Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy in adult trauma patients with bleeding

Current tests

Traditional measures of clotting (such as platelet count, bleeding time, prothrombin time (PT and APTT) have some limitations in the context of managing trauma. Amongst these,

• platelet count provides data about 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 and is thus rarely used;

• fibrinogen tests measure the functional ability of the available fibrinogen, but this test therefore measures only one part of the coagulation system and does not give an overall indication of haemostatic potential; and

• PT and APTT only provide a measure of time before initial thrombin generation, they 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, although it measures a late change in haemostasis and is not a sensitive measure (Brohi 2013).

Index tests

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 envisaged as a replacement test for traditional coagulation tests.  Both tests are currently used in routine clinical practice as both a diagnostic tool and to guide treatment.

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. Fibrin binds to the platelets, which then form a stronger clot, measured by both TEG and ROTEM in shear elasticity units as ‘clot stability’. Eventually lysis – or clot break down – is measured, and a graphic is produced that represents haemostatic performance at all these stages: clotting time, clot formation, clot stability and lysis (see detailed description in 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. These differences are detailed in Table 1.

Rationale

This systematic review forms part of the evidence for a wider NIHR-funded research programme ('Traumatic Coagulopathy & Massive Transfusion - Improving Outcomes & Saving Blood' RP-PG-0407-10036), which aims to improve outcomes for severely injured bleeding trauma patients. This programme is designed around the principle that early identification of patients who present with a TIC and effective, directed therapy will lead to improved outcomes, reduced complications and rationalised transfusions. In addition, these initiatives will result in reduced costs to the National Health Service (NHS), and a reduced logistical burden to military and humanitarian organisations (such as the Red Cross) within austere combat environments. These tests, however, require proper evaluation. Test accuracy studies have been conducted amongst evaluations thus far and should be systematically reviewed.

To complement this review we are also conducting a systematic review of prognosis studies linking measures from TEG/ROTEM with patient outcome (Hunt 2014).

Types of studies

We included all cross-sectional studies investigating the diagnostic test accuracy of TEG or ROTEM in patients with clinically suspected TIC. We would have included case-control studies due to the small number of cross-sectional studies retrieved, but we found none.

Participants

We included all studies involving adult trauma patients with clinically suspected TIC in both military and civilian settings.

Index tests

This review focused on two global tests of haemostatic function; TEG (thromboelastography - trademark of the Haemonetics Corporation, USA) and ROTEM (rotational thromboelastometry - trademark of TEM International GmbH). Thresholds are indicated in Table 1.

Target conditions

The target condition was TIC defined by standard clotting times of prothrombin time ratio (PTr) and international normalized ratio (INR).

Reference standards

In the absence of embedded clinical consensus, we used a coagulopathic range based on PTr/INR; the lower limit of the coagulopathic range being a PTr/INR reading of 1.2 or greater (Frith 2010), and the higher limit of the coagulopathic range being a PTr/INR reading of 1.5 or greater (Stainsby 2006). There is no upper threshold: 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.

PTr differs from INR, although the final numbers may be the same. The PTr calculated varies according to local thresholds and separate batches of different manufacturers' 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 PTr 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 shown in Figure 2.

Electronic searches

We searched the following bibliographic sources:

1. The Cochrane Library (all databases; 4 March 2013);

2. Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 4 March 2013);

3. Embase Classic and Embase (OvidSP) (1947 to 4 March 2013);

4. PsycINFO (OvidSP) (1806 to February Week 4 2013);

5. CINAHL (EBSCO Host) (1981 to 4 March 2013);

6. ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to March 2013);

7. ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to March 2013);

8. Prospero (2011 to March 2013);

9. LILACS (4 March 2013);

10. BIOSIS (1969 to 4 March 2013);

11. British Nursing Index (Proquest) (1994 to 4 March 2013);

12. HMIC (4 March 2013);

13. Transfusion Evidence Library (1980 to 4 March 2013);

14. Centre for Reviews and Dissemination (CRD) (4 March 2013).

The Cochrane Injuries Group Specialised Register was not searched for this review as it does not contain diagnostic test accuracy studies.

We searched the following trials registers:

• Current Controlled Trials (http://www.controlled-trials.com/) (accessed 4 March 2013);

• Clinical Trials.Gov (www.clinicaltrials.gov) (accessed 4 March 2013);

• The World Health Organization (WHO) International Trials Registry Platform (http://www.who.int/ictrp/en/) (accessed 4 March 2013).

