more commonly used in research settings. OBJECTIVES The objective was to determine the diagnostic accuracy of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for TIC in adult trauma patients with bleeding, using a reference standard of prothrombin time ratio and/or the international normalized ratio. SEARCH METHODS We ran the search on 4 March 2013. Searches ran from 1970 to current. We searched The Cochrane Library, MEDLINE (OvidSP), EMBASE Classic and EMBASE, eleven other databases, the web, and clinical trials registers. The Cochrane Injuries Group's specialised register was not searched for this review as it does not contain diagnostic test accuracy studies. We also screened reference lists, conducted forward citation searches and contacted authors. SELECTION CRITERIA We included all cross-sectional studies investigating the diagnostic test accuracy of TEG and ROTEM in patients with clinically suspected TIC, as well as case-control studies. Participants were adult trauma patients in both military and civilian settings. TIC was defined as a PTr/INR reading of 1.2 or greater, or 1.5 or greater. DATA COLLECTION AND ANALYSIS We piloted and performed all review stages in duplicate, including quality assessment using the QUADAS-2 tool, adhering to guidance in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. We analysed sensitivity and specificity of included studies narratively as there were insufficient studies to perform a meta-analysis. MAIN RESULTS Three studies were included in the final analysis. All three studies used ROTEM as the test of global haemostatic function, and none of the studies used TEG. Tissue factor-activated assay EXTEM clot amplitude (CA) was the focus of the accuracy measurements in blood samples taken near to the point of admission. These CAs were not taken at a uniform time after the start of the coagulopathic trace; the time varied from five minutes, to ten minutes and fifteen minutes. The three included studies were conducted in the UK, France and Afghanistan in both civilian and military trauma settings. In two studies, median Injury Severity Scores were 12, inter-quartile range (IQR) 4 to 24; and 22, IQR 12 to 34; and in one study the median New Injury Severity Score was 34, IQR 17 to 43.There were insufficient included studies examining each of the three ROTEM CAs at 5, 10 and 15 minutes to make meta-analysis and investigation of heterogeneity valid. The results of the included studies are thus reported narratively and illustrated by a forest plot and results plotted on the receiver operating characteristic (ROC) plane.For CA5 the accuracy results were sensitivity 70% (95% CI 47% to 87%) and specificity 86% (95% CI 82% to 90%) for one study, and sensitivity 96% (95% CI 88% to 100%) and specificity 58% (95% CI 44% to 72%) for the other.For CA10 the accuracy results were sensitivity 100% (95% CI 94% to 100%) and specificity 70% (95% CI 56% to 82%).For CA15 the accuracy results were sensitivity 88% (95% CI 69% to 97%) and specificity 100% (95% CI 94% to 100%).No uninterpretable ROTEM study results were mentioned in any of the included studies.Risk of bias and concerns around applicability of findings was low across all studies for the patient and flow and timing domains. However, risk of bias and concerns around applicability of findings for the index test domain was either high or unclear
Clinical Commentary
What is known?
Trauma induced coagulopathy (TIC) is an impairment of blood clotting that occurs soon after injury and has been reported to confer a mortality rate as high as 50%. TIC is associated with increased rates of transfusion, organ failure, sepsis and longer critical care stays. Early recognition of TIC may allow trauma teams to treat coagulopathy more rapidly and may lead to improved clinical outcomes. Historically, TIC has been defined using standard laboratory coagulation tests, most commonly the prothrombin time (PT) and the PT ratio (PTr) or INR. More recently, viscoelastic tests (VHA tests) are being used with increasing frequency, favoured by clinical teams for being both point-of-care tests and for the speed with which useful results can be obtained. There is a great deal of interest in the role that VHA tests can play in the diagnosis of TIC as well as how they can be used optimally to guide transfusion therapy.
What did this paper set out to examine?
This Cochrane review set out to determine how good TEG and ROTEM assessments were at diagnosing TIC in adult trauma patients with bleeding. This was a diagnostic test accuracy review and the accuracy of the TEG and ROTEM was compared against the PTr/INR which was used as the reference standard.
What did they show?
