Pharmacological interventions for the treatment of bleeding in people treated for blunt force or penetrating injury in an emergency department: a systematic review and network meta‐analysis

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To systematically review the optimal administration and relative efficacy of pharmacological interventions for preventing blood loss in people treated in an emergency department for bleeding caused by a blunt force or penetrating injury.

Background

Description of the condition

Traumatic injury is one of the leading causes of morbidity and mortality around the world, with 4.5 million deaths in 2017 being attributed to injuries (Haagsma 2020). Injuries may be categorised based on causative mechanism, such as road traffic accidents, other transport accidents, falls, self‐harm, drowning, fires, interpersonal violence, war, and natural disasters, etc. (Haagsma 2016). Depending on the force that caused the injury, a traumatic injury may be classified as a blunt injury or a penetrating injury. A blunt force injury may or may not breach the skin, in contrast to a penetrating injury, where the responsible object pierces the skin resulting in an open wound, such as a cut or stab wound. Both blunt and penetrating injuries can damage underlying organs, muscles, and bone significantly, causing local and systemic effects of the injury.

Bleeding is one of the most common consequences of both blunt and penetrating injuries, which, if uncontrolled, leads to hypovolaemia and shock (Hess 2008). Shock in turn leads to tissue hypoxia and acidosis, triggering an immune response and coagulopathy, eventually leading to complications such as multi‐organ failure, sepsis, and death. Early management of the bleeding trauma patient can help to minimise these cascading events and improve outcomes (Kauvar 2006). One‐third of early trauma deaths can be attributed to post‐traumatic bleeding (Sauaia 1995), thus offering a potential opportunity for the implementation of timely haemorrhage control measures to decrease this preventable burden of disease and death (Holcomb 2004).

The early management of the bleeding trauma patient involves both haemorrhage control and damage control resuscitation (ATLS  2018; NICE 2016; Rossaint 2016). Massive transfusions with stored blood are known to cause coagulopathy, acidosis, and hypothermia, which can lead to further bleeding (Brohi 2003; Chang 2016). It is therefore important to avoid entering this cycle of coagulopathy and bleeding by stopping the primary bleed at an early stage, thus decreasing the need for blood products (Holcomb 2004). Allogenic blood transfusions carry the risk of complications, such as allergic reaction or fluid overload, and can potentially transmit blood‐borne infections (Bulger 2001; Hendrickson 2016). Blood transfusion itself is also an independent predictor of unfavourable outcomes in trauma patients (Malone 2003). This reinforces haemorrhage control as an imperative and defining step in the management of the bleeding trauma patient (Gaunt 2014).

The physiological response that contributes to haemorrhage control is haemostasis, a process by which an injured blood vessel triggers the coagulation cascade to form a clot in an attempt to halt the ongoing bleed. The coagulation cascade is comprised of an intrinsic and an extrinsic pathway involving a number of interactions between the various clotting factors, eventually leading to the formation of a blood clot. Medical treatment directed towards haemorrhage control complements some of these processes, or may form a physical barrier that helps to halt the bleeding. Various pharmacological interventions are used in the bleeding trauma patient that help to decrease the need for blood product transfusion and mitigate the risk associated with blood transfusions.

Description of the intervention

This review will focus on pharmacological interventions used to reduce bleeding in patients treated for blunt force or penetrating injury in an emergency department. Pharmacological interventions to prevent bleeding provide the opportunity to reduce blood transfusion and its related complications. The interventions will include antifibrinolytic drugs, desmopressin, factor VIIa and factor XIII, fibrinogen, and sealants (glues).

Antifibrinolytic interventions include tranexamic acid, aprotinin, and epsilon‐aminocaproic acid. Tranexamic acid and epsilon‐aminocaproic acid are synthetic derivatives of lysine, whilst aprotinin is derived from bovine lung. Antifibrinolytics help to reduce blood loss through stabilising blood clots and reduce bleeding in major trauma, particularly when given early (Ker 2015). Tranexamic acid has been found to improve mortality in the bleeding trauma patient and is recommended in the early management of such patients (Roberts 2013).

Sealants (applied directly to the wound) were first used in traumatic injuries during World War II (Baird 2015), and continue to be used as a complementary therapy to halt bleeding in trauma patients (Perkins 2008). We will group sealants into those that contain fibrin and those that do not contain fibrin. Fibrin plays an important role in blood clot formation, which halts bleeding, whilst non‐fibrin sealants tend to exert their effects through mechanical expansion, which provides pressure to bleeding surfaces.

The route by which the interventions can be administered is displayed in Table 1 and include intravenous, oral, topical, and nasal modes.

1. Table of intervention variables.

Variable	TXA	Aprotinin	Epsilon‐aminocaproic acid	Desmopressin	Factor VIIa	Factor XIII	Fibrinogen	Fibrin sealants/glue	Non‐fibrin sealants
Timing
Pre‐hospital	✓	✓	✓	✓	X	X	X	✓	✓
Hospital	✓	✓	✓	✓	✓	✓	✓	✓	✓
Route
IV (injection, infusion)	✓	✓	✓	✓	✓	✓	✓	X	X
Topical	✓	X	X	X	X	X	X	✓	✓
Intranasal	X	X	X	✓	X	X	X	X	X
Subcutaneous injection	X	X	X	✓	X	X	X	X	X
IV + topical	✓	X	X	X	X	X	X	X	X
Oral	✓	X	✓	X	X	X	X	X	X
IV + oral	✓	X	X	X	X	X	X	X	X
Topical + oral	✓	X	X	X	X	X	X	X	X
Dose
Single	✓	X	✓	✓	✓	✓	✓	✓	✓
Multiple	✓	✓	X	✓	✓	✓	✓	X	X
Variable units/kg	✓	X	✓	X	✓	✓	✓	X	X
Variable trial‐set dose	✓	✓	X	✓	✓	✓	✓	✓	✓
The table is for illustrative purposes only and is based on the table from Gibbs 2019. Ticks indicate which intervention and timing/route/dose combinations are clinically possible; crosses indicate which intervention and timing/route/dose combinations are not clinically possible. IV: intravenous; TXA: tranexamic acid

How the intervention might work

Blood loss from injuries caused by major trauma causes hypotension and shock, reducing the blood available to perfuse organs. In such circumstances, blood transfusion may be required, even though it is associated with the risk of transfusion reactions and transmission of blood‐borne infections. The aim of the blood‐saving interventions (listed below) is to reduce bleeding, and ultimately reduce blood loss and the need for blood transfusion.

An explanation of how each intervention works with any potential risks is provided below.

Antifibrinolytics (tranexamic acid, aprotinin, and epsilon‐aminocaproic acid)

Antifibrinolytics act by inhibiting the process that breaks down blood clots, resulting in the clot becoming more stable. The most commonly used antifibrinolytics are tranexamic acid, aprotinin, and epsilon‐aminocaproic acid (Ker 2015). They may be administered orally, intravenously, or topically (BNF 2020). Although most of these drugs cause few adverse effects, there is a theoretical increased risk of unwanted venous blood clots associated with their use (Levy 2018; Myers 2019), and at higher doses there is concern about the risk of seizures (Lin 2016; Pabinger 2017), and an increase in the incidence of venous thrombo‐embolic events (Nishida 2017; Roberts 2020).

Desmopressin

Desmopressin stimulates the release of factor VIII (Pearson 2016), which in turn encourages blood clotting. Factor VIII is an important factor within the blood, which enables platelets to adhere to wound sites and form blood clots. It can be given intravenously, subcutaneously (under the skin), or intranasally (via the nose) (BNF 2020). Reported adverse effects include facial flushing and the possibility of low blood sodium levels, particularly with repeated doses (Desborough 2017).

Recombinant factor VIIa and factor XIII

Recombinant factor VIIa (rFVIIa) is used to treat people with haemophilia, congenital factor VII deficiency, and inhibitory alloantibodies. It has also been administered outside licenced use (off‐licence) to prevent significant blood loss during surgery (Simpson 2012). Its use in clinical trials has shown a decreased requirement for blood transfusion when given to severe trauma patients with blunt or penetrating injury (Boffard 2005). However, despite its use, the efficacy of this drug in people who do not have haemophilia remains unclear.

Recombinant factor XIII (rFXIII) protects a developing clot during formation and therefore improves clot strength. This effect is likely to depend on dose, and it has been suggested that maintaining high levels of rFXIII may prevent bleeding (Aleman 2014).

Both rFVIIa and rFXIII are administered intravenously (BNF 2020). The concern with rFVIIa is the potential increased risk of arterial blood clots, particularly in older people, however, evidence to confirm this risk is limited (Goodnough 2016).

Fibrinogen

Fibrinogen is a soluble protein present in the bloodstream. During tissue and vessel injury it is converted by the activity of thrombin to fibrin, which ultimately forms the basis of a blood clot. The formation of the blood clot helps to prevent excessive bleeding. Exogenous fibrinogen is administered intravenously by transfusion of fresh‐frozen plasma (FFP), cryoprecipitate, or fibrinogen concentrate. The timing of administration of fibrinogen in bleeding trauma patients continues to be an area of interest (Curry 2018). FFP has a lower concentration of fibrinogen than cryoprecipitate, which is prepared by controlled thawing of frozen plasma to precipitate high molecular weight proteins (factor VIII, von Willebrand factor, and fibrinogen). Fibrinogen concentrate is produced from pooled human plasma using a special procedure. Since cryoprecipitate and FFP are obtained from blood, there is the potential risk, albeit small, of viral infection due to the manufacturing process. In contrast to FFP and cryoprecipitate, the manufacturing process for fibrinogen concentrate includes viral inactivation or pasteurisation, thus minimising the risk of viral transmission (Franchini 2012).

Fibrin sealants

Fibrin sealants are wound adhesives and are administered topically. They are mostly used during bleeding to aid in haemostasis (bleeding cessation), tissue sealing, and wound healing. Sealants tend to originate from plasma and commonly contain fibrinogen, thrombin, factor XIII, and calcium chloride. Fibrin sealants may include an antifibrinolytic agent (Fischer 2011), and their final composition may vary. Allergy is a rarely noted adverse effect (Aguilera 2013).

Non‐fibrin sealants

Non‐fibrin sealants are administered topically and tend to be liquids that combine to form a film that promotes platelet activation and formation of a cluster. Non‐fibrin sealants help with blood clot formation, however, the functioning of the sealant is dependent on the individual's own fibrin contained within their blood. The term 'non‐fibrin sealants' also encompasses internal dressings and powders, which may be an alternative to tourniquet use when this is not possible. The mechanism of action of many sealants in this group is through mechanical expansion and compression of tissues. Consequently, there are many associated adverse events reported with this, including nerve compression (Baird 2015).

Why it is important to do this review

This review will aim to assess the effectiveness of various pharmacological interventions to prevent blood loss in people treated for blunt force or penetrating injury in an emergency department. Although emergency blood transfusions provide a life‐saving treatment for people who have lost blood from trauma, there are risks associated with allogenic blood transfusions, such as transfusion‐transmitted infection and serious adverse transfusion reactions (WHO 2016). In 2017 in the UK, 21 people died from transfusion‐related complications, and there were 112 incidences of major morbidity associated with blood transfusion (SHOT 2018).

The provision of safe access to blood products is a global priority for the World Health Organization, as is the minimisation of unnecessary transfusions in order to preserve a scarce resource, reduce risk, and reduce costs (WHO 2016). The cost of supplying a standard unit of red cells in the UK is GBP 138.83 at the time of writing (NCG 2020). By comparison, in 2020, an ampoule of tranexamic acid cost GBP 1.57, and an ampoule of desmopressin cost GBP 13.16 (BNF 2020). Embracing pharmacological treatments to prevent bleeding may reduce the need for blood transfusion, reduce costs, and potentially offer patients a lower risk profile.

Concerns regarding the adverse effect profile of pharmacological interventions may contribute to their limited uptake in clinical practice. Theoretically, interventions to prevent bleeding may also result in the formation of unwanted blood clots. This may be of particular concern in people with myocardial infarction or a pre‐existing increased risk of stroke or pulmonary embolism (Danninger 2015). Knowing the optimal dose could help to limit adverse effects, as well as reduce treatment costs. In addition, the timing of the intervention is important. The CRASH‐2 trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2; a large randomised controlled trial (RCT) of tranexamic acid versus placebo in people with major trauma) found that the timing of the intervention was associated with outcome (Roberts 2013). Delivery of tranexamic acid within three hours of trauma improved the chance of survival; however, when tranexamic acid was delivered three hours after injury, there was an increased risk of death from bleeding.

The optimal dose, route, and timing of many of these interventions is currently unknown, which results in uncertainty for decision makers. We will carry out a network meta‐analysis (NMA) of RCTs to provide the highest level of evidence for pharmacological interventions used to treat people with blunt or penetrating injury in emergency departments.  

Description of network meta‐analysis

Network meta‐analysis (NMA) is a type of analysis that allows the comparison of more than two treatments (Lu 2004). Network diagrams are used to represent the available evidence for each treatment comparison. Each treatment is represented by a node (vertex), and a line is used to connect the two treatments being compared (Jansen 2011). It is important to undertake an NMA like any other meta‐analysis, using a rigorous systematic approach. The network diagram will contain a mix of solid and blank lines. Solid lines indicate 'direct' comparisons for which there is evidence from clinical trials. Blank (or absent lines) indicate 'indirect' comparisons, that is those where no clinical trials have compared the interventions (Bucher 1997; Jansen 2011).