We searched the following websites (15/03/2012):

• Aggressive Research Intelligence Facility (ARIF) (http://tinyurl.com/3u9tevp);

• C-EBLM (ww.ifcc.org);

• Cochrane Diagnostic Test Accuracy Working Group (http://srdta.cochrane.org/);

• MEDION database (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 conducted citation chasing on all studies included for full text screening. Where necessary we attempted to contact authors for any additional or supporting information.

For further details on the search, including the search strategy, please see Appendix 2.

Selection of studies

Searches and deduplication were performed by the information specialist (CC) before transferring the results to HH, CH and ZZ for screening. All sources were managed using Review Manager software version 5.2 (RevMan 2012). The inclusion criteria were based on the Criteria for considering studies for this review. Three authors (HH, CH and ZZ) made decisions independently on the inclusion/exclusion of studies, using piloted criteria. Any disagreements were resolved with reference to a fourth experienced author, although in the event this was not necessary.

Data extraction and management

The reviewer extracted 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:

  • blunt/penetrating;

  • 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.

• Percentage receiving massive transfusion (defined as ≥ 10 units packed red blood cells 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, 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 2 x 2 table will be extracted where presented, i.e. true positives, false positives, true negatives and false negatives.

• QUADAS-2 items (see Table 2).

  Table 2. Quality appraisal (using QUADAS-2)

  Abbreviations CA5: clot amplitude at 5 minutes CA10: clot amplitude at 10 minutes col: column H0: hospital/ emergency room admission p: page para: paragraph PT: prothrombin time T1: triaged casualty group 1 - immediate or urgent clinical problems requiring full trauma team activation (as T2 below). T2: triaged casualty group 2 - immediate or urgent clinical problems requiring full trauma team activation (as T1 above).
  QUADAS-2 quality appraisal	Included studies
  	Davenport 2011a	Rugeri 2007	Woolley 2012
  Summary patient domain
  Was a consecutive or random sample of patients enrolled?	Yes Near consecutive, bar exclusions	Yes Clear statement that patients were consecutive. p 290 col 1 line 10	Unclear Lack of clarity regarding the proportion of T1 or T2 casualties over the study period for the whole population, and also how the sub-population that contributed to the accuracy study were chosen
  Was case control study design avoided?	Yes	Yes Could be confusion about determination of normal values for ROTEM from healthy volunteers	Yes Could be confusion about the role of the samples taken from the 50 uninjured control subjects
  Did the study avoid inappropriate exclusions?	Yes Several exclusion criteria, these all seem reasonable	Yes Minimal exclusions; 2 out of 90	Yes Exclusions not mentioned
  Risk of bias overall?	No	No
  Is there a concern that the included patients do not match the review question?	Concern: low	Concern: low	Concern: low
  Index test domain
  Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear The relative objectivity of both the ROTEM measure and the reference standard was judged to reduce the importance of this issue	Yes Clear statement that clinicians were not informed of ROTEM results p 291 col 1 line 3	Unclear No clear statement. The relative objectivity of both the ROTEM measure and the reference standard was judged to reduce the importance of this issue
  If a threshold was used was it pre-specified?	No Clear statement that choice of ROTEM measure and threshold were chosen because "there was good separation of normal and ATC curves at this time point" p 2655 col 3 para 6	No Thresholds were derived from a normal range in healthy subjects measured in the study. This is less of a problem than failure to pre-specify the exact ROTEM measure. This choice seems to have been largely made on the basis of performance	Unclear Some pre-statement for preference for measure as CA5 and CA10. Reasons why this was chosen over other possible early values such as clotting time, clot formation time or alpha angle were not provided. The threshold for CA5 and CA10 was not pre-specified, but appeared to be derived from independently measured normal values (Table 1 p 595)
  Risk of bias overall: could the conduct or interpretation of the index test have introduced bias?	Yes The failure to pre-specify was considered to represent a major threat to validity	Yes Although blind interpretation is a positive feature that was not present in other studies, the failure to pre-specify was considered to represent a major threat to validity	Unclear As for the other included studies there is a risk of bias associated with failure to pre-specify measure and threshold, but this was thought to be less than in the other two included studies, and was hence marked Risk: unclear rather than Risk: yes
  Is there a concern that the index test, its conduct or interpretation differ from the review question?	Concern: unclear There is clarity about the test apparatus. There is less clarity about whether the exact measure and threshold are those that would be used in standard practice, both because these were not pre-specified and because standard practice is not established	Concern: high There is clarity about the test apparatus. There is less clarity about whether the exact measure and threshold are those that would be used in standard practice, both because these were not pre-specified and because standard practice is not established	Concern: unclear There is clarity about the test apparatus. There is less clarity about whether the exact measure and threshold are those that would be used in standard practice, both because these were not pre-specified and because standard practice is not established
  Reference standard domain
  Is the reference standard likely to correctly classify the target condition?	No There are concerns that prolonged prothrombin time may not capture all cases of coagulopathy, even though it is the most established of the measures of coagulopathy	No There are concerns that prolonged prothrombin time may not capture all cases of coagulopathy, even though it is the most established of the measures of coagulopathy	No There are concerns that prolonged prothrombin time may not capture all cases of coagulopathy, even though it is the most established of the measures of coagulopathy
  Were the reference standard test results interpreted without knowledge of the results of the index test?	Unclear No clear statement. The relative objectivity of both the ROTEM measure and the reference standard was judged to reduce the importance of this issue	Yes Clear statement that clinicians were not informed of ROTEM results p 291 col 1 line 3	Unclear No clear statement. The relative objectivity of both the ROTEM measure and the reference standard was judged to reduce the importance of this issue
  Risk of bias overall?	Yes Reassurance about this possibility could have been provided if discrepant samples had been examined. This was not done	Yes Reassurance about his possibility could have been provided if discrepant samples had been examined. This was not done	Yes Reassurance about his possibility could have been provided if discrepant samples had been examined. This was not done
  Is there a concern that the target condition as defined by the reference standard does not match the review question?	Concern: low The reference standard matches the review question. There are however noted concerns about the risk of bias arising from imperfection in the reference standard, particularly where careful analysis of the discrepant samples (especially false positives) was not carried out	Concern: low The reference standard matches the review question. There are however noted concerns about the risk of bias arising from imperfection in the reference standard, particularly where careful analysis of the discrepant samples (especially false positives) was not carried out	Concern: low The reference standard matches the review question. There are however noted concerns about the risk of bias arising from imperfection in the reference standard, particularly where careful analysis of the discrepant samples (especially false positives) was not carried out
  Flow and timing domain
  Was there an appropriate interval between index test and reference standard?	Yes Clear evidence that ROTEM and PT done on same sample.	Yes Reasonable evidence that ROTEM and PT done on same sample	Yes Reasonable evidence that ROTEM and PT done on same sample
  Did all patients receive a reference standard?	Yes	Yes	Yes
  Did all patients receive the same reference standard?	Yes	Yes	Yes
  Were all patients included in the analysis?	Yes	Yes	Yes
  Risk of bias overall?	No	No	No
  Other issues	-	Multiple samples seem to have been taken from each patient, but seems reasonably clear that only the samples at admission (H0) were used in the analysis	Lack of clarity about whether some samples came from the same patient

