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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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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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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.
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Association of red blood cell transfusion and in-hospital mortality in patients admitted to the intensive care unit: a systematic review and meta-analysis
Zheng Y, Lu C, Wei S, Li Y, Long L, Yin P
Critical Care (London, England). 2014;18((6):):515.
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INTRODUCTION Previous research has debated whether red blood cell (RBC) transfusion is associated with decreased or increased mortality in patients admitted to the intensive care unit (ICU). We conducted a systematic review and meta-analysis to assess the relationship of RBC transfusion with in-hospital mortality in ICU patients. METHODS We carried out a literature search on Medline (1950 through May 2013), Web of Science (1986 through May 2013) and Embase (1980 through May 2013). We included all prospective and retrospective studies on the association between RBC transfusion and in-hospital mortality in ICU patients. The relative risk for the overall pooled effects was estimated by random effects model. Sensitivity analyses were conducted to assess potential bias. RESULTS The meta-analysis included 28,797 participants from 18 studies. The pooled relative risk for transfused versus nontransfused ICU patients was 1.431 (95% CI, 1.105 to 1.854). In sensitivity analyses, the pooled relative risk was 1.211 (95% CI, 0.975 to 1.505) if excluding studies without adjustment for confounders, 1.178 (95% CI, 0.937 to 1.481) if excluding studies with relative high risk of bias, and 0.901 (95% CI, 0.622 to 1.305) if excluding studies without reporting hazard ratio (HR) or relative risk (RR) as an effect size measure. Subgroup analyses revealed increased risks in studies enrolling patients from all ICU admissions (RR 1.513, 95%CI 1.123 to 2.039), studies without reporting information on leukoreduction (RR 1.851, 95%CI 1.229 to 2.786), studies reporting unadjusted effect estimates (RR 3.933, 95%CI 2.107 to 7.343), and studies using odds ratio as an effect measure (RR 1.465, 95%CI 1.049 to 2.045). Meta-regression analyses showed that RBC transfusion could decrease risk of mortality in older patients (slope coefficient -0.0417, 95%CI -0.0680 to -0.0154). CONCLUSIONS There is lack of strong evidence to support the notion that ICU patients who receive RBC transfusion have an increased risk of in-hospital death. In studies adjusted for confounders, we found that RBC transfusion does not increase the risk of in-hospital mortality in ICU patients. Type of patient, information on leukoreduction, statistical method, mean age of patient enrolled and publication year of the article may account for the disagreement between previous studies.
Clinical Commentary
Dr Annemarie Docherty, University of Edinburgh, Edinburgh, UK.
What is known?
Anaemia is prevalent in critically ill patients, and is associated with poor outcomes including acute myocardial infarction, heart failure, chronic kidney disease and risk of death. In critically ill patients, the standard method of reversing anaemia is with transfusion of red blood cells, with the aim of improving oxygen delivery to the tissues. However, blood transfusion is not without risks. These include immunosuppression, risk for infection, transfusion reactions and transfusion-related acute lung injury. There is conflicting evidence surrounding the association between red blood cell transfusion and mortality, with some studies suggesting a higher risk of death in transfused patients, and others finding a lower risk of death.
What did this paper set out to examine?
The authors have set out to examine whether there is an association between red blood cell transfusion and mortality in critically ill patients. The authors have performed a meta-analysis of all published retrospective and prospective observational studies comparing red blood cell transfused with non-transfused ICU patients, looking at all-cause in-hospital mortality, and risk factors of death in transfused patients.
What did they show?
The authors identified 18 observational studies which looked at mortality of transfused patients. Eight studies were prospective, and the other ten retrospective, six studies were very high overall quality, nine studies high overall quality and three studies median overall quality. The overall pooled risk ratio of in-hospital mortality of transfused patients compared to non-transfused patients was 1.431 (95%CI 1.105 to 1.854). However, in order to account for the impact of the observational design of the studies on the results, they performed several sensitivity analyses, including only studies that adjusted for confounders, only high quality studies, and only studies that included risk or hazard ratios. When only including studies that adjusted for confounding (of particular importance in observational studies), the RR was 1.211 (95%CI 0.795 to 1.505). The authors performed a subgroup analysis looking at different types of admission (sepsis and shock, surgical, trauma, and other). There was no association between RBC transfusion and mortality in each type of admission, however the pooled effect estimate suggested that type of admission was a significant predictor of in-hospital mortality. Other significant predictors were age of patient, and year of publication. Recent studies were more likely to report lower risk ratios, which the authors suggest means that blood transfusion may have got safer over time.
What are the implications for practice and for future work?
As a result of these observational limitations, although this systematic review suggests that RBC transfusion is not linked to in-hospital mortality, a randomised controlled trial designed and powered to answer this question would be required to determine causality. This review suggests that in the heterogenous ICU population, there is no association between RBC transfusion and in-hospital mortality after adjustment for confounders. Clinicians can perhaps be reassured that there does not appear to be an inherent risk with RBC transfusion, and that the decision to transfuse should be based on assessment of the patient’s physiological status and comorbidity.