An NMA uses data from direct comparisons to estimate the effects of indirect comparisons that have not yet been assessed in a clinical trial (Caldwell 2005; Jansen 2011; Jansen 2013; Song 2003). This allows NMA to 'fill gaps' in the evidence by pooling data from direct clinical trial comparisons, and deduce information about missing comparisons in the network (Krahn 2013; Salanti 2014). To draw robust conclusions, the NMA assumes that all the people and trials included in the network are sufficiently similar in terms of effect modifiers across all direct comparisons (Jansen 2013).

A further benefit of NMA is that it can aid clinical decision making by providing results in an accessible format. Outputs can be tabulated in a hierarchy to show results by treatment and outcome. This is particularly useful, as all relevant evidence can be included in one table, indicating both benefits and risks of a given treatment (Hoaglin 2011; Jansen 2011; Sutton 2008; van der Valk 2009).

Objectives

To systematically review the optimal administration and relative efficacy of pharmacological interventions for preventing blood loss in people treated in an emergency department for bleeding caused by a blunt force or penetrating injury.

Methods

Criteria for considering studies for this review

Types of studies

We will include RCTs. If the process of randomisation is unclear, we will contact the trial authors to obtain further information. If we are unable to contact the authors, we will include the trial in the review and consider it to be at unclear risk of bias. To be eligible, trials must compare at least one of our interventions of interest (placebo versus active treatment, or active treatment versus another active treatment). We will use both abstracts and full‐text publications if they report adequate information about study design, participant characteristics, and interventions. We will only include trials that have been prospectively registered, unless the final trial report was published before 2010 (Roberts 2015).

Types of participants

We will include participants who have undergone treatment in an emergency department for bleeding caused by a blunt or penetrating injury. There will be no restrictions on age, gender, or ethnicity. If an eligible trial contains a mixed age group which includes a paediatric population, then we will perform subgroup analysis of the data.

Mechanisms causing blunt force trauma or penetrating injury will include but are not limited to the following.

• Fall from height

• Fall from horse or other moving object

• Injury from a falling object

• Assault with a blunt object

• Motor vehicle collisions

• Bicycle accidents

• Accidental falls

• Sporting injuries

• Punches and kicks

• Blast injury

• Crush injury

• Stabbing

• Gun shot

• Nail gun wounds

• Shrapnel injury

• Sharp‐glass injury

If an eligible trial contains a mixed population of people (e.g. bleeding due to trauma and other causes), then we will only use data contributed by our population of interest. If no subgroup data are given, and we are unable to contact the corresponding author to provide this information, we will include the trial if at least 80% of the sample size is from our population of interest. We will include participants if they were taking anticoagulant medication or antiplatelet therapy at the time of injury. We will exclude participants with known bleeding disorders, such as haemophilia.

Types of interventions

Eligible trials will have compared one or more of the following interventions:

• antifibrinolytics:

  • tranexamic acid;

  • aprotinin;

  • epsilon‐aminocaproic acid;

• desmopressin;

• recombinant factor VIIa and factor XIII;

• fibrinogen‐containing products;

• fibrin sealants;

• non‐fibrin sealants.

We will not combine different interventions and treatments in the NMA other than those listed above. Trials must compare an intervention of interest versus placebo, or an intervention of interest versus another intervention of interest. We will include trials that use interventions of interest combined with another agent or blood product in each arm (e.g. tranexamic acid plus platelets versus placebo plus platelets), as we consider that the effect of the additional agent in both arms will cancel out.

To explore the optimal treatment pathway, we will consider interventions administered over a range of doses, as both single or multiple doses via intravenous, subcutaneous, intranasal, oral, or topical routes, and at different timings.

The variations in dose, route, and times for interventions may differ greatly. We expect that tranexamic acid will be the intervention most commonly assessed in the included trials, therefore we anticipate this to be the focus of our NMA.

Types of outcome measures

We will use the outcome measures below to assess the relative hierarchy of our interventions.

Primary outcomes

• Death within 48 hours of presentation in the emergency department

• Proportion of participants receiving allogenic blood transfusions in the emergency department

Secondary outcomes

• All‐cause mortality (deaths occurring up to 30 days after the injury)

• Death within 6 hours of presentation in the emergency department

• Number of participants receiving allogenic blood within 24 hours of injury

• Mean number of red blood cell units transfused per person (within 30 days)

• Development of measurable coagulopathy during hospital stay (within 30 days)

• Length of hospital stay

• Length of intensive care unit (ICU) stay

• Adverse events:

  • thromboembolism (deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) (within 30 days)

  • transfusion reactions (acute) (within 24 hours)

  • suspected serious adverse drug reactions (within 30 days)

Death within 48 hours of presentation presentation in the emergency department has been included as a primary outcome after a recent paper analysing outcome measures in clinical trials of treatments for acute severe haemorrhage. It was found that all‐cause mortality has low power, lacks generalisability and can obscure harmful effects. The suggestion is to use cause specific mortality or time‐specific mortality as a proxy in certain circumstances (Brenner 2018). 

For suspected serious adverse drug reactions, we will use the International Conference on Harmonisation Good Clinical Practice (ICH‐GCP) definition of a serious adverse drug reaction (ICH‐GCP 2018). If studies report different measures, we will record and present the information to the expert panel prior to extracting data to determine an appropriate analysis strategy.

We will also collect and present any data on cost or resource information reported in the included trials. This will not constitute a formal economic evaluation, but it will provide a useful insight that may be of interest for those involved in decision making.

Search methods for identification of studies

The Information Specialist (CD) from the Systematic Review Initiative will generate the search strategies in conjunction with the Cochrane Injuries Group's Information Specialist (Jane Dennis).

Electronic searches

Bibliographic databases

We will search the following databases for systematic reviews and RCTs:

• Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library (current issue);

• MEDLINE (OvidSP, 1946 onwards);

• PubMed (for epublications ahead of print only);

• Embase (OvidSP, 1974 onwards);

• CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost, 1937 onwards);

• Transfusion Evidence Library (1950 onwards).

We will search the following resources for ongoing trials:

• CENTRAL, the Cochrane Library (current issue);

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/);

• World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/en).

Searches will be combined in the MEDLINE, Embase, and CINAHL databases with adaptations of the recommended Cochrane RCT filter, Lefebvre 2020, and the Scottish Intercollegiate Guidelines Network (SIGN) systematic review filters (www.sign.ac.uk/search-filters.html). Searches will not be limited by language or date. Search strategies for all databases are presented in Appendix 1.

Searching other resources

To supplement the database searches, we will handsearch the bibliographies of all included trials, relevant review articles, and other current evidence in order to identify additional trials missed by the electronic searches. We will also contact the authors of ongoing trials to obtain any unpublished data. We will contact authors a maximum of three times.

We will check the reference lists of included trials and relevant systematic reviews to identify any trials not found by the electronic searches. We will also check for relevant retraction statements and errata for the included trials.

Data collection and analysis

We will undertake the systematic review using the methods described in Chapter 5 of the Cochrane Handbook for Systematic Reviews of Interventions (Li 2020). We will run analyses using Review Manager 5 and Stata 15 (Review Manager 2020; Stata 2017).

Selection of studies

Three review authors (VE, AN and AH) will independently screen the titles and abstracts of citations identified by the electronic searches for potential eligibility. If the title and abstract of the citation are found to be irrelevant, we will exclude it at this stage. The same review authors will then independently screen the full‐text articles of the citations considered to be potentially eligible against the criteria set out in this protocol. If the information needed to make a decision regarding eligibility is insufficient, we will request additional information from the corresponding author of the trial. We will contact the author up to three times within six weeks. If there is no response after six weeks of our initial attempted contact, we will exclude the study. We will keep records of the study selection process and use the information to generate a PRISMA flowchart to illustrate the study flow (Moher 2009). We will record reasons for the exclusion of trials at the full‐text review stage in the 'Characteristics of excluded studies' table. If we encounter translation needs, we will use colleagues or Cochrane resources such as Task Exchange.

Data extraction and management

Three review authors (VE, JS  and AH) will independently use a standardised, piloted form to undertake data extraction of the included trials. The form will be designed following the methods described in chapter 5 of the Cochrane Handbook for Systematic Reviews of Interventions (Li 2020). The three  review authors (VE, JS and AH) will not be blinded to authors, institutions, or outcomes of the trials they are extracting. Colleagues providing translation support will be expected to help extract data. We will pilot the data extraction form on two included trials selected at random (equally split between the review authors). Following this process, if necessary, we will make amendments to the data extraction form.

We will contact corresponding authors up to three times to request further trial data. We will classify the data as unobtainable if there is no response from the authors within six weeks of the initial email request. If a conflict arises over data sources, we will give preference to published data over unpublished data, as published work is more likely to have undergone a rigorous peer‐review process.

The potential dose, route, and timing combinations for each intervention are illustrated in Table 1. There are numerous treatment pathway combinations for each intervention, which will makes it difficult to decide on an approach for data synthesis prior to data extraction. To overcome this, we will use a staged approach to carry out data extraction. In the first stage, three review authors (VE, JS and AH ) will extract trial, participant, and intervention characteristics. Using these data, we will convene an independent blinded external expert panel to categorise the clinically meaningful interventions by dose, route, and timing, in order to decide which to compare. The external expert panel will also help us to create clinically meaningful groups ready for data analysis. Once this process has been completed, the three  review authors (VE, JS and AH) will independently extract the outcome data.

We will extract data for the following items and list these and the outcomes from each trial in the 'Characteristics of included studies' table.

• General information: name of review author carrying out data extraction, date of data extraction, study identifier, surname and contact address of first author, language of trial.

• Trial information: RCT trial design – location of where the trial was run, setting, sample size, duration of trial, power calculation, treatment arms, randomisation, inclusion and exclusion criteria, comparability of groups, length of study.

• Characteristics of participants: age, sex, breakdown of total numbers for those randomised and analysed,  site of injury, severity of injury (as and if reported by trialist), dropouts (percentage in each arm) with reasons and protocol violations, participants on anticoagulants or antiplatelet therapy at the time of injury.

• Characteristics of interventions: number of treatment arms, description of experimental arm(s), description of control arm(s), timing, dose, and route of administration of intervention, and other differences between intervention arms.

• Outcomes (all within 30 days of injury unless otherwise specified): mortality within 48 hours of admission to the emergency department, allogenic blood transfusion in emergency department, mortality due to any cause, mortality within six hours of admission to the emergency department, allogenic blood transfusion within 24 hours of injury, mean number of units of red blood cells transfused, length of ICU and hospital stay, and adverse effects (thromboembolism, transfusion reactions (within 24 hours), and adverse drug reactions). We will use the ICH‐GCP definition of serious adverse events (ICH‐GCP 2018). Where that definition is not used in the included studies, we will extract information about how 'adverse effect' and 'serious adverse effect' were defined in each study.

• Risk of bias assessment: allocation concealment, blinding (participants, personnel, outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias.

We will extract arm‐level data, rather than study‐level data, from both abstracts and full‐text papers. If there are multiple publications from the same trial, we will use one extraction form and obtain maximal data through extracting data from all available publications. If insufficient information is given in the full text, we will contact the corresponding author, study group, or sponsor to obtain additional data. Where studies have multiple publications, we will collate the reports of the same study so that each study, rather than each report, is the unit of interest for the review, and such studies will have a single identifier with multiple references. We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the full review.

Whilst extracting trial data, we will collect any data about cost, resource usage, and quality of life provided in the included studies. Whilst this will not form a formal economic evaluation, it will offer useful information that may guide decision making. Should any quality of life data be available, we will comment on these outcomes descriptively in our discussion.

We will list all treatment arms in each study in the 'Characteristics of included studies' table.

Two review authors (VE and JS) will independently enter data into Review Manager 5 or Review Manager Web (Review Manager 2020, RevMan Web 2019). Each review author will cross‐check the other review author's entries for accuracy.

Assessment of risk of bias in included studies

We will assess the quality of the included trials using the Cochrane risk of bias tool (ROB1) described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will test the tool on a random sample of trials. Three  review authors (VE, JS and AH) ) will independently assess the risk of bias within each trial and classify it as low, high, or unclear. The judgements of the two review authors will be compared and consensus reached; if there is discrepancy, a third review author (SB) will be consulted. We will report our judgements in the risk of bias table for each trial.

Using the information generated, we will look for statistical heterogeneity in each trial and perform sensitivity analyses accordingly. We will assess risk of bias for the following domains:

• selection bias (random sequence generation and allocation concealment);

• performance bias (blinding of participants and personnel);

• detection bias (blinding of outcome assessment);

• attrition bias (incomplete outcome data);

• reporting bias (selective reporting); and

• other forms of bias.

We will classify each of the domains listed above as follows:

• low risk: if the criterion has been adequately fulfilled in the study;

• high risk: if the criterion has not been fulfilled in the study;

• unclear risk: if insufficient information is provided to permit a definitive judgement.

Measures of treatment effect

When extracting data for dichotomous outcomes (proportion of participants needing an allogenic blood transfusion, mortality, adverse events), we will record the number of participants and events in both the intervention and control arms. We will express the results as odds ratios with 95% confidence intervals (CIs).

