Target condition being diagnosed
Trauma-induced coagulopathy (TIC) can be defined as an impairment of blood clotting occurring early after injury (Frith 2010). A diagnosis of TIC on admission carries a mortality rate amongst patients of up to 50%, and is often associated with increased burdens of transfusion, greater risks of organ injury and septic complications, and longer stays in critical care (Brohi 2003; MacLeod 2003; Maegele 2007). Worldwide, trauma is the leading cause of mortality and disability in adults under the age of 36 years old (Hess 2009) and 40% of all trauma deaths (in the UK) are as a result of haemorrhage (Frith 2010), whilst shock and coagulopathy upon admission have both been independently associated with massive transfusion and increased mortality (Spinella 2009). Equally in the combat setting, bleeding is the largest cause of death on the battlefield (Holcomb 2007).
Various terms such as TIC, ‘acute traumatic coagulopathy' (ATC) and ‘acute coagulopathy of trauma shock’ are used to describe these early coagulation changes. None of these terms have taken particular precedence and all are widespread within the trauma literature. For the purposes of this review we will use the term ‘trauma-induced coagulopathy’ (TIC) to describe the hypocoagulable changes that occur within the first 24 hours following injury due to a variety of different and highly interlinked causes, i.e. hypoperfusion, ongoing bleeding and consumption of clotting factors, haemodilution, acidosis, hypothermia and ATC. In the absence of embedded clinical consensus, the coagulopathic range we will be using is based on pro-thrombin time ratio (PTr) /International Normalized Ratio (INR). Anyone with a PTr/INR count of above 1.2, or above 1.5, is considered coagulopathic (further detail is given in the section on Reference standards). These figures were reached through review of the literature and discussion by the report authors, including experts in haematology and trauma medicine.
The aetiology of coagulopathy associated with trauma is not fully understood. In non-trauma situations, blood clots form through a chain of actions; first, platelets form a sticky clump (or ‘white clot’) on the blood vessel wall at the site of injury. This clot is weak, but soon a cascade of clotting proteins generates fibrin, a protein which meshes the platelets and some red blood cells together to produce a far stronger clot (or ‘red clot’). This process is called coagulation, but it can become disordered - and this happens in around a quarter of trauma patients. The underlying reasons for this disruption are still unknown, but the combination of tissue damage and shock are contributory factors, as is the presence of hypoperfusion through severe blood loss (Barts & The London 2011).
Early recognition of the nature of the clotting defect has been acknowledged as increasingly important to guide replacement of clotting factors alongside blood volume maintenance and red cell replacement. However, there are no validated methods to effectively guide therapy. This leads to both over-transfusion and under-transfusion, reduction in efficacy, increased wastage and exposure to risk. These issues can be exacerbated in disasters where timely availability of blood and component therapy is vital but severely resource constrained.
Standard blood tests - i.e. the ‘current tests’ - are performed as soon as possible on arrival to hospital (see Figure 1). There is no hierarchy of tests performed at admission, but rather a group of tests - i.e. activated partial thromboplastin time (APTT), PTr/INR and full blood count (FBC). The choice of these tests is very variable and follows local hospital practice. In some centres, especially across Europe, thromboelastography (TEG)/thromboelastometry (ROTEM) are standard tests. In the UK the use of TEG and ROTEM is increasing, but has - up until now - mainly been in the experimental and research fora.
|Figure 1. Clinical pathway for emergency department identification of trauma-induced coagulopathy.|
Traditional measures of clotting such as platelet count, bleeding time, PT and APTT have some limitations in the context of managing trauma. Amongst these,
- platelet count provides numbers of how many platelets are present but gives no information about how they function;
- bleeding time measured through the application of a cuff also assesses platelet function, but is impractical in the bleeding patient;
- fibrinogen readings allow measurement of fibrinogen levels in the blood, but this is specific to fibrinogen and does not give an overall indication of coagulopathic function;
- PT and APTT only provide a measure of time before initial thrombin generation, are performed on platelet-poor plasma, were designed to evaluate clotting factor deficiencies (not acquired coagulopathy), and are known to be poor predictors of bleeding in these circumstances (Dzik 2004).