This paper included 3 cross-sectional studies (including 430 patients in total), with civilian and military patients. No RCTs were identified. All three studies compared ROTEM to standard clotting tests and no study was specifically designed to evaluate test accuracy. The included studies focussed on a single ROTEM measure -EXTEM clot amplitude (CA) to assess TIC, but the time points that CA values were reported varied i.e. CA5, CA10 and CA15 (result at 5, 10 or 15 minutes). The reference standard that the studies used also varied with 2 studies using a PTr > 1.5 and 1 study using a PTr > 1.2.
The authors found that the 3 studies provided very little evidence on the accuracy of ROTEM and no evidence for TEG in the diagnosis of TIC. 4 domains were evaluated for risk of bias, and bias was thought to be high for two domains: (a) the choice of index test (ie ROTEM) and (b) the choice of reference standard (ie PTr/INR). The authors highlighted that this raised concerns around the interpretation of sensitivity and specificity results of the 3 studies.
What are the implications for practice and for future work?
The conclusion from this review was that there were no high quality data to confirm the accuracy of TEG or ROTEM in the diagnosis of TIC and the authors recommended that VHA tests should be limited to the research setting only.
Future research will need to focus on several areas. Interventional studies looking at the effect of ROTEM/TEG guided algorithms for diagnosis or even treatment of TIC, when compared to standard treatment without a VHA device, may be required to fully evaluate the use of these devices. However, without consensus about which VHA (or indeed standard clotting test) parameter(s) diagnose TIC the value of these interventions will be limited.
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Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial
Roberts I, Prieto-Merino D, Manno D
Critical Care (London, England). 2014;18((6):):685.
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Abstract
INTRODUCTION To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days. METHODS Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258. RESULTS The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR <3 hours = 0.78, 0.68 to 0.90; HR >3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise. CONCLUSIONS Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.
Clinical Commentary
What is known?
The CRASH-2 trial, an international, multicentre randomized controlled trial involving over 20 000 patients published in Lancet in 2010, has shown that administration of tranexamic acid (TXA), an antifibrinolytic, to bleeding trauma patients within 3 hours of injury significantly reduces death due to bleeding (p = 0.0077), as well as all-cause mortality (20% reduction)(p = 0.0035) as compared to placebo. TXA is a synthetic derivative of lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen as well as by interfering with the binding of plasmin to fibrin.
What did this paper set out to examine?
The authors set out to investigate the mechanism of action of TXA in bleeding in trauma patients by examining the timing of its effect on mortality in patients evaluated via the CRASH-2 trial. There is debate in the literature as to whether TXA functions by reducing inflammation by reducing plasmin, a pro-inflammatory mediator, or if TXA functions by simply reducing blood loss. The authors hypothesized that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of injury when bleeding should be most profuse. Their belief was that if TXA reduces mortality by an anti-inflammatory mechanism its effect should be greater in the days following the injury.
What did they show?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.
What are the implications for practice and for future work?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.
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Risks associated with red blood cell transfusion in the trauma population, a meta-analysis
Patel SV, Kidane B, Klingel M, Parry N
Injury. 2014;45((10):):1522-33.
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Abstract
INTRODUCTION A previous meta-analysis has found an association between red blood cell (RBC) transfusions and mortality in critically ill patients, but no review has focused on the trauma population only. OBJECTIVES To determine the association between RBC transfusion and mortality in the trauma population, with secondary outcomes of multiorgan failure (MOF) and acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). DATA SOURCES EMBASE (1947-2012) and MEDLINE (1946-2012). STUDY ELIGIBILITY CRITERIA Randomized controlled trials and observational studies were to be included if they assessed the association between RBC transfusion and either the primary (mortality) or secondary outcomes (MOF, ARDS/ALI). PARTICIPANTS Trauma patients. EXPOSURE Red blood cell transfusion. METHODS A literature search was completed and reviewed in duplicate to identify eligible studies. Studies were included in the pooled analyses if an attempt was made to determine the association between RBC and the outcomes, after adjusting for important confounders. A random effects model was used for and heterogeneity was quantified using the I(2) statistic. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS 40 observational studies were included in the qualitative review. Including studies which adjusted for important confounders found the odds of mortality increased with each additional unit of RBC transfused (9 Studies, OR 1.07, 95%CI 1.04-1.10, I(2) 82.9%). The odds of MOF (3 studies, OR 1.08, 95%CI 1.02-1.14, I(2) 95.9%) and ARDS/ALI (2 studies, OR 1.06, 95%CI 1.03-1.10, I(2) 0%) also increased with each additional RBC unit transfused. CONCLUSIONS We have found an association between RBC transfusion and the primary and secondary outcomes, based on observational studies only. This represents the extent of the published literature. Further interventional studies are needed to clarify how limiting transfusion can affect mortality and other outcomes. Copyright 2014 Elsevier Ltd. All rights reserved.