We recorded variability between operators and assay conditions where available, although this was often not reported in primary studies. Particular care was required in recording many of these items (particularly index test and reference standard) due lack of standardisation. Two authors (HH and CH) piloted the extraction form using two primary diagnostic studies, with a third author (NC) in place to resolve disagreements. The data extraction form was accompanied by a briefing document explaining how it should be used. Data were 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 carried out quality assessment using a checklist approach to assess the quality of primary studies, on the QUADAS-2 instrument and in line with advice given in Reitsma 2009. Independently, we scored each item as ‘yes’, ‘no’ or ‘unclear’ as recommended by the Cochrane Handbook for Diagnostic Test Accuracy Reviews (Deeks 2010). A categorisation of 'unclear' is generally considered to be a marker of poor quality, so we took care to account for the possibility that failing to report an item was reasonable given the circumstances in which the study was conducted. Results are presented in the Methodological quality of included studies with further detail in Table 2.

Statistical analysis and data synthesis

We used Review Manager software (version 5.2) to conduct our analysis. We analysed the accuracy of TEG and ROTEM compared to the reference standard as detailed in the review protocol (Hunt 2013), with the intention to consider values greater than 1.2 and greater than 1.5 separately - although insufficient data were available to render this necessary. Updates may be able to incorporate this discrimination if sufficient data are available. Our a priori commitment to exploring the TEG and ROTEM test type as a potential source of heterogeneity was unnecessary, as all of the studies included used ROTEM as their index test. However, regardless of results it should be noted that ROTEM and TEG are not interchangeable. Whilst the underlying mechanism of measuring shear elastic modulus is similar, the tests use different clotting activators, different methodology and require different treatment algorithms (Hagemo 2013b; Sankarankutty 2012). Therefore, TEG and ROTEM would not have been formally compared.