In addition, evidence has suggested that APTT and PT are not able to provide an indication of when a patient is in a hypercoagulable state (Park 2009).
Despite these weaknesses, in practical terms PT remains the current standard of practice.
Newer global haemostatic function technologies such as TEG and ROTEM enable ‘point of care’ measurement, using whole blood samples, of the initiation and progress of coagulation as well as final clot strength and lysis and the dynamics of clot formation. For the purposes of this study, TEG and ROTEM are being envisaged as a replacement test for traditional clotting tests. Both tests are currently used in routine clinical practice as both a diagnostic tool and to guide treatment.
Both TEG (trademark of Haemonetics Corporation, USA: www.haemonetics.com) and ROTEM (trademark of TEM International GmbH: www.rotem.de) work by measuring shear elastic modulus during clot formation and subsequent fibrinolysis. In both tests the whole blood sample is placed in a sample cup or ‘cuvette’ into which a cylindrical pin is immersed, leaving a small gap between the bottom of the pin and the base of the cuvette. The subsequent movement of the blood (designed to emulate sluggish circulation) is where the main difference lies between the two methods. When the sample blood begins to clot (i.e. fibrin begins to form, measured as clotting time or ‘time to clot’), the movement of the pin becomes restricted with increasing firmness and this kinetic is transferred to the machinery of the TEG or ROTEM unit.
The next stage of the coagulation process is platelet aggregation, where platelets build in the blood vessel walls at the site of injury, and fibrin binds to the platelets which then forms a stronger clot, measured in both TEG and ROTEM in shear elasticity units as ‘clot stability’. Eventually lysis – or clot break down – is measured, and a graphic is produced which represents haemostatic performance at all these stages: clotting time, clot formation, clot stability and lysis (see Appendix 1).
Whilst both TEG and ROTEM measure clotting time, clot formation, clot strengthening, amplitude of clot, maximum strength of clot, and clot lysis, they use slightly different terms or lettering to designate these features. We draw out these differences in detail in Appendix 2 and Table 1.
This systematic review will form part of the evidence for a wider research programme which aims to improve outcomes for severely injured bleeding trauma patients, designed around the principle that early identification of patients who present with a trauma-induced coagulopathy and effective, directed therapy will lead to improved outcomes, reduced complications, rationalised transfusions, reduced costs to the National Health Service (NHS) and a reduced logistical burden to the military and humanitarian organisations (such as the Red Cross) within austere combat environments. However, these tests require proper evaluation. Test accuracy studies have been conducted amongst evaluations thus far and should be systematically reviewed.
To complement this review we also propose to carry out a systematic review of prognosis studies linking measures from TEG/ROTEM with patient outcome. This cannot be included in The Cochrane Library at present.
To determine the diagnostic accuracy of global tests of haemostatic function (thromboelastography (TEG) and thromboelastometry (ROTEM)) in adult trauma patients with bleeding.
Criteria for considering studies for this review
Types of studies
We will include cross-sectional studies investigating the diagnostic test accuracy of TEG or ROTEM in patients with clinically suspected trauma-induced coagulopathy. We will expand the inclusion criteria to include case control studies if the number of sources retrieved is insufficient for a valid systematic review and possible meta-analysis. Pragmatically, we have set this level at less than 100 patients in total in the included studies.
We will include adult trauma patients with clinically suspected trauma-induced coagulopathy. We will include studies in both military and civilian settings.
Two global tests of haemostatic function will be used; TEG (thromboelastography - trademark of the Haemonetics Corporation, USA) and ROTEM (rotational thromboelastometry - trademark of TEM International GmbH). Thresholds are indicated in Table 1.
The target condition will be trauma-induced coagulopathy defined by standard clotting times of pro-thrombin time ratio (PTr) and International Normalized Ratio (INR).