However, when extracting arm‐level data for continuous outcomes (e.g. mean number of allogenic blood transfusions per participant), we will record means, standard deviations (or medians with interquartile ranges), and the total number of participants in both the intervention and control arms. If only study‐level data are available, we will note the reported effect size and standard errors. If the data allow, we will use Stata to do the quantitative analyses (Stata 2017).

For continuous outcome data measured using the same scale, we will use mean difference with a 95% CI. However, if this outcome is measured using different scales, we will use standardised mean difference with 95% CI.

Unit of analysis issues

When performing pair‐wise meta‐analyses, we will treat trials with multiple treatment comparisons as individual, independent two‐arm studies. However, this will not be the case in the NMA, where we will include all comparisons, if and when there are adequate data to do so. These trials will be analysed by taking into account the respective treatment effects. The NMA method correctly accounts for correlations in relative effects from trials with more than two arms. We will analyse data using the participant as the unit of analysis.

Dealing with missing data

We will handle missing data using the approach described in Chapter 10 of the Cochrane Handbook for Systematic Reviewsof Interventions (Deeks 2020). We will contact corresponding authors of studies to obtain missing data. We will keep a record of the number of participants lost to follow‐up in each trial. If an included trial has a mixed population, we will only extract data from the relevant population. If this is not possible, we will contact the authors up to three times to request additional information. If we are still unable to obtain the information, and the missing data are thought to lead to serious bias, we will perform a sensitivity analysis to assess the impact of the missing outcome data.

Assessment of heterogeneity

Assessment of clinical and methodological heterogeneity within treatment comparisons

If the extracted data appear to be homogeneous, we will amalgamate the data and undertake an NMA. We will look for clinical and methodological heterogeneity within each comparison by comparing trial and baseline characteristics across the included trials. If we find important clinical or methodological heterogeneity, meta‐analysis may not be possible. In such a case we will instead provide a descriptive summary.

When performing the NMA, we will assume a common estimate for heterogeneity across all our comparisons, and we will estimate a value for the total I² value across the network. We will assess statistical heterogeneity across the whole network based on the magnitude of the heterogeneity variance parameter (Tau²), which we will estimate from the NMA models. We will perform a likelihood ratio test for the null hypothesis of no heterogeneity versus presence of heterogeneity.

For pair‐wise meta‐analyses, there may be different heterogeneity variances for each pair‐wise comparison. We will assess the heterogeneity within each pair using the I² statistic and 95% CI (an I² statistic greater than 50% will indicate moderate heterogeneity), which demonstrates variability that is not due to random error. If heterogeneity is present, we will investigate this by performing a subgroup meta‐regression where possible (Deeks 2020).

Assessment of reporting biases

We will investigate the presence of small‐study effects in the pair‐wise meta‐analyses through funnel plots and linear regression, if there are at least 10 studies. We will consider a P value of 0.10 or below as statistically significant. Several factors can contribute to the association between study effect size and funnel plot asymmetry. We will differentiate between funnel plot asymmetry caused by publication bias using contour‐enhanced funnel plots (Peters 2008). The contour lines in the plot demonstrate levels of statistical significance. We will assume that a lack of studies in areas of non‐significance will show signs of publication bias.

Data synthesis

We will use Stata to undertake a multivariate NMA which will treat each comparison as a different outcome. We will perform the analyses using the network package in Stata (Stata 2017). We will provide the estimated treatment effect for each comparison with a 95% CI. For pair‐wise meta‐analyses, we will perform direct treatment comparisons using the methods described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2020). Where data are sufficiently homogeneous, we will perform meta‐analyses in Review Manager 5 or Review Manager Web (Review Manager 2020; RevMan Web 2019). Forest plots illustrating these results will be shown with 95% CIs for all analyses. Both review authors (VE and AH) will enter data into Review Manager 5 or Review Manager Web, and will cross‐check each other's data entry for accuracy.

Where appropriate, we will categorise interventions into clinically meaningful groups during the first stage of data extraction. Each group will act as a single node within the network. We will run sensitivity analyses using different groupings. Each group will contain one type of pharmacological intervention, for example only tranexamic acid, but may include a narrow dose range, route and timing variables, so as to have a pharmacologically similar predicted effect.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis

If the data allow, we will perform subgroup analyses and network meta‐regression for the following variables, to explain any heterogeneity, inconsistency, or both:

• site of injury;

• participants on anticoagulant or antiplatelet therapy at the time of injury.

The justification for the choice of subgroups is detailed in Data extraction and management.

Investigation of heterogeneity

Whilst performing pair‐wise meta‐analyses, we will evaluate heterogeneity in each pair‐wise comparison using the I² statistic (with 95% CI). For the NMA, we will estimate the heterogeneity variance parameter Tau² and use it to assess statistical heterogeneity within the network. We will also estimate a total I² statistic for the whole network (see Assessment of heterogeneity).

Assessment of statistical inconsistency

To gauge any inconsistency within each loop of the network, we will use the 'loop' inconsistency model of Lu and Ades (Lu 2006), employing the luades option in Stata (Stata 2017). This will give an assessment of consistency within each loop of the network. If there are no closed loops, we will calculate transitivity to determine the presence of inconsistency. We will assume there is common heterogeneity within each loop. We will present results in a forest plot through the network graphs package in Stata. If we find evidence of global inconsistency, we will use the node‐splitting method to explore this further (Dias 2010).

Sensitivity analysis

We will examine the strength of the overall results by performing sensitivity analyses, where appropriate, with and without the trials thought to be at high risk of bias. A sensitivity analysis is used to determine the robustness of an assessment by examining the extent to which results are affected by changing the methods or models of analysis, values of unmeasured variables or assumptions.

We will perform our main analyses using studies deemed as being at low risk of bias, and then undertake a sensitivity analysis that incorporates all the included studies. We will look at the effect of participant dropout, and will categorise the trials into groupings of:

• less than 20% dropout;

• 20% to 50% dropout; and

• more than 50% dropout.

We will analyse each group separately. We will explore heterogeneity using a fixed‐effect model to assess sensitivity.

Summary of findings and assessment of the certainty of the evidence

We will create a 'Summary of findings' table for each intervention for the following outcomes: need for allogenic blood transfusion in the emergency department or within 24 hours of injury, all‐cause mortality (deaths occurring within 30 days after the injury), mean number of red blood cell transfusion units per person (within 30 days), length of ICU and hospital stay, and adverse events (within 30 days).

We will use the GRADE approach, which involves consideration of study limitations, consistency of effect, imprecision, indirectness, and publication bias, to assess the certainty of the evidence contributing data to the analyses for the prespecified outcomes. We will use the methods described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2020), employing GRADEpro GDT software (GRADEpro GDT).

Two review authors (VE and AH) will independently judge the certainty of the evidence. Any disagreements will be resolved by discussion or by consulting a third review author (SB). We will provide justifications in the 'Summary of findings' table for downgrading of the certainty of the evidence in order to aid the reader's understanding of the review, and we will incorporate these judgements into the review for each outcome.

For the NMA, we will evaluate the confidence of the evidence using the CINeMA framework (Confidence in Network Meta‐Analysis) (Salanti 2014). We will use the online CINeMA tool, which assesses confidence for each comparison within the network and is based on within‐study bias, across‐studies bias, indirectness, imprecision, heterogeneity, and incoherence (CINeMA 2017).

We will create a summary of findings table before writing the 'Results' and 'Authors' conclusions' sections of the review.

Appendices

Appendix 1. Search strategies

CENTRAL

#1        MeSH descriptor: [Multiple Trauma] explode all trees

#2        MeSH descriptor: [Shock, Traumatic] explode all trees

#3        MeSH descriptor: [Trauma Severity Indices] explode all trees

#4        MeSH descriptor: [Traumatology] this term only

#5        MeSH descriptor: [Trauma Centers] this term only

#6        MeSH descriptor: [Amputation, Traumatic] this term only

#7        MeSH descriptor: [Blast Injuries] this term only

#8        ((trauma* or injur* or wound*) near/3 (critical* or massive* or major* or serious* or severe* or life‐threatening* or combat* or battlefield* or penetrating or nonpenetrating or non‐penetrating or blunt or multip* or abdominal* or thoracic or thorax or chest or torso or head or neck or arm* or leg* or skin or "soft tissue" or "soft tissues" or traffic or vehicle* or vehicular or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian* or stab* or lacerat* or knife or knives or crush* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or collision* or fall* or assault* or shrapnel)):ti,ab

#9        (trauma* or polytrauma* or ((blunt or penetrating or stab* or shooting or combat* or gunshot* or blast* or bomb* or battle* or massive* or major* or shock* or critical* or serious* or severe* or life‐threatening* or catastrophic or multiple) near/5 (injur* or wound* or casualt*))):ti

#10      ((trauma* or polytrauma*) near/5 (surg* or patient* or multipl* or injur* or victim* or casualt* or h?emorrhag* or bleed* or blood loss* or coagulopath*)):ti,ab

#11      #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10

#12      MeSH descriptor: [Military Medicine] this term only

#13      MeSH descriptor: [Military Personnel] this term only

#14      MeSH descriptor: [Rupture] explode all trees

#15      MeSH descriptor: [Wounds, Penetrating] explode all trees

#16      MeSH descriptor: [Wounds, Nonpenetrating] explode all trees

#17      MeSH descriptor: [Wounds and Injuries] this term only

#18      MeSH descriptor: [Lacerations] this term only

#19      MeSH descriptor: [Trauma, Nervous System] explode all trees

#20      MeSH descriptor: [Accidental Falls] this term only

#21      MeSH descriptor: [Abdominal Injuries] explode all trees

#22      MeSH descriptor: [Athletic Injuries] this term only

#23      MeSH descriptor: [Accidents, Traffic] this term only

#24      MeSH descriptor: [Crush Injuries] explode all trees

#25      MeSH descriptor: [Soft Tissue Injuries] explode all trees

#26      MeSH descriptor: [Thoracic Injuries] explode all trees

#27      MeSH descriptor: [Craniocerebral Trauma] explode all trees

#28      (polytrauma* or crush syndrome or "open wound" or "open wounds" or "puncture wound" or "puncture wounds" or incision* or "incised wound" or "incised wounds" or ((military or battle* or combat* or trauma* or traffic) near/3 surviv*)):ti,ab

#29      (accident* near/3 (critical* or massive* or catastroph* or major or serious* or severe* or life‐threatening* or traffic or vehicl* or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian*)):ti,ab

#30      (stab* or lacerat* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel or accident*):ti

#31      ((trauma* or combat* or gunshot* or blast* or battle*) near/2 (victim* or injur* or casualt*)):ti,ab

#32      #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31

#33      MeSH descriptor: [Hemorrhage] explode all trees

#34      (haemorrhag* or hemorrhag* or bleed* or bloodloss* or blood loss* or exsanguin* or hypovolemi* or hypovolaemi* or coagulopath* or haematoma* or hematoma* or damage control resuscitation or DIC):ti,ab

#35      #33 or #34

#36      #32 and #35

#37      ((head or brain or cerebrocranial* or cranial* or craniocerebral* or cerebral or intracranial* or intra‐cranial* or intracortical* or intra‐cortical* or subcortical* or sub‐cortical* or subdural* or extradural* or subarachnoid* or intra‐parenchymal* or intraparenchymal* or intraventricul* or intra‐ventricular* or periventricular* or peri‐ventricular* or cerebell* or cerebrum or corpus callosum or posterior fossa or hemispher*) near/5 (trauma* or injur* or wound* or haemorrhage* or hemorrhag* or bleed* or haematoma* or hematoma*)):ti,ab

#38      MeSH descriptor: [Hemorrhage] this term only

#39      (trauma* or polytrauma*)

#40      #38 and #39

#41      ((critical* or massive* or major* or serious* or severe* or life‐threatening* or catastrophic*) near/2 (haemorrhag* or hemorrhag* or bleed* or blood loss*)):ti

#42      #11 or #36 or #37 or #40 or #41

#43      MeSH descriptor: [Antifibrinolytic Agents] this term only

#44      MeSH descriptor: [Tranexamic Acid] this term only

#45      MeSH descriptor: [Aminocaproic Acid] explode all trees

#46      (antifibrinolytic* or anti‐fibrinolytic* or antifibrinolysin* or antiplasmin* or plasmin inhibitor* or tranexamic or tranhexamic or cyclohexanecarboxylic acid* or amcha or t‐amcha or amca or transamin or amchafibrin or anvitoff or spotof or cyklokapron or femstrual or ugurol):ti,ab

#47      (AMCHA or amchafibrin or amikapron or amstat or antivoff or caprilon or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse or fibrinon or hemostan or hexacapron):ti,ab

#48      (hexakapron or kalnex or lysteda or rikaparin or ronex or theranex or tranexam or tranexanic or tranexic or "trans achma" or transexamic or trenaxin or TXA):ti,ab

#49      (fibrinolysis near/2 inhibitor*):ti,ab

#50      (Agretax or Bio‐Stat or Capiloc or Capitrax or Clip Inj or Clot‐XL or Clotawin‐T or Coastat or Cuti or Cymin or Dubatran or Espercil or Examic or Existat or Extam or Fibran or Gynae‐Pil or Hemstate or Kapron or Menogia or Monitex or Nestran or Nexamic or Nexi‐500 or Nexmeff or Nicolda or Nixa‐500 or Pause or Rheonex or Sylstep TX or Synostat or T‐nex or T Stat or T Stat or Tanmic or Temsyl‐T or Texakind or Texanis or Texapar or Texid or Thams or Tonopan or Traklot or Tramic or Tramix or Tranarest or Trance Inj or Tranecid or Tranee or Tranemic or Tranex or Tranexa or Tranfib or Tranlok or Transtat or Transys or Transcam or Tranxi or Trapic or Traxage or Traxamic or Traxyl or Trenaxa or Trexamic or Trim Inj or Tx‐1000 or Tx 500 or Wistran or X‐Tran or Xamic):ti,ab