Results are test accuracy data which form the components of the 2 x 2 table, sensitivity and specificity and their 95% confidence interval (CI). These results have been tabulated and are presented according to the different ROTEM sub-measures used in Data table 1, Data table 2 and Data table 3. These data are also presented graphically (in forest plots Figure 3, and summary receiver operating characteristic (ROC) plots Figure 4). A narrative analysis was conducted with conclusions based on patterns of results. Quantitative meta-analysis was not appropriate as there were too few studies to estimate the parameters of meta-analytic models.

Investigations of heterogeneity

There was an insufficient number of studies included in the review for us to conduct formal investigations of heterogeneity. The approach specified in the protocol is recorded in Appendix 3, and will be used, should the review be updated in the future.

Sensitivity analyses

As no meta-analysis was conducted, no sensitivity analysis was required. Should the review be updated in future, we will follow guidance in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Macaskill 2010).

Assessment of reporting bias

We did 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.

Clotting time

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

Clot formation is the time from the start of clot formation until the clot firmness (or strength) reaches an arbitrary pre-defined value (in both ROTEM and TEG this is 20 mm firmness). 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).

Alpha angle

This denotes the angle of the curve during initial clot formation and is a measure of the rapidity of fibrin polymerisation. The alpha angle in TEG is defined as the slope between R and K and in ROTEM 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/clot amplitude

Amplitude of clot ('CA' 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). 

Clot lysis

Both tests give readings for clot lysis (CL in TEG, e.g. CL30, CL60; and LY in ROTEM, e.g. LY30, LY60).

Literature searching

A line in the search strategy was altered between publication of the protocol and the searches being run. A truncation marker was moved to increase the sensitivity of the search, in order to account for thromboelastometry if it was expressed as thrombelasto-metry/-graphy.

Previous line: (thromboelastom$ or thrombelastom$ or (thromb$ adj2 elastom$) or (rotational adj2 thrombelast) or ROTEM or tem international).mp.

New line: (thromboelasto$ or thrombelasto$ or (thromb$ adj2 elastom$) or (rotational adj2 thrombelast) or ROTEM or tem international).mp.

All strategies were checked by CC and HH.

Websearching

• Aggressive Research Intelligence Facility (ARIF) via http://tinyurl.com/3u9tevp

• C-EBLM

• Diagnostic Test Accuracy Working Group (Cochrane) via http://srdta.cochrane.org/

• Google

• 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

Fowards Citation Chasing

Methods

Criteria for considering studies for this review

Types of studies

Cross-sectional studies investigating the diagnostic test accuracy of TEG or ROTEM in patients with clinically suspected TIC will be eligible. 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.

Participants

All studies including adult trauma patients with clinically suspected TIC will be eligible. Studies in both military and civilian settings will be included.

Index tests

Two global tests of haemostatic function will be used, TEG (thromboelastography - whose name is a trademark of the Haemoscope Corporation, USA http://www.haemoscope.com/) and ROTEM (rotational thromboelastometry - trademark of TEM International GmbH http://www.rotem.de/site/index.php). Normal thresholds are indicated in Table 1.

Target conditions

The target condition will be TIC defined by standard clotting times of PTr and INR.

Reference standards

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), with the lower limit of the range 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.

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 (PT) 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 PT (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 in Figure 1.

Search methods for identification of studies

A sensitive search strategy will be used to identify literature relating to the index test for this review. This strategy will not be limited by language but will be limited by date to 1990-current and to human only populations. The test technology has been established since 1948, but the date limit has been set to 1990 in order to maximise study quality and capture the more recent versions of the technology in current use.

Electronic searches

The following bibliographic resources will be searched: British Nursing Index, Biosis, Centre for Reviews and Dissemination databases, CINAHL, The Cochrane Library, Conference Proceedings Citation Index- Science (CPCI-S), Conference Proceedings Citation Index- Social Science & Humanities (CPCI-SSH), EMBASE, HMIC, MEDLINE in Process, MEDLINE, PsycINFO, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), LILACS and the Transfusion Evidence Library.