In the absence of embedded clinical consensus, the coagulopathic range we will be using is based on PTr/INR, with the lower limit of the range being a PTr/INR reading of 1.2 or greater (Frith 2010), and the upper limit of 1.5 or greater (Stainsby 2006). There is no upper limit to the range: anyone with a PTr/INR count of above 1.2, or above 1.5, is considered coagulopathic. These figures were reached through discussion by the report authors, including experts in haematology and trauma medicine. We will exclude studies using different cut-offs (i.e. not a PTr/INR reading of 1.2 or greater, or a PTr/INR reading of 1.5 or greater).
PTr differs from INR, although the final numbers may be the same. The PTr calculated varies depending on local thresholds and separate batches of different manufacturer’s reagent involved in conducting the prothrombin time test. In an effort to standardise this measurement, the INR is calculated as the ratio of a patient’s prothrombin time compared to a mean normal PTr (calculated by determining the mean of 30 or more patients who are representative of the local hospital population), computed to the power of the International Sensitivity Index (ISI), which is itself calculated by the manufacturer to give an indication of how each batch of tissue factor corresponds to an international reference. The equation for calculation is at Figure 2.
|Figure 2. INR calculation.|
Search methods for identification of studies
We will use a sensitive search strategy to identify literature relating to the index tests for this review. This strategy will not be limited by language but will be limited by date to ‘1970 to current’ and to ‘human only’ populations.
We will search the following bibliographic resources:
- The Cochrane Library,
- British Nursing Index,
- Centre for Reviews and Dissemination databases,
- Conference Proceedings Citation Index - Science (CPCI-S),
- Conference Proceedings Citation Index - Social Science & Humanities (CPCI-SSH),
- MEDLINE in Process,
- Science Citation Index Expanded (SCI-EXPANDED),
- Social Sciences Citation Index (SSCI),
- the Transfusion Evidence Library.
We will search the following trial registers:
- Current Controlled Trials,
- Clinical Trials.Gov,
- the WHO International Trials Registry Platform via http://www.who.int/ictrp/en/
We will search the following websites:
- Aggressive Research Intelligence Facility (ARIF) via http://tinyurl.com/3u9tevp,
- Cochrane Diagnostic Test Accuracy Working Group via http://srdta.cochrane.org/,
- MEDION database via http://www.mediondatabase.nl,
- Haemonetics Corporation http://www.haemonetics.com/en.aspx,
- TEM Innovations GmbH http://www.rotem.de/site/index.php.
Searching other resources
We will conduct citation chasing on all studies included for full text screening. We will attempt to contact authors for any additional or supporting information.
For further details on the search, including the search strategy, please see Appendix 3.
Data collection and analysis
Selection of studies
CC will run the searches, collate the results and remove duplicates before transferring them to HH and CH for screening. All sources will be managed using Review Manager software version 5.2 (RevMan 2012). The inclusion criteria will be based on the Criteria for considering studies for this review. Decisions on inclusion/exclusion of studies will be made independently by two authors (HH and CH) using piloted criteria. Disagreements will be resolved with reference to a third experienced author (SS and PP).
Data extraction and management
We will extract the following data (where available) into a bespoke data extraction table:
- Author, year of study, year of publication, journal reference;
- Study design and timing of data collection (prospective/retrospective);
- Study population and participant characteristics (age, sex, setting – e.g. hospital, region, country, other details given)
- Trauma type:
- traumatic brain injury (TBI)/no TBI,
- Site of injury;
- Trauma severity as measured by:
- Injury Severity Score (ISS),
- New ISS (NISS), and
- Trauma ISS (TRISS);
- Length of time from injury to admission;
- % receiving massive transfusion (defined as ≥ 10 units packed red blood cells (PRBC) in 24 hours, or the replacement of an equivalent amount of blood to an entire circulating blood volume of the patient within 24 hours (Doran 2010));
- Mean and interquartile range (IQR) number of units of blood and blood components (fresh frozen plasma (FFP), platelets and cryoprecipitate) transfused;
- Temperature (% hypothermic at 33 degrees or below), systolic blood pressure (% shocked), and base deficit (% with hypoperfusion) on admission;
- Duration of bleed at point of testing;
- Reference test used (PTr/INR) and any other measures taken (of, for example, PT, APTT, fibrinogen level, platelet count, fibrinogen degradation products);
- Index test used (TEG/ROTEM) and version of device;
- Any details about device reliability;
- When tests were carried out in treatment phase (i.e. pre/post transfusion, timings);
- Data from the 2x2 table will be extracted where presented, i.e. true positives, false positives, true negatives and false negatives;
- QUADAS-2 items (see Appendix 3).