#51      (ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or epsilonaminocapronsav or ethaaminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or neocaprol or resplamin or tachostyptan):ti,ab

#52      (lederle or acikaprin or afibrin or amicar or caprocid or capracid or capramol or caprogel or caprolest or caprolisin* or caprolysin* or capromol or epsikapron or hemocaprol or caproamin or EACA or caprolest or capralense or hexalense or hamostat or hemocid):ti,ab

#53      (aminohexanoic or aminocaproic or aminohexanoic or amino caproic or amino‐caproic or amino‐n‐hexanoic):ti,ab

#54      #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53

#55      MeSH descriptor: [Aprotinin] this term only

#56      (antagosan or antilysin* or aprotimbin or apronitin* or aprotinin* or bayer a128 or contrical or contrycal or contrykal or dilmintal or frey inhibitor or kontrycal or Kunitz inhibitor or gordox or haemoprot or kallikrein‐trypsin inactivator or iniprol or kontrikal or kontrykal or kunitz pancreatic trypsin inhibitor or midran or pulmin or tracylol or trascolan or trasilol or tra?ylol or traskolan or zymofren or pancreas antitrypsin or protinin or riker 52g or Rivilina zymofren):ti,ab

#57      #55 or #56

#58      MeSH descriptor: [Factor VIIa] this term only

#59      (factor viia or factor 7a or rfviia or fviia or novoseven* or novo seven* or aryoseven or acset or eptacog* or proconvertin):ti,ab

#60      (activated near/1 (factor seven or factor vii or rfvii or fvii)):ti,ab

#61      (factor seven or factor vii or factor 7):ti

#62      #58 or #59 or #60 or #61

#63      MeSH descriptor: [Fibrinogen] this term only

#64      ("fibrinogen concentrate" or "factor I" or Haemocomplettan* or Riastap* or Fibryga* or Fibryna*):ti,ab

#65      #63 or #64

#66      MeSH descriptor: [Deamino Arginine Vasopressin] this term only

#67      (desmopressin* or vasopressin deamino or D amino D arginine vasopressin or deamino 8 d arginine vasopressin or vasopressin desamino 8 arginine or desmotabs or DDAVP or desmogalen or adin or adiuretin or concentraid or d void or dav ritter or deamino 8 dextro arginine vasopressin or deamino 8d arginine vasopressin or deamino dextro arginine vasopressin or deaminovasopressin or defirin or defirin melt or desmirin pr desmomelt or desmopresina or desmospray or desmotab* or desurin or emosint or enupresol or minirin or minirinette or minirinmelt or minrin or minurin or miram or nictur or noctisson or nocturin or nocutil or nordurine or novidin or nucotil or octim or octostim or presinex or stimate or wetirin):ti,ab

#68      #66 or #67

#69      MeSH descriptor: [Factor XIII] 2 tree(s) exploded

#70      (factor xiii or fxiii or fibrin stabili?ing factor* or Tretten* or Catridecacog):ti,ab

#71      #69 or #70

#72      MeSH descriptor: [Tissue Adhesives] explode all trees

#73      MeSH descriptor: [Collagen] explode all trees and with qualifier(s): [therapeutic use ‐ TU]

#74      MeSH descriptor: [Thrombin] explode all trees and with qualifier(s): [therapeutic use ‐ TU]

#75      MeSH descriptor: [Gelatin] explode all trees and with qualifier(s): [therapeutic use ‐ TU]

#76      MeSH descriptor: [Gelatin Sponge, Absorbable] this term only

#77      ((fibrin* or collagen or cellulose or gelatin or gel or thrombin* or albumin or hemostatic* or haemostatic* or alginate) near/3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste or powder*)):ti,ab

#78      ((nonfibrin* or non‐fibrin* or synthetic* or non‐biological* or nonbiological* or biological*) near/3 (glue* or seal* or adhesive*)):ti,ab

#79      (surgical* near/3 (glue* or sealant* or adhesive*)):ti,ab

#80      ((fibrin* or collagen or cellulose or gelatin or thrombin) near/3 (hemosta* or haemosta*)):ti,ab

#81      (8Y or Aafact or Actif‐VIII or Advate or Artiss or Bioglue or Biocol or Collaseal or Omrixil or Transglutine or Raplixa or Evarrest or Aleviate or Alphanate or Amofil or Beriate or Beriplast or Biostate or Bolheal or Cluvot or Conco‐Eight‐HT or Crosseel or Crosseal or Crosseight or Emoclot or Evarrest or Evicel or Factane or Fanhdi or Fibrogammin P or Green VIII or Green VIII Factor or Greengene or Greenmono or Greenplast or Haemate or Haemate P or Haemate P or Haemate P500 or Haemate‐P or Haemoctin or Haemoctin SDH or Haemoctin‐SDH or Hemaseel or Hemaseal or Hemofil M or Hemoraas or Humaclot or Humafactor‐8 or Humate‐P or Immunate or Innovate or Koate or Koate‐DVI or Kogenate Bayer or Kogenate FS or Monoclate‐P or NovoThirteen or Octafil or Octanate or Octanate or Optivate or Quixil or Talate or Tisseel or Tisseal or Tissel or Tissucol or Tricos or Vivostat or Voncento or Wilate or Wilnativ or Wilstart or Xyntha):ti,ab

#82      (Glubran or Gluetiss or Ifabond or Indermil or LiquiBand or TissuGlu or Evithrom or Floseal or Hemopatch or Gel‐Flow or Gelfoam or Gelfilm or Recothrom or Surgifoam or Surgiflo* or "rh Thrombin" or Thrombi‐Gel or Thrombi‐Pad or Thrombin‐JMI or Thrombinar or Thrombogen or Thrombostat):ti,ab

#83      (porcine gelatin or bovine collagen or bovine gelatin or nu‐knit or arista or hemostase or vita sure or thrombin‐jmi or thrombinjmi or avicel or vivagel or lyostypt or tabotamp or arterx or omnex or veriset):ti,ab

#84      (polysaccharide next (sphere* or hemostatic powder)):ti,ab

#85      MeSH descriptor: [Chitosan] this term only

#86      MeSH descriptor: [Polyethylene Glycols] this term only and with qualifier(s): [therapeutic use ‐ TU]

#87      MeSH descriptor: [Hydrogel, Polyethylene Glycol Dimethacrylate] 5 tree(s) exploded and with qualifier(s): [therapeutic use ‐ TU]

#88      MeSH descriptor: [Polyurethanes] explode all trees and with qualifier(s): [pharmacology ‐ PD, adverse effects ‐ AE, toxicity ‐ TO, administration & dosage ‐ AD, therapeutic use ‐ TU]

#89      ((polymer‐derived elastic* or polymer tissue adhesive* or elastic hydrogel* or glutaraldehyde or PEG‐based or polyurethane‐based tissue or polyethylene glycol* or polyvinyl alcohol‐based tissue or PVA‐based tissue or natural biopolymer* or polypeptide‐based or protein‐based or polysaccharide‐based or chitosan or poliglusam or cyanoacrylic or cyanoacrylate or cyacrin or dextran‐based or chondroitin sulfate‐based or mussel‐inspired elastic* or glycol hydrogel or polymer‐based) next (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste* or powder*)):ti,ab

#90      MeSH descriptor: [Cellulose, Oxidized] this term only

#91      (absorbable cellulose or resorbable cellulose or oxidi?ed cellulose or carboxycellulose or oxycellulose or cellulosic acid or oxycel or oxidi?ed regenerated cellulose):ti,ab

#92      (BioGlue or Progel or Duraseal or Coseal or FocalSeal or ADAL‐1 or AdvaSeal or Pleuraseal or Angio‐Seal or Avitene or Instat or Helitene or Helistat or TDM‐621 or Dermabond or Tissueseal or PolyStat or Raplixa or Spongostan or Surgicel or Surgilux or Tachosil or Traumstem):ti,ab

#93      (collagen‐thrombin or thrombin‐collagen or gelatin‐fibrinogen or fibrinogen‐gelatin or gelatin‐thrombin or thrombin‐gelatin or fibrinogen‐thrombin or thrombin‐fibrinogen or collagen‐fibrinogen or fibrinogen‐collagen or microfibrillar collagen or CoStasis or "GRF Glue" or GR‐Dial or Algosterile or TraumaStat or HemCon or ChitoFlex or Celox or QuikClot or WoundStat or Vitagel or TachSeal or TachoComb or Cryoseal):ti,ab

#94      #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93

#95      MeSH descriptor: [Blood Coagulation Factors] this term only

#96      (prothrombin near/5 (complex* or concentrate*))

#97      (PCC* or 3F‐PCC* or 4F‐PCC* or Beriplex* or Feiba* or Autoplex* or Ocplex* or Octaplex* or Kcentra* or Cofact or Prothrombinex* or "Proplex‐T" or Prothroraas* or Haemosolvex* or Prothromplex* or "HT Defix" or Facnyne* or Kaskadil* or Kedcom* or Confidex* or PPSB or Profil?ine* or Pronativ* or Proplex* or Prothar* or ProthoRAAS* or Protromplex* or "Pushu Laishi" or "Uman Complex")

#98      #95 or #96 or #97

#99      (((haemosta* or hemosta* or antihaemorrhag* or antihemorrhag* or anti haemorrhag* or anti‐hemorrhag*) next (drug* or agent* or treat* or therap*)) or ((coagulat* or clotting) next factor*)):ti,ab

#100    #54 or #57 or #62 or #65 or #68 or #71 or #94 or #98 or #100

#101    #42 and #100

MEDLINE

1. exp Multiple Trauma/          

2. exp Shock, Traumatic/          

3. exp Trauma Severity Indices/

4. Traumatology/         

5. Trauma Centers/      

6. Amputation, Traumatic/       

7. Blast Injuries/          

8. exp Crush Syndrome/

9. ((trauma* or injur* or wound*) adj3 (critical* or massive* or major* or serious* or severe* or life‐threatening* or penetrating or nonpenetrating or non‐penetrating or blunt or multip* or abdominal* or thoracic or thorax or chest or torso or head or neck or arm* or leg* or skin or soft tissue* or traffic or vehicle* or vehicular or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian* or stab* or lacerat* or stab* or knife or knives or crush* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel)).tw,kf.

10. (trauma* or polytrauma* or ((blunt or penetrating or stab* or shooting or combat* or gunshot* or blast* or bomb* or battle* or massive* or major or shock* or critical* or serious* or severe* or life‐threatening* or catastrophic or multiple) adj5 (injur* or wound* or casualt*))).ti,kf.

11. ((trauma* or polytrauma*) adj5 (surg* or patient* or multipl* or injur* or victim* or casualt* or h?emorrhag* or bleed* or blood loss* or coagulopath*)).tw,kf.  

12. or/1‐11      

13. Military Medicine/ 

14. Military Personnel/

15. exp Rupture/         

16. exp Wounds, Penetrating/ 

17. exp Wounds, Nonpenetrating/       

18. "Wounds and Injuries".sh,kf.          

19. Lacerations/          

20. exp Trauma, Nervous System/        

21. Accidental Falls/    

22. exp Abdominal Injuries/     

23. Athletic Injuries/    

24. Accidents, Traffic/  

25. exp Crush Injuries/ 

26. exp Soft Tissue Injuries/     

27. exp Thoracic Injuries/         

28. exp Craniocerebral Trauma/

29. (polytrauma* or crush syndrome or open wound* or puncture wound* or incision* or incised wound* or ((military or battle* or combat* or trauma* or traffic) adj3 surviv*)).tw,kf.      

30. (accident* adj3 (critical* or massive* or catastroph* or major or serious* or severe* or life‐threatening* or traffic or vehicl* or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian*)).tw,kf.         

31. (stab* or lacerat* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel or accident*).ti,kf.

32. ((trauma* or combat* or gunshot* or blast* or battle*) adj2 (victim* or injur* or casualt*)).tw,kf.

33. or/13‐32    

34. exp Hemorrhage/ or Shock, Hemorrhagic/  

35. (haemorrhag* or hemorrhag* or bleed* or bloodloss* or blood loss* or exsanguin* or hypovolemi* or hypovolaemi* or coagulopath* or hematoma* or haematoma* or damage control resuscitation or DIC).mp.        

36. 34 or 35     

37. 33 and 36  

38. ((head or brain or cerebrocranial* or cranial* or craniocerebral* or cerebral or intracranial* or intra‐cranial* or intracortical* or intra‐cortical* or subcortical* or sub‐cortical* or subdural* or extradural* or subarachnoid* or intra‐parenchymal* or intraparenchymal* or intraventricul* or intra‐ventricular* or periventricular* or peri‐ventricular* or cerebell* or cerebrum or corpus callosum or posterior fossa or hemispher*) adj5 (trauma* or injur* or wound* or haemorrhag* or hemorrhag* or bleed* or haematoma* or hematoma*)).tw,kf.       

39. *Hemorrhage/ and (trauma* or polytrauma*).mp. 