The following trials registers will be hand-searched: Current Controlled Trials, Clinical Trials.Gov and the WHO International Trials Registry Platform via http://www.who.int/ictrp/en/

The following websites will be searched:

• Aggressive Research Intelligence Facility (ARIF) via http://tinyurl.com/3u9tevp

• C-EBLM

• Diagnostic Test Accuracy Working Group (Cochrane) via http://srdta.cochrane.org/

• Google

• MEDION database via http://www.mediondatabase.nl/

• http://srdta.cochrane.org/

• Haemonetics Corporation http://www.haemoscope.com/

• TEM Innovations GmbH http://www.rotem.de/site/index.php

Searching other resources

Citation chasing will be conducted on all studies included on full text. Attempts will be made to conduct authors for any additional or supporting information. For further details on the search, including the strategy, please see Appendix 2.

Data collection and analysis

Selection of studies

All sources will be managed using Review Manager 5 software. The inclusion criteria will be based on the “Criteria for considering the studies for this review” detailed above. Decisions on inclusion/exclusion of studies will be made independently by two reviewers (HH and CH) using piloted criteria. Disagreements will be resolved with reference to a third experienced reviewer (SS and PP). The systematic review of diagnostic test accuracy of coagulation tests will target prospective cohort studies measuring accuracy relative to a reference standard and rigorous evaluation of time taken to obtain coagulation results.

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 and severity (Injury Severity Score – ISS).

• Patient history.

• Pre-admission treatment, especially blood transfusion and/or additives.

• Blood temperature and duration of bleed at point of testing.

• Reference test used (PTr/INR) and any other measures taken (e.g. 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 2 x 2 table will be extracted where presented, i.e. true positives, false positives, true negatives and false negatives.

• QUADAS-2 items (see Table 2).

Where available, variability between operators and assay conditions will be recorded. Particular care is likely to be required on many of these items (index test and reference standard) because of lack of standardisation. The abstraction form will be piloted by two authors (HH and CH) 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 abstracted by one reviewer (HH) and checked by a second (CH), with a third author (NC) providing moderation as required.

Assessment of methodological quality

Quality assessment will be carried out using a checklist approach to assess the quality of primary studies based on the QUADAS-2 instrument (see Table 2) in line with advice given in Chapter 9, ‘Assessing Methodological Quality’ in the Cochrane Handbook for Diagnostic Test Accuracy Reviews (Reitsma 2009). We will independently score each item as ‘Yes’, ‘No’ or ‘Unclear’, and will omit three reporting items from the QUADAS-2 list, addressing the description of the index test, reference standard and selection criteria, as recommended by the Cochrane Handbook for Diagnostic Test Accuracy (Deeks 2010). 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. Results will be presented 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. Results will be the components of the 2 x 2 table, sensitivity and specificity and their 95% confidence intervals (CI). These will be tabulated and presented graphically (forest plots and receiver operating characteristic (ROC) space). The 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, the approach will be to calculate a summary receiver operating characteristic (SROC) curve using a hierarchical SROC (HSROC) model. Use of a bivariate model will also be considered depending on the data (Reitsma 2009), but a priori uncertainty about thresholds and the likelihood of implicit thresholds suggests the HSROC model may be slightly preferable in the first instance. A summary of results table will be generated. 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.

The number of uninterpretable results will be tabulated and commented on. Analysis and presentation of results will be carried out in line with advice in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Macaskill 2010).

We will carefully scrutinise 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 tabulated and summarised narratively.

Investigations of 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 initial approach will be to perform sequential sub-group analyses using the analytical framework detailed below. We will consider whether using co-variates in the HSROC model will add to any insights gained from these sub-group analyses.

The provisional framework for investigating heterogeneity will include the following.

• Type of global measure of haemostatic function (TEG/ROTEM).

• Time blood sample taken relative to trauma (< 1 h/> 1 h).

• Nature of reference standard (INR/PTr of 1.2 ≥; INR/PTr of 1.5 ≥).

• Prevalence of acute traumatic coagulopathy (ATC; 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 associated with massive transfusion (yes or mixed/no).

• Case-control study design (if these are included).

• Other aspects of study quality, particularly blinding of index test and reference standard.

There are no specific plans for the investigation of heterogeneity of the data concerning uninterpretable results or further investigation of discrepant results.

Sensitivity analyses

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 be assessing reporting bias because its impact in test accuracy is unclear and the tools for investigating it are in the early stages of development.