Where available, we will record variability between operators and assay conditions. Particular care is likely to be required on many of these items (index test and reference standard) because of lack of standardisation. Two authors (HH and CH) will pilot the extraction form using two primary diagnostic studies. A third author (NC) will resolve disagreements. The form will be accompanied by a briefing document explaining how it should be used. Data will be extracted by one author (HH) and checked by a second (CH), with a third author (NC) providing moderation as required.
Assessment of methodological quality
We will carry out quality assessment using a checklist approach to assess the quality of primary studies based on the QUADAS-2 instrument (see Appendix 2) in line with advice given in Reitsma 2009. We will independently score each item as ‘Yes’, ‘No’ or ‘Unclear’ as recommended by the Cochrane Handbook for Diagnostic Test Accuracy Reviews (http://srdta.cochrane.org/). A categorisation of 'unclear' will generally be considered a marker of poor quality, so care will be taken to account for the possibility that failing to report an item was reasonable given the circumstances in which the study was conducted. We will present results narratively in the text, and in an appropriate graphic representation of quality assessment (such as a table).
Statistical analysis and data synthesis
We will consider the accuracy of TEG and ROTEM compared to the reference standard as detailed above, considering > 1.2 and > 1.5 separately. We will not formally compare TEG and ROTEM although we will explore test type as a potential explanation for any heterogeneity. Results will be the components of the 2x2 table, sensitivity and specificity and their 95% confidence interval (CI). These will be tabulated and presented graphically (forest plots and receiver operating characteristic (ROC) space). Our initial approach to analysis is likely to be qualitative, with conclusions based on patterns of results. Quantitative meta-analysis may be appropriate where the quantity and nature of the included studies permit. If meta-analysis is possible, our approach will be to calculate a summary ROC (sROC) curve using an hierarchical summary ROC (HSROC) model. We will also consider using a bivariate model depending on the data, but a priori uncertainty about thresholds, and the likelihood of implicit thresholds, suggest the HSROC model may be slightly preferable in the first instance. We will generate a summary of results table. If feasible and appropriate, translation of any summary results into natural frequencies and other metrics such as predictive values will be considered to facilitate improved understanding to readers.
We will tabulate and comment on the number of uninterpretable results. We will carry out analysis and presentation of results in line with advice in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy.
We will scrutinise carefully all the included studies for any further investigation of discrepant results between the index test and reference standards (False Positives (FP) and False Negatives (FN)), ideally based on independent clinical review of all available findings, with the purpose of considering whether it was global haemostatic function or traditional measures of clotting which was giving the better indication of true disease state. Any results will be tabulated and summarised narratively.
Investigations of heterogeneity
If there is a sufficient number of studies we investigate heterogeneity. With respect to test accuracy results, we will assume that important heterogeneity beyond that accounted for by chance will be present and will need to be investigated. Our approach will be to perform subgroup analyses using the analytical framework detailed below, using HSROC models.
The provisional framework for investigating heterogeneity will include:
- Type of global measure of haemostatic function (TEG/ROTEM)
- Time blood sample taken relative to trauma ( ≤ 1h/ >1h)
- Nature of reference standard (INR/PTr of > 1.2; INR/PTr of > 1.5)
- Prevalence of TIC (excluding case-control studies if these are included)
- Participant type, especially severity of trauma and mechanism of injury (blunt/penetrating)
- Setting (military or civilian)
- Whether trauma was associated with massive transfusion (yes or mixed/no)
- Case-control study design (if these are included)
- Other aspects of study quality, particularly blinding of the index test and reference standard.