40. ((critical* or massive* or major* or serious* or severe* or life‐threatening* or catastrophic*) adj2 (h?emorrhag* or bleed* or blood loss*)).ti,kf.      

41. 12 or 37 or 38 or 39 or 40   

42. Antifibrinolytic Agents/      

43. Tranexamic Acid/   

44. Aminocaproic Acid/

45. (antifibrinolytic* or anti‐fibrinolytic* or antifibrinolysin* or antiplasmin* or plasmin inhibitor* or tranexamic or tranhexamic or cyclohexanecarboxylic acid* or amcha or trans‐4‐aminomethyl‐cyclohexanecarboxylic acid* or t‐amcha or amca or "kabi 2161" or transamin or amchafibrin or anvitoff or spotof or cyklokapron or cyclo‐F or femstrual or ugurol or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or antivoff or caprilon or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse or fibrinon or hemostan or hexacapron or hexakapron or kalnex or lysteda or rikaparin or ronex or theranex or tranexam or tranexanic or tranexic or trans achma or transexamic or trenaxin or TXA or (fibrinolysis adj2 inhibitor*)).tw,kf.

46. (Agretax or Bio‐Stat or Capiloc or Capitrax or Clip Inj or Clot‐XL or Clotawin‐T or Coastat or Cuti or Cymin or Dubatran or Espercil or Examic or Existat or Extam or Fibran or Gynae‐Pil or Hemstate or Kapron or Menogia or Monitex or Nestran or Nexamic or Nexi‐500 or Nexmeff or Nicolda or Nixa‐500 or Pause or Rheonex or Sylstep TX or Synostat or T‐nex or T Stat or T Stat or Tanmic or Temsyl‐T or Texakind or Texanis or Texapar or Texid or Thams or Tonopan or Traklot or Tramic or Tramix or Tranarest or Trance Inj or Tranecid or Tranee or Tranemic or Tranex or Tranexa or Tranfib or Tranlok or Transtat or Transys or Transcam or Tranxi or Trapic or Traxage or Traxamic or Traxyl or Trenaxa or Trexamic or Trim Inj or Tx‐1000 or Tx 500 or Wistran or X‐Tran or Xamic).tw,kf.           

47. (6‐aminohexanoic or amino?caproic or amino?hexanoic or amino caproic or amino‐caproic or amino‐n‐hexanoic or cy‐116 or cy116 or lederle or acikaprin or afibrin or amicar or caprocid or capracid or capramol or caprogel or caprolest or caprolisin* or caprolysin* or capromol or epsikapron or hemocaprol or caproamin or EACA or caprolest or capralense or hexalense or hamostat or hemocid or cl 10304 or cl10304 or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or epsilonaminocapronsav or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or resplamin or tachostyptan).tw,kf.

48. or/42‐47    

49. Aprotinin/ 

50. (antagosan or antilysin* or aprotimbin or apronitin* or aprotinin* or bayer a128 or contrical or contrycal or contrykal or dilmintal or frey inhibitor or kontrycal or Kunitz inhibitor or gordox or haemoprot or kallikrein‐trypsin inactivator).tw,kf.      

51. (iniprol or kontrikal or kontrykal or kunitz pancreatic trypsin inhibitor or midran or pulmin or tracylol or trascolan or trasilol or tra?ylol or traskolan or zymofren or pancreas antitrypsin or protinin or riker 52g or Rivilina zymofren).tw,kf.     

52. or/49‐51    

53. Factor VIIa/

54. (factor viia or factor 7a or rfviia or fviia or novoseven* or novo seven* or aryoseven or acset or eptacog* or proconvertin).tw,kf.      

55. ((activated adj2 factor seven) or (activated adj2 factor vii) or (activated adj3 rfvii) or (activated adj2 fvii)).tw,kf.        

56. (factor seven or factor vii or factor 7).ti.      

57. 53 or 54 or 55 or 56

58. Fibrinogen/ad, ae, de, sd, tu, th, to 

59. *Fibrinogen/         

60. (fibrinogen concentrate* or factor I or Haemocomplettan* or Riastap* or Fibryga* or Fibryna*).tw,kf.          

61. 58 or 59 or 60        

62. Deamino Arginine Vasopressin/      

63. (desmopressin* or vasopressin deamino or D‐amino D‐arginine vasopressin or deamino‐8‐d‐arginine vasopressin or vasopressin 1‐desamino‐8‐arginine or desmotabs or DDAVP or desmogalen or adin or adiuretin or concentraid or d‐void or dav ritter or deamino 8 dextro arginine vasopressin or deamino 8d arginine vasopressin or deamino dextro arginine vasopressin or deaminovasopressin or defirin or defirin melt or desmirin or desmomelt or desmopresina or desmospray or desmotab* or desurin or emosint or enupresol or minirin or minirinette or minirinmelt or minrin or minurin or miram or nictur or noctisson or nocturin or nocutil or nordurine or novidin or nucotil or octim or octostim or presinex or stimate or wetirin).tw,kf.        

64. 62 or 63     

65. exp Factor XIII/      

66. (factor XIII or fXIII or fibrin stabili?ing factor* or Tretten* or Catridecacog).tw,kf.     

67. 65 or 66     

68. exp Tissue Adhesives/        

69. *Adhesives/

70. Collagen/tu

71. Thrombin/tu          

72. Gelatin/tu 

73. Gelatin Sponge, Absorbable/          

74. ((fibrin* or collagen or cellulose or gelatin or gel or thrombin* or albumin or hemostatic* or haemostatic* or alginate) adj3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste or powder*)).tw,kf.         

75. ((nonfibrin* or non‐fibrin* or synthetic* or non‐biological* or nonbiological* or biological*) adj3 (glue* or seal* or adhesive*)).tw,kf.

76. (surgical* adj3 (glue* or sealant* or adhesive*)).tw,kf.        

77. ((fibrin* or collagen or cellulose or gelatin or thrombin) adj3 (hemosta* or haemosta*)).tw,kf.

78. (8Y or Aafact or Actif‐VIII or Advate or Artiss or Bioglue or Biocol or Collaseal or Omrixil or Transglutine or Raplixa or Evarrest or Aleviate or Alphanate or Amofil or Beriate or Beriplast or Biostate or Bolheal or Cluvot or Conco‐Eight‐HT or Crosseel or Crosseal or Crosseight or Emoclot or Evarrest or Evicel or Factane or Fanhdi or Fibrogammin P or Green VIII or Green VIII Factor or Greengene or Greenmono or Greenplast or Haemate or Haemate P or Haemate P or Haemate P500 or Haemate‐P or Haemoctin or Haemoctin SDH or Haemoctin‐SDH or Hemaseel or Hemaseal or Hemofil M or Hemoraas or Humaclot or Humafactor‐8 or Humate‐P or Immunate or Innovate or Koate or Koate‐DVI or Kogenate Bayer or Kogenate FS or Monoclate‐P or NovoThirteen or Octafil or Octanate or Octanate or Optivate or Quixil or Talate or Tisseel or Tisseal or Tissel or Tissucol or Tricos or Vivostat or Voncento or Wilate or Wilnativ or Wilstart or Xyntha).tw,kf.          

79. (Glubran or Gluetiss or Ifabond or Indermil or LiquiBand or TissuGlu).tw,kf. 

80. (Evithrom or Floseal or Hemopatch or Gel‐Flow or Gelfoam or Gelfilm or Recothrom or Surgifoam or Surgiflo* or "rh Thrombin" or Thrombi‐Gel or Thrombi‐Pad or Thrombin‐JMI or Thrombinar or Thrombogen or Thrombostat).tw,kf.   

81. (porcine gelatin or bovine collagen or bovine gelatin or nu‐knit or arista or hemostase or vita sure or thrombin‐jmi or thrombinjmi or avicel or vivagel or lyostypt or tabotamp or arterx or omnex or veriset).tw,kf.        

82. (polysaccharide adj (sphere* or hemostatic powder)).tw,kf.

83. *Chitosan/ 

84. (chitosan* or mucoadhesive or muco‐adhesive or Celox Gauze or ChitoGauze or Combat Gauze).tw,kf.        

85. *Polyethylene Glycols/       

86. *Hydrogel, Polyethylene Glycol Dimethacrylate/     

87. Polyurethanes/ad, ae, pd, tu, to     

88. ((polymer‐derived elastic* or polymer tissue adhesive* or elastic hydrogel* or glutaraldehyde or PEG‐based or polyurethane‐based tissue or polyethylene glycol* or polyvinyl alcohol‐based tissue or PVA‐based tissue or natural biopolymer* or polypeptide‐based or protein‐based or polysaccharide‐based or poliglusam or cyanoacrylic or cyanoacrylate or cyacrin or dextran‐based or chondroitin sulfate‐based or mussel‐inspired elastic* or glycol hydrogel or polymer‐based) adj3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste* or powder*)).tw,kf.

89. Cellulose, Oxidized/

90. (absorbable cellulose or resorbable cellulose or oxidi?ed cellulose or carboxycellulose or oxycellulose or cellulosic acid or oxycel or oxidi?ed regenerated cellulose).tw,kf.

91. (BioGlue or Progel or Duraseal or Coseal or FocalSeal or ADAL‐1 or AdvaSeal or Pleuraseal or Angio‐Seal or Avitene or Instat or Helitene or Helistat or TDM‐621 or Dermabond or Tissueseal or PolyStat or Raplixa or Spongostan or Surgicel or Surgilux or Tachosil or Traumstem).tw,kf.        

92. (collagen‐thrombin or thrombin‐collagen or gelatin‐fibrinogen or fibrinogen‐gelatin or gelatin‐thrombin or thrombin‐gelatin or fibrinogen‐thrombin or thrombin‐fibrinogen or collagen‐fibrinogen or fibrinogen‐collagen or microfibrillar collagen or CoStasis or "GRF Glue" or GR‐Dial or Algosterile or TraumaStat or HemCon or ChitoFlex or Celox or QuikClot or WoundStat or Vitagel or TachSeal or TachoComb or Cryoseal).tw,kf.      

93. or/68‐92    

94. Hemostatics/ad, th, tu       

95. (((haemosta* or hemosta* or antihaemorrhag* or antihemorrhag* or anti‐haemorrhag* or anti‐hemorrhag*) adj5 (drug* or agent* or treat* or therap* or dressing* or emergenc*)) or ((coagulat* or clotting) adj factor*)).tw,kf.        

96. 48 or 52 or 57 or 61 or 64 or 67 or 93 or 94 or 95    

97. 41 and 96  

98. Meta‐Analysis/ or Network Meta‐Analysis/  

99. Systematic Review/

100. "Systematic Reviews as Topic"/ or "Meta‐Analysis as Topic"/          

101. ((meta analy* or metaanaly*) and (trials or studies)).ab.    

102. (meta analy* or metaanaly*).ti,kf.

103. ((systematic* or evidence‐based) adj2 (review* or overview*)).tw,kf.        

104. (evidence synthes* or cochrane or medline or pubmed or embase or cinahl or cinhal or lilacs or "web of science" or science citation index or scopus or search terms or literature search or electronic search* or comprehensive search* or systematic search* or published articles or search strateg* or reference list* or bibliograph* or handsearch* or hand search* or manual* search*).ab.  

105. Cochrane Database of systematic reviews.jn.        

106. ((additional adj (papers or articles or sources)) or (relevant adj (journals or articles))).ab.    

107. ((electronic* or online) adj (sources or resources or databases)).ab.

108. network meta‐analys*.tw,kf.        

109. or/98‐108

110. Review.pt.

111. Randomized Controlled Trials as Topic/     

112. selection criteria.ab. or critical appraisal.ti.

113. (data adj (abstraction or extraction or analys*)).ab.

114. exp Randomized Controlled Trial/ 

115. or/111‐114          

116. 110 and 115        

117. 109 or 116

118. exp Randomized Controlled Trial/ 

119. Controlled Clinical Trial/ or Clinical Trial Protocol/ 

120. (randomi* or randomly or placebo*).tw,kf.

121. trial.ti,kf. 