Summary

The recent Cochrane review by Hunt and colleagues draws the conclusion that viscoelastic testing such as TEG and ROTEM in trauma should, at present, be limited to research purposes and not clinical practice (1). Although the review of the literature is robust, the included studies are all fundamentally flawed, and, as such, the review and conclusions are equally limited. The three main studies included by Hunt all focus on a comparison of ROTEM to conventional coagulation testing (CCT), including the prothrombin time (PT) and international normalized ratio (INR). It is well documented, as Hunt and colleagues mention in their discussion, that the use of CCT as a standard for the measurement of trauma-induced coagulopathy (TIC) has never been rigorously and prospectively validated. In fact, correlation with clinical and hemostatic history is necessary for accurate interpretation of CCT, and measurement of PT and INR alone miss major components of coagulation, including the intrinsic pathway, platelet function, and the presence of inhibitors (2).

Furthermore, hyperfibrinolysis is a major component of TIC and has been shown to directly correlate with mortality in trauma patients (3,4). Treatment with antifibrinolytic therapy has demonstrated reduced mortality in bleeding trauma patients, as demonstrated by a prior Cochrane review (5). TEG and ROTEM provide a quantitative assessment of fibrinolysis which is missed by using only PT and INR. A thorough assessment of TIC should include clinical evidence of impaired hemostasis and potentially can be monitored through transfusion requirements. Using these endpoints, multiple authors have demonstrated that viscoelastic measurements are superior to CCT in predicting the risk of bleeding and need for transfusion (6,7).

In summary, including only studies using comparison of ROTEM to PT and INR without any assessment of clinical bleeding inserts a major form of selection bias into the referenced Cochrane review by Hunt and colleagues (1). Caution should be exercised in concluding that TEG and ROTEM should be limited to research - what is lacking in the literature is a robust, prospective randomized study to compare TEG/ROTEM to PT/INR in the context of clinically important markers of coagulopathy. Numerous studies comparing TEG/ROTEM to relevant clinical assessments of TIC, as referenced above, provide clinical equipoise for such an analysis as well as the ongoing use of viscoelastic testing in clinical practice until such a study is completed.

References:

1. Hunt H, Stanworth S, Curry N, Woolley T, Cooper C, Ukoumunne O, Zhelev Z, Hyde C. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev. 2015 Feb 16;2:CD010438. [Epub ahead of print]

2. Kamal AH, Tefferi A, Pruthi RK, How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults. Mayo Clin Proc. 2007 2007 Jul;82(7):864-73)

3. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg 2012; 73:365-370; discussion 370

4. Chapman MP, Moore EE, Ramos CR, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg 2013; 75:961-967; discussion 967

5. Roberts I, Shakur H, Ker K, Coats T; CRASH-2 Trial collaborators. Antifibrinolytic therapy for acute traumatic injury. Cochrane Database Syst Rev. 2012;12:CD004896. Review.

6. McCully SP, Fabricant LJ, Kunio NR, Groat TL, Watson KM, Differding JA, Deloughery TG, Schreiber MA. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg. 2013 Dec;75(6):947-53

7. Holcomb JB, Minei KM, Scerbo ML, Radwan ZA, Wade CE, Kozar RA, Gill BS, Albarado R, McNutt MK, Khan S, Adams PR, McCarthy JJ, Cotton BA. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012 Sep;256(3):476-86

Reply

Our thanks to the commentator for his interest and observations on our recently-published systematic review 'Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy (TIC) in adult trauma patients with bleeding', and we welcome the opportunity to engage with those who have an interest in this area. We address each main point in turn.

The commentator disputes the acceptability of using PT and INR as reference standards. We have sympathy with this assertion and address the issue at some length within the review, both in terms of recognition within the Objectives and Background sections and suggestions for future research in the Discussion section. Within the Discussion section, we explicitly address the issues raised by the commentator in the section headed ’Is test accuracy important?’ (p.16-17). In particular, we advance the potential for authors creating a composite reference standard definition comprising, for instance, high PTr or low fibrinogen levels, and suggest the potential for using quasi-clinical definitions of coagulopathy.

The commentator appropriately raises the potential importance of hyperfibrinolysis. However we note that hyperfibrinolysis is a specific component of TIC which is usually considered separately, and this is the approach we took. This is largely because the optimal indicators of TEG/ROTEM suggesting hyperfibrinolysis are probably not the same as those suggesting hypocoagulability (although they are clearly inter-connected); the most appropriate reference standard in an accuracy study would be different too. Evidence suggests that whereas marked hyperfibrinolysis is readily identifiable by ROTEM, mild or moderate hyperfibrinolysis is not (Raza et al., 2013); thus its value is not self-evident as is suggested. Further, the benefit from treatment with tranexamic acid mentioned as being demonstrated by CRASH-2 did not require specific diagnosis of hyperfibrinolysis by TEG/ROTEM.