We have no specific plans to investigate heterogeneity of the data concerning uninterpretables or conduct further investigation of discrepant results.
In the unlikely event that heterogeneity is not present and the effect of important covariates has not already been analysed, we will investigate the robustness of any summary estimates of test accuracy to the aspects of study quality indicated in the framework for investigating heterogeneity above.
Assessment of reporting bias
We will not assess reporting bias because its impact in test accuracy is unclear and the tools for investigating it are in the early stages of development.
Thanks to Roger Luddington for the use of his diagram of the thromboelastic trace. Thanks also to Jenny Lowe for providing administrative support.
Appendix 1. Results interpretation of the thromboelastic trace
See Figure 3.
Appendix 2. TEG and ROTEM equivalent methods
In TEG, clotting time is measured as R (reaction time), N (whole blood) (normal values for kaolin activated TEG in whole blood) and N (Cit, kaolin) (normal values for kaolin activated TEG in citrated and recalcified blood). In ROTEM, clotting time is measured as CT (clotting time), N (Cit, INTEM) (normal values for contact) and N (Cit, EXTEM) (normal values for tissue factor).
Clot formation is measured in TEG as K (kinetics) and - as above - N (whole blood) and N (Cit, kaolin). In ROTEM, CFT (clot formation time) is measured as before as N (Cit, INTEM) and N (Cit, EXTEM).
Clot strengthening is measured in both TEG and ROTEM as the alpha angle - in TEG this is defined as the slope between R and K and in ROTEM this is the slope of tangent at 2 mm amplitude. Again, both tests give the alpha angle as N (whole blood) and N (Cit, kaolin) for TEG and N (Cit, INTEM) and N (Cit, EXTEM) for ROTEM.
Amplitude of clot
Amplitude of clot (or ‘A’) is given at set times in both tests.
Maximum clot firmness
The maximum strength of the clot is measured in TEG as maximum amplitude (MA) and in ROTEM as maximum clot firmness (MCF), and both tests give this measurement both as N (whole blood) and N (Cit, kaolin) for TEG and N (Cit, INTEM) and N (Cit, EXTEM) for ROTEM - although ROTEM also reports tissue factor plus platelet inhibitor cytochalasin D (Cit, FIBTEM).
Both tests give readings for clot lysis as CL in TEG (e.g. CL30, CL60) and LY in ROTEM (e.g. LY30, LY60).
Appendix 3. Search strategy
Despite the work by Vincent 2003, who found high rates of inclusion using a bespoke diagnostic test accuracy (DTA) filter, there remain noted difficulties in searching for and locating DTA studies (Vincent 2003; Doust 2005; Leeflang 2006; Bayliss 2008; de Vet 2008).
With these points in mind, this annexe details our search approaches in this review.
Whiting 2011 found that a search approach which used clusters of 'condition' and 'index test' search terms offered the best sensitivity to a DTA search (Whiting 2011): a view shared by the latest edition of the Cochrane DTA Handbook (de Vet 2008).
In reference to the above, our search strategy uses only the index terms, and will be run without methodological filters, with a view to conducting a highly sensitive search. The search strategy has been peer reviewed by the review authors to ensure that clinical concepts have been addressed.
Date parameters: 1946 to November Week 1 2012
Date searched: Thursday, November 8th 2012
Strategy checked by: HH
File Name: Medline3124.txt
As suggested by the Cochrane Handbook, and by others, the search will not be limited by language, in order to avoid a potential language bias (Moher 2000; de Vet 2008). The search will be limited to ‘human only’ populations and by date, ‘1970 to current’.
We have chosen the following resources to search for this review as they reflect the most likely places to find DTA studies.
This list has been cross-checked against other DTA reviews, and includes literature searching to identify any additional resources which might be used. Bayliss 2008 and Fraser 2006 were of particular use here.