122. Clinical Trials as Topic/     

123. Clinical Trial, Phase III/ or ("phase 3" or "phase3" or "phase III" or P3 or "PIII").tw,kf.

124. or/118‐123          

125. 117 or 124

126. (exp Animals/ or exp Animal Experimentation/ or exp Models, Animal/) not Humans/        

127. Editorial.pt.         

128. 126 or 127

129. 125 not 128         

130. 97 and 129

PubMed

#1 ((trauma*[TI] OR polytrauma*[TI] OR blunt[TI] OR penetrating[TI] OR stab*[TI] OR shooting[TI] OR combat*[TI] OR gunshot*[TI] OR blast*[TI] OR bomb*[TI] OR battle*[TI] OR massive*[TI] OR major*[TI] OR shock*[TI] OR critical*[TI] OR serious*[TI] OR severe*[TI] OR life‐threatening*[TI] OR catastrophic[TI] OR multipl*[TI]) AND (injur*[TI] OR wound*[TI]))

#2 ((trauma*[TIAB] OR polytrauma*[TIAB]) AND (patient*[TIAB] OR multipl*[TIAB] OR injur*[TIAB] OR victim*[TIAB] OR casualt*[TIAB] OR hemorrhag*[TIAB] OR haemorrhag*[TIAB] OR bleed*[TIAB] OR blood loss*[TIAB] OR coagulopath*[TIAB]))

#3 (polytrauma*[TIAB] OR "crush syndrome"[TIAB] OR "open wound"[TIAB] OR "open wounds"[TIAB] OR "puncture wound"[TIAB] OR "puncture wounds"[TIAB] OR incision*[TIAB] or "incised wound"[TIAB] OR "incised wounds"[TIAB] OR ((military[TIAB] OR battle*[TIAB] OR combat*[TIAB] OR trauma*[TIAB] OR traffic[TIAB]) AND surviv*[TIAB]))

#4 (accident*[TIAB] AND (critical*[TIAB] OR massive*[TIAB] OR catastroph*[TIAB] OR major*[TIAB] OR serious*[TIAB] OR severe*[TIAB] OR life‐threatening*[TIAB] OR traffic[TIAB] OR vehicle*[TIAB] OR vehicular*[TIAB] OR automobile*[TIAB] OR motorcar*[TIAB] OR road*[TIAB] OR motorcycl*[TIAB] OR car[TIAB] OR cars[TIAB] OR riding[TIAB] OR sport*[TIAB] OR athlet*[TIAB] OR bicycle*[TIAB] OR cycle*[TIAB] OR cycling[TIAB] OR pedestrian*[TIAB]))
#5 (stab*[TI] OR lacerat*[TI] OR shooting[TI] OR gunshot*[TI] OR blast*[TI] OR bomb*[TI] OR explosi*[TI] OR disaster*[TI] OR catastroph*[TI] OR combat*[TI] OR battlefield*[TI] OR fall*[TI] OR collision*[TI] OR assault*[TI] OR shrapnel[TI] OR accident*[TI])

#6 ((trauma*[TIAB] OR combat*[TIAB] OR gunshot*[TIAB] OR blast*[TIAB] OR battle*[TIAB]) AND (victim*[TIAB] OR injur*[TIAB] OR casualt*[TIAB]))

#7 ((head[TI] OR brain[TI] OR cerebrocranial*[TI] OR cranial*[TI] OR craniocerebral*[TI] OR cerebral[TI] OR intracranial*[TI] OR intra‐cranial*[TI] OR intracortical*[TI] OR intra‐cortical*[TI] OR subcortical*[TI] OR sub‐cortical*[TI] OR subdural*[TI] OR extradural*[TI] OR subarachnoid*[TI] OR intra‐parenchymal*[TI] OR intraparenchymal*[TI] OR intraventricul*[TI] OR intra‐ventricular*[TI] OR periventricular*[TI] OR peri‐ventricular*[TI] OR cerebell*[TI] OR cerebrum[TI] OR corpus callosum[TI] OR posterior fossa[TI] OR hemispher*[TI]) AND (trauma*[TI] OR injur*[TI] OR wound*[TI] OR haemorrhag*[TI] OR hemorrhag*[TI] OR bleed*[TI] OR haematoma*[TI] OR hematoma*[TI]))

#8 ((trauma*[TIAB] OR polytrauma*) AND (patient*[TIAB] OR multipl*[TIAB] OR injur*[TIAB] OR victim*[TIAB] OR casualt*[TIAB] OR hemorrhag*[TIAB] OR haemorrhag*[TIAB] OR bleed*[TIAB] OR blood loss*[TIAB] OR haematoma*[TIAB] OR hematoma*[TIAB] OR coagulopath*[TIAB]))

#9 ((critical*[TI] OR massive*[TI] OR major*[TI] OR serious*[TI] OR severe*[TI] OR life‐threatening*[TI] OR catastrophic*[TI]) AND (hemorrhag*[TI] OR haemorrhag*[TI] OR bleed*[TI] OR blood loss*[TI]))

#10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

#11 (hemostatic*[TIAB] OR antifibrinolytic*[TIAB] OR anti‐fibrinolytic*[TIAB] OR tranexamic[TIAB] OR EACA[TIAB] OR aminocaproic[TIAB] OR aprotinin[TIAB] OR desmopressin[TIAB] OR DDAVP[TIAB] OR "factor viia"[TIAB] OR novoseven[TIAB] OR aryoseven[TIAB] OR fibrinogen[TIAB] OR prothrombin[TIAB] OR thrombin[TIAB] OR haemocomplettan[TIAB] OR Riastap[TIAB] OR Fibryna[TIAB] OR Fibryga[TIAB] OR factor XIII[TIAB] OR Tretten[TIAB] OR sealant[TIAB] OR adhesive[TIAB] OR collagen[TIAB] OR cellulose[TIAB] OR gelatin[TIAB] OR alginate[TIAB] OR glue[TIAB] OR matrix[TIAB] OR sponge[TIAB] OR fleece[TIAB] OR foam[TIAB] OR scaffold[TIAB] OR patch*[TIAB] OR sheet*[TIAB] OR gelfoam[TIAB] OR chitosan[TIAB] OR hydrogel[TIAB] OR polyethylene glycol[TIAB] OR tachocomb[TIAB] OR BioGlue[TIAB] OR Surgicel[TIAB] OR Veriset[TIAB] OR Evithrom[TIAB] OR Floseal[TIAB] OR Tachosil[TIAB] OR Cryoseal[TIAB] OR Hemopatch[TIAB] OR Progel[TIAB] OR Duraseal[TIAB] OR Coseal[TIAB] OR FocalSeal[TIAB] OR Algosterile[TIAB] OR TraumaStat[TIAB] OR HemCon[TIAB] OR ChitoFlex[TIAB] OR Celox[TIAB] OR QuikClot[TIAB] OR WoundStat[TIAB] OR Vitagel[TIAB] OR TachSeal[TIAB] OR iniprol[TIAB] OR kontrikal[TIAB] OR CloSys[TIAB] OR Glubran[TIAB] OR Gluetiss[TIAB] OR Ifabond[TIAB] OR Indermil[TIAB] OR LiquiBand[TIAB] OR Octafil[TIAB] OR Octanate[TIAB] OR Optivate[TIAB] OR Quixil[TIAB] OR Tisseel[TIAB] OR Tissucol[TIAB] OR TissuGlu[TIAB] OR Thrombi‐Gel[TIAB] OR Vivostat[TIAB] OR Voncento[TIAB] OR Wilate[TIAB] OR Wilnativ[TIAB] OR Wilstart[TIAB])

#12 (random* OR blind* OR "control group" OR placebo* OR controlled OR trial* OR "systematic review" OR "meta‐analysis" OR metaanalysis OR "evidence synthesis" OR "literature search" OR medline[TIAB] OR pubmed[TIAB] OR cochrane[TIAB] OR embase[TIAB])

#13 (publisher[sb] OR inprocess[sb] OR pubmednotmedline)

#14 #10 AND #11 AND #12 AND #13

Embase

1. Multiple Trauma/     

2. Penetrating Trauma/ or Traumatic Amputation/       

3. exp Traumatology/   

4. Battle Injury/ or Blast Injury/

5. Blunt Trauma/ or Crush Trauma/       

6. Gunshot Injury/ or Missile Wound/ or Stab Wound/  

7. exp Traumatic Shock/

8. ((trauma* or injur* or wound*) adj3 (critical* or massive* or major* or serious* or severe* or life‐threatening* or penetrating or nonpenetrating or non‐penetrating or blunt or multip* or abdominal* or thoracic or thorax or chest or torso or head or neck or arm* or leg* or skin or soft tissue* or traffic or vehicle* or vehicular or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian* or stab* or lacerat* or stab* or knife or knives or crush* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel)).tw,kw.    

9. (trauma* or polytrauma* or ((blunt or penetrating or stab* or shooting or combat* or gunshot* or blast* or bomb* or battle* or massive* or major or shock* or critical* or serious* or severe* or life‐threatening* or catastrophic or multiple) adj3 (injur* or wound*))).ti,kw.          

10. ((trauma* or polytrauma*) adj5 (patient* or multipl* or injur* or victim* or casualt* or h?emorrhag* or bleed* or blood loss* or coagulopath*)).tw,kw.           

11. or/1‐10      

12. *Military Medicine/

13. *Accidental Injury/

14. exp *Abdominal Injury/     

15. exp *Thorax Injury/

16. exp *Spinal Cord Injury/     

17. *Organ Injury/       

18. exp *Pelvis Injury/ 

19. exp *Injury Scale/ or *Injury Severity/        

20. *Rupture/ 

21. *Sport Injury/        

22. exp *Soft Tissue Injury/      

23. exp *Skin Injury/    

24. *Knife Cut/ or *Laceration/

25. *Spine Injury/        

26. exp *"Head and Neck Injury"/         

27. *Injury/ or *Wound/          

28. *Traffic Accident/ or *Seatbelt Injury/        

29. *Aircraft Accident/

30. *Explosion/ and *Injury/    

31. *Falling/ and *Injury/         

32. exp *Disaster/ and *Injury/

33. exp *Nuclear Accident/      

34. (polytrauma* or crush syndrome or open wound* or puncture wound* or incision* or incised wound* or ((military or battle* or combat* or trauma* or traffic) adj3 surviv*)).tw,kw.    

35. (accident* adj3 (critical* or massive* or catastroph* or major or serious* or severe* or life‐threatening* or traffic or vehicl* or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian*)).tw,kw.        

36. (stab* or lacerat* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel or accident*).ti,kw.

37. ((trauma* or combat* or gunshot* or blast* or battle*) adj2 (victim* or injur* or casualt*)).tw,kw.  

38. or/12‐37    

39. *Exsanguination/ or *Hemorrhagic Hypotension/ or Hemorrhagic Shock/ or Wound Hemorrhage/   

40. *Bleeding/ or *Abdominal Bleeding/ or exp *Brain Hemorrhage/    

41. (haemorrhag* or hemorrhag* or bleed* or bloodloss* or blood loss* or exsanguin* or hypovolemi* or hypovolaemi* or coagulopath* or hematoma* or haematoma* or damage control resuscitation or DIC).mp.        

42. or/39‐41    

43. 38 and 42  

44. ((head or brain or cerebrocranial* or cranial* or craniocerebral* or cerebral or intracranial* or intra‐cranial* or intracortical* or intra‐cortical* or subcortical* or sub‐cortical* or subdural* or extradural* or subarachnoid* or intra‐parenchymal* or intraparenchymal* or intraventricul* or intra‐ventricular* or periventricular* or peri‐ventricular* or cerebell* or cerebrum or corpus callosum or posterior fossa or hemispher*) adj5 (trauma* or injur* or wound* or haemorrhage* or hemorrhag* or bleed* or haematoma* or hematoma*)).tw,kw.    

45. (*Hemorrhagic Shock/ or *Bleeding/) and (trauma* or polytrauma*).mp.    

46. ((critical* or massive* or major* or serious* or severe* or life‐threatening* or catastrophic*) adj2 (h?emorrhag* or bleed* or blood loss*)).ti,kw.    

47. 11 or 43 or 44 or 45 or 46   

48. Antifibrinolytic Agent/       

49. Tranexamic Acid/   

50. Aminocaproic Acid/

51. (antifibrinolytic* or anti‐fibrinolytic* or antifibrinolysin* or antiplasmin* or plasmin inhibitor* or tranexamic or tranhexamic or cyclohexanecarboxylic acid* or amcha or trans‐4‐aminomethyl‐cyclohexanecarboxylic acid* or t‐amcha or amca or "kabi 2161" or transamin or amchafibrin or anvitoff or spotof or cyklokapron or cyclo‐F or femstrual or ugurol or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or antivoff or caprilon or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse or fibrinon or hemostan or hexacapron or hexakapron or kalnex or lysteda or rikaparin or ronex or theranex or tranexam or tranexanic or tranexic or trans achma or transexamic or trenaxin or TXA or (fibrinolysis adj2 inhibitor*)).tw,kw.

52. (Agretax or Bio‐Stat or Capiloc or Capitrax or Clip Inj or Clot‐XL or Clotawin‐T or Coastat or Cuti or Cymin or Dubatran or Espercil or Examic or Existat or Extam or Fibran or Gynae‐Pil or Hemstate or Kapron or Menogia or Monitex or Nestran or Nexamic or Nexi‐500 or Nexmeff or Nicolda or Nixa‐500 or Pause or Rheonex or Sylstep TX or Synostat or T‐nex or T Stat or T Stat or Tanmic or Temsyl‐T or Texakind or Texanis or Texapar or Texid or Thams or Tonopan or Traklot or Tramic or Tramix or Tranarest or Trance Inj or Tranecid or Tranee or Tranemic or Tranex or Tranexa or Tranfib or Tranlok or Transtat or Transys or Transcam or Tranxi or Trapic or Traxage or Traxamic or Traxyl or Trenaxa or Trexamic or Trim Inj or Tx‐1000 or Tx 500 or Wistran or X‐Tran or Xamic).tw,kw.           

53. (6‐aminohexanoic or amino?caproic or amino?hexanoic or amino caproic or amino‐caproic or amino‐n‐hexanoic or cy‐116 or cy116 or lederle or acikaprin or afibrin or amicar or caprocid or capracid or capramol or caprogel or caprolest or caprolisin* or caprolysin* or capromol or epsikapron or hemocaprol or caproamin or EACA or caprolest or capralense or hexalense or hamostat or hemocid or cl 10304 or cl10304 or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or epsilonaminocapronsav or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or resplamin or tachostyptan).tw,kw.         

54. or/48‐53    

55. Aprotinin/ 

56. (antagosan or antilysin* or aprotimbin or apronitin* or aprotinin* or bayer a128 or contrical or contrycal or contrykal or dilmintal or frey inhibitor or kontrycal or Kunitz inhibitor or gordox or haemoprot or kallikrein‐trypsin inactivator).tw,kw.     