The commentator cites two studies, claiming they “demonstrate that viscoelastic measurements are superior to CCT in predicting the risk of bleeding and the need for transfusion”. We examined this claim. McCully et al. (2013) examines measures of TEG and CCT before and after FFP transfusions in 106 stable trauma and surgical patients. The majority of patients appear to be surgical with only 36/106 identified as being from the “Trauma/critical care” service. Massive transfusion was an exclusion criterion. Our main concern is thus whether the circumstances in which TEG is being used are equivalent to those of interest in our review. Further risk of bleeding and need for transfusion do not seem to have been addressed by the study.

Holcomb et al. (2012) is a study of 1974 consecutive trauma patients in which admission rapid TEG (r-TEG) and CCTs (PT; aPTT; INR; platelets; and fibrinogen) were correlated against each other and outcome measures such as 0-6h transfusion of RBC, plasma, platelets; substantial bleeding; massive transfusion; and mortality. With the exception of using r-TEG rather than TEG, the study is typical of one which we would include in our review of prognosis studies proposed in our discussion section. However this study usefully illustrates the difficulty of interpreting such studies, particularly in isolation. Thus in Holcomb et al. for the outcome predicting massive transfusion, the r-TEG measure alpha-angle <56^o is the strongest predictor with an odds ratio (OR) of 8.99 [this means that massive transfusion is nearly 9 times more likely where alpha-angle <56^o, than in patients where it is 56^o or above], and so consistent with the claim that r-TEG are stronger predictors than CCTs (where the OR are lower). However the 95% CI around the OR of 8.99 are 2.9 to 28.3, showing that there is considerable uncertainty. As a corollary the risk associated with INR>1.5 is 3.4, so the difference in risk between the r-TEG value and the CCT value could be explained by chance. To reinforce this issue in the outcome predicting substantial bleeding, the strongest predictor is this time a CCT measure, INR>1.5 OR 3.4 (95% CI 1.7 to 7.0) but again the difference between this and the strongest r-TEG predictor, alpha-angle <56^o, OR 2.7 could be explained by chance. A further important issue is that it is likely that both CCT and r-TEG measures were being used to guide transfusion during the study so the risks measured include a treatment effect. Given these issues we think the claim by the commentator, and indeed the conclusion by the original authors that “Admissions CCTs can be replaced with r-TEG.” is overstated.

Finally the commentator contests our suggestion that TEG and ROTEM as used in adult trauma patients with bleeding should only be used for research. However, the commentator acknowledges that a robust prospective randomized study is required to compare TEG/ROTEM to PT/INR, so he is agreeing with us; as such trials are unlikely if TEG/ROTEM is in widespread use in day-to-day trauma care practice. We also draw attention in our review to the fact that such trials are in progress and the help that similar trials have provided in clarifying the use of TEG/ROTEM in routine cardiac surgery. However, we also note that such trials are unlikely to be successful where TEG/ROTEM measures which indicate treatment decisions are not specified, and the nature of these treatments decisions is vague.

References:

Holcomb JB, Minei KM, Scerbo ML, Radwan ZA, Wade CE, Kozar RA et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Annals of Surgery 2012;256(3),476-86.

McCully SP, Fabricant LJ, Kunio NR, Groat TL, Watson KM, Differding JA et al. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. Journal of Trauma and Acute Care Surgery 2013;75(6),947-53.

Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors C et al. The incidence and magnitude of fibrinolytic activation in trauma patients. Journal of Thrombosis and Haemostasis 2013;11:307-14.

Contributors

Harriet Hunt, Simon Stanworth, Nicola Curry, Tom Woolley, Chris Cooper, Obioha Ukoumunne, Zhivko Zhelev and Chris Hyde