- British Nursing Index (BNI) via ProQuest
- Centre for Reviews and Dissemination (CRD) through http://www.crd.york.ac.uk/crdweb/SearchPage.asp
- CINAHL via EBSCO
- The Cochrane Library through http://www.thecochranelibrary.com
- Conference Proceedings Citation Index- Science (CPCI-S) via ISI*
- Conference Proceedings Citation Index- Social Science & Humanities (CPCI-SSH) via ISI*
- EMBASE via OVID
- HMIC via OVID
- MEDLINE in Process via OVID
- MEDLINE via OVID
- PsycINFO via OVID
- Science Citation Index Expanded (SCI-EXPANDED) via ISI*
- Social Sciences Citation Index (SSCI) via ISI*
- Transfusion Evidence Library via www.transfusionevidencelibrary.com
- Current Controlled Trials via http://www.controlled-trials.com/
* these resources will be searched through the Web of Science interface hosted by ISI.
Bayliss 2008 reviewed the following internet resources for locating DTA systematic reviews. This review also included DARE and HTA, which will be searched as part of the approach detailed above (Bayliss 2008).
We will include an internet search on Google, the manufacturer websites for the index tests relevant to this review, and the Cochrane DTA group website. Given the nature of our search, and the specific nature of what we are looking for, generic websites would not seem to be the best tools in locating diagnostic reviews.
- Aggressive Research Intelligence Facility (ARIF) via http://tinyurl.com/3u9tevp
- Diagnostic Test Accuracy Working Group (Cochrane) via http://srdta.cochrane.org/
- MEDION database via http://www.mediondatabase.nl/
- Haemonetics Corporation http://www.haemonetics.com/en.aspx
- TEM Innovations GmbH http://www.rotem.de/site/index.php
We will use a combined approach of database searching and supplementary techniques.
Doust 2005 highlights the importance of snowballing in DTA reviews to maximize sensitivity, and the approach identified by Greenhalgh 2005 improved identification of includable studies (Doust 2005; Greenhalgh 2005). Snowballing will be especially important to this review in view of findings by Whiting 2011 that, despite not using a DTA filter, a condition and index search in MEDLINE also missed potential studies (Whiting 2011).
Accordingly, we will employ 'citation chasing' for all included studies identified by our searching. Science Citation Index/Social Science Citation Index will be used for forward citation chasing and the bibliography of each included paper will be screened for retrieval by HH and CH.
We will attempt to contact authors of included studies.
We will activate citation alerts on included studies to keep abreast of any developments whilst the review is in process.
We will take a view on running update searches, whilst de-duplicating any citation alerts that have been identified, if/when the technology is updated. The review syntax will be checked for any changes to controlled syntax at this time. These searches will run from the date of the main search and use the same resources as above.
Any includable, diagnostic test accuracy studies located will be forwarded to the Cochrane Diagnostic Test Accuracy Methods Group Specialised Register.
Appendix 4. QUADAS-2 quality assessment
(from http://www.bris.ac.uk/quadas/quadas-2 18/05/2012)
|Figure 4. QUADAS-2 page 1|
|Figure 5. QUADAS-2 page 2|
|Figure 6. QUADAS-2 page 3.|
When will the index test lead to ‘concerns regarding applicability’?
When there is concern that it is being misapplied, used in a situation different from that stated in the research question, or interpreted in a way that is out of the bounds of the research question.
How will we define whether the reference standard is ‘likely to correctly classify the target condition’ or not?
If there is evidence of misapplication, e.g. being used in the wrong environment, or generating noticeably different results than those expected without reasonable explanation.
What is the ‘appropriate interval’ between index and reference tests?
This would be a judgement based upon the professional opinion of our clinical experts.
Contributions of authors
Writing the first draft of the protocol - Harriet Hunt
Methodological advice - Chris Hyde, Pablo Perel
Content advice - all authors
Editing protocol - all authors
Declarations of interest
Sources of support
- Dutch Cochrane Centre, Netherlands.Training
- Cochrane Diagnostic Test Accuracy Working Group, UK.Technical support
- NHS Blood and Transplant through an NIHR Programme Grant for Applied Research, UK.Project funding
- NIHR CLAHRC, UK.We acknowledge support from the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health in England.