57. (iniprol or kontrikal or kontrykal or kunitz pancreatic trypsin inhibitor or midran or pulmin or tracylol or trascolan or trasilol or tra?ylol or traskolan or zymofren or pancreas antitrypsin or protinin or riker 52g or Rivilina zymofren).tw,kw.   

58. or/55‐57    

59. Blood Clotting Factor 7a/   

60. (factor viia or factor 7a or rfviia or fviia or novoseven* or novo seven* or aryoseven or acset or eptacog* or proconvertin).tw,kw.     

61. ((activated adj2 factor seven) or (activated adj2 factor vii) or (activated adj3 rfvii) or (activated adj2 fvii)).tw,kw.       

62. (factor seven or factor vii or factor 7).ti.      

63. 59 or 60 or 61 or 62

64. Fibrinogen Concentrate/    

65. (fibrinogen concentrate* or factor I or Haemocomplettan* or Riastap* or Fibryga* or Fibryna*).tw,kw.        

66. 64 or 65     

67. Desmopressin/      

68. (desmopressin* or vasopressin deamino or D‐amino D‐arginine vasopressin or deamino‐8‐d‐arginine vasopressin or vasopressin 1‐desamino‐8‐arginine or desmotabs or DDAVP or desmogalen or adin or adiuretin or concentraid or d‐void or dav ritter or deamino 8 dextro arginine vasopressin or deamino 8d arginine vasopressin or deamino dextro arginine vasopressin or deaminovasopressin or defirin or defirin melt or desmirin or desmomelt or desmopresina or desmospray or desmotab* or desurin or emosint or enupresol or minirin or minirinette or minirinmelt or minrin or minurin or miram or nictur or noctisson or nocturin or nocutil or nordurine or novidin or nucotil or octim or octostim or presinex or stimate or wetirin).tw,kw.       

69. 67 or 68     

70. Blood Clotting Factor 13/   

71. (factor xiii or fxiii or fibrin stabili?ing factor* or Tretten* or Catridecacog).tw,kw.     

72. 70 or 71     

73. exp Tissue Adhesive/          

74. *Adhesive Agent/  

75. *Wound Dressing/ 

76. ((fibrin* or collagen or cellulose or gelatin or gel or thrombin* or albumin or hemostatic* or haemostatic* or alginate) adj3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste or powder*)).tw,kw.        

77. ((nonfibrin* or non‐fibrin* or synthetic* or non‐biological* or nonbiological* or biological*) adj3 (glue* or seal* or adhesive*)).tw,kw.         

78. (surgical* adj3 (glue* or sealant* or adhesive*)).tw,kw.      

79. ((fibrin* or collagen or cellulose or gelatin or thrombin) adj3 (hemosta* or haemosta*)).tw,kw.

80. (8Y or Aafact or Actif‐VIII or Advate or Artiss or Raplixa or Evarrest or Aleviate or Alphanate or Amofil or Beriate or Beriplast or Biostate or Bolheal or Cluvot or Conco‐Eight‐HT or Crosseel or Crosseal or Crosseight or Emoclot or Evarrest or Evicel or Factane or Fanhdi or Fibrogammin P or Green VIII or Green VIII Factor or Greengene or Greenmono or Greenplast or Haemate or Haemate P or Haemate P or Haemate P500 or Haemate‐P or Haemoctin or Haemoctin SDH or Haemoctin‐SDH or Hemaseel or Hemaseal or Hemofil M or Hemoraas or Humaclot or Humafactor‐8 or Humate‐P or Immunate or Innovate or Koate or Koate‐DVI or Kogenate Bayer or Kogenate FS or Monoclate‐P or NovoThirteen or Octafil or Octanate or Octanate or Optivate or Quixil or Talate or Tisseel or Tisseal or Tissel or Tissucol or Tricos or Vivostat or Voncento or Wilate or Wilnativ or Wilstart or Xyntha).tw,kw.

81. (Glubran or Gluetiss or Ifabond or Indermil or LiquiBand or TissuGlu).tw,kw.

82. Collagen Sponge/ or Collagen Dressing/      

83. Gelatin Sponge/ or Gelfoam/          

84. (Evithrom or Floseal or Hemopatch or Gel‐Flow or Gelfoam or Gelfilm or Recothrom or Surgifoam or Surgiflo* or "rh Thrombin" or Thrombi‐Gel or Thrombi‐Pad or Thrombin‐JMI or Thrombinar or Thrombogen or Thrombostat).tw,kw.  

85. *Chitosan/ 

86. (chitosan* or mucoadhesive or muco‐adhesive or Celox Gauze or ChitoGauze or Combat Gauze).tw,kw.       

87. Hydrogel Dressing/

88. Fibrinogen plus Thrombin/ 

89. Polyvinyl Alcohol Sponge/  

90. (porcine gelatin or bovine collagen or bovine gelatin or nu‐knit or arista or hemostase or vita sure or thrombin‐jmi or thrombinjmi or avicel or vivagel or lyostypt or tabotamp or arterx or omnex or veriset).tw,kw.      

91. (polysaccharide adj (sphere* or hemostatic powder)).tw,kw.

92. ((polymer‐derived elastic* or polymer tissue adhesive* or elastic hydrogel* or glutaraldehyde or PEG‐based or polyurethane‐based tissue or polyethylene glycol* or polyvinyl alcohol‐based tissue or PVA‐based tissue or natural biopolymer* or polypeptide‐based or protein‐based or polysaccharide‐based or chitosan or poliglusam or cyanoacrylic or cyanoacrylate or cyacrin or dextran‐based or chondroitin sulfate‐based or mussel‐inspired elastic* or glycol hydrogel or polymer‐based) adj3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste* or powder*)).tw,kw.

93. Oxidized Cellulose/

94. Oxidized Regenerated Cellulose/    

95. Recombinant Thrombin/    

96. Tachocomb/          

97. (absorbable cellulose or resorbable cellulose or oxidi?ed cellulose or carboxycellulose or oxycellulose or cellulosic acid or oxycel or oxidi?ed regenerated cellulose).tw,kw.         

98. (BioGlue or Progel or Duraseal or Coseal or FocalSeal or ADAL‐1 or AdvaSeal or Pleuraseal or Angio‐Seal or Avitene or Instat or Helitene or Helistat or TDM‐621 or Dermabond or Tissueseal or PolyStat or Raplixa or Spongostan or Surgicel).tw,kw.  

99. (Tachosil or Traumstem or CoStasis or "GRF Glue" or GR‐Dial or Algosterile or TraumaStat or HemCon or ChitoFlex or Celox or QuikClot or WoundStat or Vitagel or TachSeal or TachoComb or Cryoseal).tw,kw.  

100. (collagen‐thrombin or thrombin‐collagen or gelatin‐fibrinogen or fibrinogen‐gelatin or gelatin‐thrombin or thrombin‐gelatin or fibrinogen‐thrombin or thrombin‐fibrinogen or collagen‐fibrinogen or fibrinogen‐collagen or microfibrillar collagen).tw,kw.      

101. or/73‐100

102. Prothrombin Complex/    

103. (prothrombin adj5 (complex* or concentrate*)).tw,kw.     

104. (PCC* or 3F‐PCC* or 4F‐PCC* or Beriplex* or Feiba* or Autoplex* or Ocplex* or Octaplex* or Kcentra* or Cofact or Prothrombinex* or "Proplex‐T" or Prothroraas* or Haemosolvex* or Prothromplex* or "HT Defix" or Facnyne* or Kaskadil* or Kedcom* or Confidex* or PPSB or Profil?ine* or Pronativ* or Proplex* or Prothar* or ProthoRAAS* or Protromplex* or "Pushu Laishi" or "Uman Complex").tw,kw.    

105. or/102‐104          

106. Hemostatic Agent/

107. (((haemosta* or hemosta* or antihaemorrhag* or antihemorrhag* or anti‐haemorrhag* or anti‐hemorrhag*) adj5 (drug* or agent* or treat* or therap* or dressing* or emergenc*)) or ((coagulat* or clotting) adj factor*)).tw,kw.       

108. 54 or 58 or 63 or 66 or 69 or 72 or 101 or 105 or 106 or 107          

109. Meta Analysis/     

110. (meta analy* or metaanaly*).ti,kw.

111. ((meta analy* or metaanaly*) and (trials or studies)).ab.    

112. Systematic Review/          

113. ((systematic* or evidence‐based) adj2 (review* or overview*)).tw,kw.       

114. (evidence synthes* or cochrane or medline or pubmed or embase or cinahl or cinhal or lilacs or "web of science" or science citation index or scopus or search terms or literature search or electronic search* or comprehensive search* or systematic search* or published articles or search strateg* or reference list* or bibliograph* or handsearch* or hand search* or manual* search*).ab.  

115. ((electronic* or online) adj (sources or resources or databases)).ab.

116. ((additional adj (papers or articles or sources)) or (relevant adj (journals or articles))).ab.    

117. or/109‐116          

118. Review.pt.

119. (data extraction or selection criteria).ab.  

120. 118 and 119        

121. 117 or 120

122. Editorial.pt.         

123. 121 not 122         

124. crossover‐procedure/ or double‐blind procedure/ or randomized controlled trial/ or single‐blind procedure/          

125. (random* or factorial* or crossover* or cross over* or cross‐over* or placebo* or doubl* blind* or singl* blind* or assign* or allocat* or volunteer*).mp.           

126. 123 or 124 or 125

127. (exp animal/ or nonhuman/) not exp human/        

128. 126 not 127         

129. 47 and 108 and 128

CINAHL

S1        (MH "Trauma") OR (MH "Multiple Trauma") OR (MH "Crush Injuries") OR (MH "Blast Injuries") OR (MH "Amputation, Traumatic") OR (MH "Shock, Traumatic+")

S2        (MH "Trauma Severity Indices")

S3        (MH "Traumatology")

S4        (MH "Trauma Centers")

S5        TI ( ((trauma* or injur* or wound*) N3 (critical* or massive* or major* or serious* or severe* or life‐threatening* or combat* or battlefield* or penetrating or nonpenetrating or non‐penetrating or blunt or multip* or collision* or fall* or abdominal or thoracic or thorax or chest or torso or head or neck or arm* or leg* or skin or soft tissue* or traffic or vehicle* or vehicular or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian* or stab* or lacerat* or stab* or knife or knives or crush* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel)) ) OR AB ( ((trauma* or injur* or wound*) N3 (critical* or massive* or major* or serious* or severe* or life‐threatening* or combat* or battlefield* or penetrating or nonpenetrating or non‐penetrating or blunt or multip* or collision* or fall* or abdominal or thoracic or thorax or chest or torso or head or neck or arm* or leg* or skin or soft tissue* or traffic or vehicle* or vehicular or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian* or stab* or lacerat* or stab* or knife or knives or crush* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel)) )

S6        TI (trauma* or polytrauma* or open wound* or puncture wound* or incision* or incised wound* or ((blunt or penetrating or stab* or shooting or combat* or gunshot* or blast* or bomb* or battle* or massive* or major or shock* or critical* or serious* or severe* or life‐threatening* or catastrophic or multiple) N5 (injur* or wound* or casualt*))) OR AB (trauma* or polytrauma* or open wound* or puncture wound* or incision* or incised wound* or ((blunt or penetrating or stab* or shooting or combat* or gunshot* or blast* or bomb* or battle* or massive* or major or shock* or critical* or serious* or severe* or life‐threatening* or catastrophic or multiple) N5 (injur* or wound* or casualt*)))

S7        TI ( ((trauma* or polytrauma*) N5 (surg* or patient* or multipl* or injur* or victim* or casualt* or h?emorrhag* or bleed* or blood loss* or coagulopath*)) ) OR AB ( ((trauma* or polytrauma*) N5 (surg* or patient* or multipl* or injur* or victim* or casualt* or h?emorrhag* or bleed* or blood loss* or coagulopath*)) )

S8        S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7

S9        (MH "Military Medicine")

S10      (MH "Military Personnel")

S11      (MH "Rupture+")

S12      (MH "Wounds and Injuries") OR (MH "Abdominal Injuries+") OR (MH "Accidental Injuries") OR (MH "Athletic Injuries") OR (MH "Head Injuries") OR (MH "Neck Injuries") OR (MH "Soft Tissue Injuries+") OR (MH "Tears and Lacerations") OR (MH "Thoracic Injuries+") OR (MH "Wounds, Nonpenetrating+") OR (MH "Wounds, Penetrating+") OR (MH "Wounds, Gunshot") OR (MH "Wounds, Stab")
S13      TI ( (polytrauma* or crush syndrome or open wound* or puncture wound* or incision* or incised wound* or ((military or battle* or combat* or trauma* or traffic) N3 surviv*)) ) OR AB ( (polytrauma* or crush syndrome or open wound* or puncture wound* or incision* or incised wound* or ((military or battle* or combat* or trauma* or traffic) N3 surviv*)) )

S14      TI ( (accident* N3 (critical* or massive* or catastroph* or major or serious* or severe* or life‐threatening* or traffic or vehicl* or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian*)) ) OR AB ( (accident* N3 (critical* or massive* or catastroph* or major or serious* or severe* or life‐threatening* or traffic or vehicl* or automobile* or motorcar* or road* or motorcycle* or car or cars or riding or sport* or athlet* or bicycle* or cycle* or cycling or pedestrian*)) )