Clinical Commentary
Dr Annemarie Docherty, University of Edinburgh, Edinburgh, UK.
What is known?
Death from haemorrhage is the second most common cause of death in the trauma population and a high proportion of severely injured patients receive red blood cell transfusions. Evidence from randomised controlled trials in critically ill patients support a restrictive transfusion threshold, however the effect of transfusion on outcomes in trauma may differ due to the timing and amount of transfusion required. Trauma patients may be unstable or actively bleeding, as opposed to the slow decline in haemoglobin often seen in critical care. Evidence in the trauma population is based primarily on small observational studies.
What did this paper set out to examine?
This systematic review and meta-analysis set out to assess the association between red blood cell transfusion and mortality in the trauma population. Secondary outcomes included acute respiratory distress syndrome or acute lung injury (ARDS/ALI) and multiorgan failure. Comparative observational and interventional studies were eligible for inclusion.
What did they show?
The authors included 40 studies in the qualitative review. No randomised controlled trials addressed the study question. All studies were observational cohort studies, which increased the risk of selection bias and confounding. Particularly relevant confounders were injury severity and other measures of shock which were strongly associated with the study outcomes. The authors assessed the quality of the studies using the Newcastle-Ottawa Scale, and the quality of the meta-analysis using the GRADE guidelines.
There was significant heterogeneity. Study size varied from 29 to 25,299. Timing of red blood cell transfusion varied considerably from studies that included transfusion within 24-48 hours only, total in-hospital transfusion, to studies that excluded patients transfused within 48 hours of admission. There were also marked differences in the categorisation of red blood cell transfusion: continuous variable (per unit change), binary variable (transfused/not transfused) and a categorical variable. In addition to this, patient populations also varied: multiply injured patients, patients with only one system injured, massively transfused patients, patients only admitted to the intensive care unit, surgical patients only, intubated patients only, and various injury severity score cutoffs.
Seventeen studies attempted to determine the effect of transfusion on mortality after adjusting for important confounders, and nine of these had enough information to be pooled in the meta-analysis. Eight studies found that red blood cell transfusion was associated with increased odds of mortality, and the adjusted pooled analysis showed an increase in the odds of mortality with each additional unit transfused (OR 1.07, 95%CI 1.04-1.10, p<0.001, I^2=94.6%). The authors graded this evidence as low.
Six studies attempted to determine the adjusted association with multiorgan failure. The odds of multiorgan failure increased with each additional unit of blood (OR 1.08, 95%CI 1.02-1.14, p=0.012, I^2=95.9%). The grade of evidence was moderate.
Six studies assessed the adjusted association between transfusion and ARDS, but only two had enough information to be included in the meta-analysis (transfused vs not transfused: OR 2.04, 95%CI 1.47-2.83, p<0.001, I^2=0%). The authors graded this evidence as very low.
What are the implications for practice and for future work?
The observational studies all showed an association between transfusion and mortality and other negative outcomes. However, there was considerable heterogeneity between the studies, and as the authors acknowledge, it is likely that significant confounding persisted even after attempts to adjust for injury and illness severity. The authors have graded the evidence as very low to moderate, and it is not possible to refine red blood cell transfusion practice in trauma on the basis of these observational studies.
This systematic review highlights the lack of evidence for red blood cell transfusion in trauma, and the need for a robust randomised controlled trial in this population. This would minimise confounding and bias, and give a definitive answer regarding the effect of red blood cell transfusion on mortality.