Summary

We read the recent Cochrane review (1) concerning the use of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for the evaluation of trauma induced coagulopathy (TIC) with interest. Given that TIC is a multifactorial disease, the ideal test for its detection should be one that incorporates all vital elements of coagulation as well as thrombolysis. Clinicians have recognized for years that the standard laboratory tests (prothrombin time [PT], international normalized ratio [INR], and partial thromboplastin time [aPTT]) correlate poorly with observed hemostasis during trauma surgery (2). The stated objective of the review was to “determine the accuracy” of TEG and ROTEM for TIC, using the reference standards PT or INR. Because TEG and ROTEM, which mimic venous clotting, are global approaches to the assessment of coagulation incorporating platelet and clotting factor function as well as the elements of thrombolysis, is not surprising that a single test of a factor pathway (PT or INR) doesn’t correlate well with a test of comprehensive hemostasis. It is well known that the mortality of trauma patients is significantly higher when fibrinolysis is present (4). Both TEG and ROTEM are very sensitive to fibrinolysis, whereas the PT and INR are not. Therefore, we believe that PT or INR are not ideal comparators for TEG and ROTEM in patients with TIC.

Essential to the care of critically injured patients is the prediction of which patients will require transfusion therapy, and which blood components they will require. In this regard, recent work by Holcomb et al demonstrated the superiority of rTEG to conventional coagulation tests in the prediction of transfusion requirements for all four major blood products (3). Furthermore, recent work by McCully et al (5) suggests that using INR as a measure of TIC may actually be harmful in that INR overestimates TIC when compared to TEG and clotting factor activity. This overestimation led directly to the transfusion of additional units of FFP, increasing these patients’ risk of a transfusion related complication (6), as well as their cost of care.

A common criticism regarding the utility of TEG or ROTEM in the evaluation of TIC is not test accuracy or validity, but rather the time involved in getting results. Trauma patients can require a large volume of blood products over a very short period of time. Because both TEG and ROTEM can often require greater than 30 minutes for test completion, the clinical picture may drastically change during this time period, rendering the results unhelpful. The exception is the diagnosis of fibrinolysis, which usually does not improve with blood component therapy. However, advances in TEG technology have led to the development of the Rapid Thromboelastograph (rTEG), which adds tissue factor to the standard kaolin to activate the clotting process. Cotton et al (7) demonstrated that with the addition of a bedside remote graphical display of the evolving tracing, key elements of the rTEG were available to guide resuscitative efforts within 5 minutes, and that a near complete tracing was observable in 15 minutes. It is on the basis of these observations that we submit that TEG technology does in fact have a role in the evaluation and management of the exsanguinating trauma patient.

In summary, we believe that PT and INR are poor reference standards for the evaluation of TEG or ROTEM in trauma patients, because they clearly test different aspects of clotting function.

Shannon Kilkelly, Lawrence Lottenberg, Mark J Rice

References
1. Hunt H, Stanworth S, Curry N, Woolley T, Cooper C, Ukoumunne O, Zhelev Z, Hyde C. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev. 2015 Feb 16;2

2. Kashuk et al. Primary fibrinolysis is integral in the pathogenesis of acute coagulopathy of trauma. Annuals of Surgery 2010:252:434-42

3. Holcomb et al. Admission Rapid Thromboelastography Can Replace Conventional Coagulation Tests in the Emergency Department. Annals of Surgery 2012 256:476-84

4. Cotton et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. Journal of Trauma and Acute Care Surgery 2012 Aug;73(2):365-70

5. McCully et al. The International Normalized Ratio Overestimates Coagulopathy in Stable Trauma and Surgical Patients. Journal of Trauma and Acute Care Surgery. 2014 76(2) 264-71

6. Watson GA, Sperry JL, RosengartMR, et al. Inflammation and Host Response to Injury Investigators. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma. 2009;67(2):221-227

7. Cotton et al. Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. Journal of Trauma 2011 Aug;71(2):407-14

Reply

We thank the correspondents for their comments on our systematic review Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma-induced coagulopathy (TIC) in adult trauma patients with bleeding.

As indicated in our response to the previous feedback on this review (Feedback 1), we have sympathy with the assertion that PT and INR are not ideal reference standards. We address the issue of imperfect reference standards at some length within the review, both in terms of recognition within the Objectives and Background sections and suggestions for future research in the Discussion section. Within the Discussion section we address these issues in detail, particularly advancing potential for researchers to create a composite reference standard as well as the possible utility of quasi-clinical definitions of coagulopathy.

In light of the feedback received, we recognise that this information could be made explicit in the more frequently-accessed Abstract and Plain Language Summary sections. We have therefore updated these sections to recognise the limitations of reference standards, and thank the commentators for their contribution.

Contributors

Harriet Hunt, Simon Stanworth, Nicola Curry, Tom Woolley, Chris Cooper, Obioha Ukoumunne, Zhivko Zhelev and Chris Hyde