S15      TI (stab* or lacerat* or shooting or gunshot* or blast* or bomb* or explosi* or disaster* or catastroph* or combat* or battlefield* or fall* or collision* or assault* or shrapnel or accident*)

S16      TI ( ((trauma* or combat* or gunshot* or blast* or battle*) N2 (victim* or injur* or casualt*)) ) OR AB ( ((trauma* or combat* or gunshot* or blast* or battle*) N2 (victim* or injur* or casualt*)) )

S17      TI ( ((head or brain or cerebrocranial* or cranial* or craniocerebral* or cerebral or intracranial* or intra‐cranial* or intracortical* or intra‐cortical* or subcortical* or sub‐cortical* or subdural* or extradural* or subarachnoid* or intra‐parenchymal* or intraparenchymal* or intraventricul* or intra‐ventricular* or periventricular* or peri‐ventricular* or cerebell* or cerebrum or corpus callosum or posterior fossa or hemispher*) N3 (trauma* or injur* or wound* or haemorrhage* or hemorrhag* or bleed* or haematoma* or hematoma*)) ) OR AB ( ((head or brain or cerebrocranial* or cranial* or craniocerebral* or cerebral or intracranial* or intra‐cranial* or intracortical* or intra‐cortical* or subcortical* or sub‐cortical* or subdural* or extradural* or subarachnoid* or intra‐parenchymal* or intraparenchymal* or intraventricul* or intra‐ventricular* or periventricular* or peri‐ventricular* or cerebell* or cerebrum or corpus callosum or posterior fossa or hemispher*) N3 (trauma* or injur* or wound* or haemorrhage* or hemorrhag* or bleed* or haematoma* or hematoma*)) )

S18      S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16

S19      (MH "Hemorrhage+")

S20      TX (haemorrhag* or hemorrhag* or bleed* or bloodloss* or blood loss* or exsanguin* or hypovolemi* or hypovolaemi* or hematoma* or haematoma* or coagulopath* or damage control resuscitation or DIC)

S21      S19 OR S20

S22      S18 AND S21

S23      (MM "Hemorrhage")

S24      TX trauma* or polytrauma*

S25      S23 AND S24

S26      TI ((critical* or massive* or major* or serious* or severe* or life‐threatening* or catastrophic*) N2 (hemorrhag* or haemorrhag* or bleed* or blood loss*))

S27      S8 OR S17 OR S22 OR S25 OR S26

S28      (MH "Antifibrinolytic Agents") OR (MH "Aminocaproic Acids") OR (MH "Tranexamic Acid")
S29      TI ( (antifibrinolytic* or anti‐fibrinolytic* or antifibrinolysin* or antiplasmin* or plasmin inhibitor* or tranexamic or tranhexamic or cyclohexanecarboxylic acid* or amcha or trans‐4‐aminomethyl‐cyclohexanecarboxylic acid* or t‐amcha or amca or "kabi 2161" or transamin or amchafibrin or anvitoff or spotof or cyklokapron or cyclo‐F or femstrual or ugurol or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or antivoff or caprilon or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse or fibrinon or hemostan or hexacapron or hexakapron or kalnex or lysteda or rikaparin or ronex or theranex or tranexam or tranexanic or tranexic or trans achma or transexamic or trenaxin or TXA or (fibrinolysis N2 inhibitor*)) ) OR AB ( (antifibrinolytic* or anti‐fibrinolytic* or antifibrinolysin* or antiplasmin* or plasmin inhibitor* or tranexamic or tranhexamic or cyclohexanecarboxylic acid* or amcha or trans‐4‐aminomethyl‐cyclohexanecarboxylic acid* or t‐amcha or amca or "kabi 2161" or transamin or amchafibrin or anvitoff or spotof or cyklokapron or cyclo‐F or femstrual or ugurol or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or antivoff or caprilon or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or frenolyse or fibrinon or hemostan or hexacapron or hexakapron or kalnex or lysteda or rikaparin or ronex or theranex or tranexam or tranexanic or tranexic or trans achma or transexamic or trenaxin or TXA or (fibrinolysis N2 inhibitor*)) )          
S30      TI ( (6‐aminohexanoic or amino?caproic or amino?hexanoic or amino caproic or amino‐caproic or amino‐n‐hexanoic or cy‐116 or cy116 or lederle or acikaprin or afibrin or amicar or caprocid or capracid or capramol or caprogel or caprolest or caprolisin* or caprolysin* or capromol or epsikapron or hemocaprol or caproamin or EACA or caprolest or capralense or hexalense or hamostat or hemocid or cl 10304 or cl10304 or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or epsilonaminocapronsav or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or resplamin or tachostyptan) ) OR AB ( (6‐aminohexanoic or amino?caproic or amino?hexanoic or amino caproic or amino‐caproic or amino‐n‐hexanoic or cy‐116 or cy116 or lederle or acikaprin or afibrin or amicar or caprocid or capracid or capramol or caprogel or caprolest or caprolisin* or caprolysin* or capromol or epsikapron or hemocaprol or caproamin or EACA or caprolest or capralense or hexalense or hamostat or hemocid or cl 10304 or cl10304 or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsilcapramin or epsilon amino caproate or epsilon aminocaproate or epsilonaminocaproic or epsilonaminocapronsav or etha?aminocaproic or ethaaminocaproich or emocaprol or hepin or ipsilon or jd?177or neocaprol or nsc?26154 or resplamin or tachostyptan) )
S31      S28 OR S29 OR S30      

S32      (MH "Aprotinin")         

S33      TI ( (antagosan or antilysin* or aprotimbin or apronitin* or aprotinin* or bayer a128 or contrical or contrycal or contrykal or dilmintal or frey inhibitor or kontrycal or Kunitz inhibitor or gordox or haemoprot or kallikrein‐trypsin inactivator) ) OR AB ( (antagosan or antilysin* or aprotimbin or apronitin* or aprotinin* or bayer a128 or contrical or contrycal or contrykal or dilmintal or frey inhibitor or kontrycal or Kunitz inhibitor or gordox or haemoprot or kallikrein‐trypsin inactivator) ) 

S34      TI ( (iniprol or kontrikal or kontrykal or kunitz pancreatic trypsin inhibitor or midran or pulmin or tracylol or trascolan or trasilol or tra?ylol or traskolan or zymofren or pancreas antitrypsin or protinin or riker 52g or Rivilina zymofren) ) OR AB ( (iniprol or kontrikal or kontrykal or kunitz pancreatic trypsin inhibitor or midran or pulmin or tracylol or trascolan or trasilol or tra?ylol or traskolan or zymofren or pancreas antitrypsin or protinin or riker 52g or Rivilina zymofren) )      

S35      S32 OR S33 OR S34      

S36      TX ( (factor viia or factor 7a or rfviia or fviia or novoseven* or novo seven* or aryoseven or acset or eptacog* or proconvertin) ) OR TX ( ((activated N2 factor seven) or (activated N2 factor vii) or (activated N3 rfvii) or (activated N2 fvii)) )     

S37      TX (factor seven or factor vii or factor 7)

S38      S36 OR S37      

S39      (MH "Fibrinogen")       

S40      TX (fibrinogen concentrate* or factor I or Haemocomplettan* or Riastap* or Fibryga* or Fibryna*)        

S41      S39 OR S40      

S42      (MH "Desmopressin")  

S43      TI ( (desmopressin* or vasopressin deamino or D‐amino D‐arginine vasopressin or deamino‐8‐d‐arginine vasopressin or vasopressin 1‐desamino‐8‐arginine or desmotabs or DDAVP or desmogalen or adin or adiuretin or concentraid or d‐void or dav ritter or deamino 8 dextro arginine vasopressin or deamino 8d arginine vasopressin or deamino dextro arginine vasopressin or deaminovasopressin or defirin or defirin melt or desmirin or desmomelt or desmopresina or desmospray or desmotab* or desurin or emosint or enupresol or minirin or minirinette or minirinmelt or minrin or minurin or miram or nictur or noctisson or nocturin or nocutil or nordurine or novidin or nucotil or octim or octostim or presinex or stimate or wetirin) ) OR AB ( (desmopressin* or vasopressin deamino or D‐amino D‐arginine vasopressin or deamino‐8‐d‐arginine vasopressin or vasopressin 1‐desamino‐8‐arginine or desmotabs or DDAVP or desmogalen or adin or adiuretin or concentraid or d‐void or dav ritter or deamino 8 dextro arginine vasopressin or deamino 8d arginine vasopressin or deamino dextro arginine vasopressin or deaminovasopressin or defirin or defirin melt or desmirin or desmomelt or desmopresina or desmospray or desmotab* or desurin or emosint or enupresol or minirin or minirinette or minirinmelt or minrin or minurin or miram or nictur or noctisson or nocturin or nocutil or nordurine or novidin or nucotil or octim or octostim or presinex or stimate or wetirin) )          

S44      S42 OR S43      

S45      TX (factor XIII or fXIII or fibrin stabili?ing factor* or Tretten* or Catridecacog)    

S46      (MH "Tissue Adhesives")          

S47      (MH "Fibrin Tissue Adhesive")  

S48      (MH "Collagen/TU")     

S49      (MH "Thrombin/TU")    

S50      (MH "Surgical Sponges")           

S51      TI ( ((fibrin* or collagen or cellulose or gelatin or gel or thrombin* or albumin or hemostatic* or haemostatic*) N3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste or powder*)) ) OR AB ( ((fibrin* or collagen or cellulose or gelatin or gel or thrombin* or albumin or hemostatic* or haemostatic*) N3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste or powder*)) )     

S52      TI ( ((nonfibrin* or non‐fibrin* or synthetic* or non‐biological* or nonbiological* or biological*) N3 (glue* or seal* or adhesive*)) ) OR AB ( ((nonfibrin* or non‐fibrin* or synthetic* or non‐biological* or nonbiological* or biological*) N3 (glue* or seal* or adhesive*)) )  

S53      TI ( (surgical* N3 (glue* or sealant* or adhesive*)) ) OR AB ( (surgical* N3 (glue* or sealant* or adhesive*)) )      

S54      TI ( ((fibrin* or collagen or cellulose or gelatin or thrombin* or albumin or hemostatic* or haemostatic* or alginate) N3 (hemosta* or haemosta*)) ) OR AB ( ((fibrin* or collagen or cellulose or gelatin or thrombin* or albumin or hemostatic* or haemostatic* or alginate) N3 (hemosta* or haemosta*)) )

S55      TI ( (8Y or Aafact or Actif‐VIII or Advate or Artiss or Bioglue or Biocol or Collaseal or Omrixil or Transglutine or Raplixa or Evarrest or Aleviate or Alphanate or Amofil or Beriate or Beriplast or Biostate or Bolheal or Cluvot or Conco‐Eight‐HT or Crosseel or Crosseal or Crosseight or Emoclot or Evarrest or Evicel or Factane or Fanhdi or Fibrogammin P or Green VIII or Green VIII Factor or Greengene or Greenmono or Greenplast or Haemate or Haemate P or Haemate P or Haemate P500 or Haemate‐P or Haemoctin or Haemoctin SDH or Haemoctin‐SDH or Hemaseel or Hemaseal or Hemofil M or Hemoraas or Humaclot or Humafactor‐8 or Humate‐P or Immunate or Innovate or Koate or Koate‐DVI or Kogenate Bayer or Kogenate FS or Monoclate‐P or NovoThirteen or Octafil or Octanate or Octanate or Optivate or Quixil or Talate or Tisseel or Tisseal or Tissel or Tissucol or Tricos or Vivostat or Voncento or Wilate or Wilnativ or Wilstart or Xyntha) ) OR AB ( (8Y or Aafact or Actif‐VIII or Advate or Artiss or Bioglue or Biocol or Collaseal or Omrixil or Transglutine or Raplixa or Evarrest or Aleviate or Alphanate or Amofil or Beriate or Beriplast or Biostate or Bolheal or Cluvot or Conco‐Eight‐HT or Crosseel or Crosseal or Crosseight or Emoclot or Evarrest or Evicel or Factane or Fanhdi or Fibrogammin P or Green VIII or Green VIII Factor or Greengene or Greenmono or Greenplast or Haemate or Haemate P or Haemate P or Haemate P500 or Haemate‐P or Haemoctin or Haemoctin SDH or Haemoctin‐SDH or Hemaseel or Hemaseal or Hemofil M or Hemoraas or Humaclot or Humafactor‐8 or Humate‐P or Immunate or Innovate or Koate or Koate‐DVI or Kogenate Bayer or Kogenate FS or Monoclate‐P or NovoThirteen or Octafil or Octanate or Octanate or Optivate or Quixil or Talate or Tisseel or Tisseal or Tissel or Tissucol or Tricos or Vivostat or Voncento or Wilate or Wilnativ or Wilstart or Xyntha) )        

S56      TI ( (Glubran or Gluetiss or Ifabond or Indermil or LiquiBand or TissuGlu) ) OR AB ( (Glubran or Gluetiss or Ifabond or Indermil or LiquiBand or TissuGlu) )        

S57      TI ( (Evithrom or Floseal or Hemopatch or Gel‐Flow or Gelfoam or Gelfilm or Recothrom or Surgifoam or Surgiflo* or "rh Thrombin" or Thrombi‐Gel or Thrombi‐Pad or Thrombin‐JMI or Thrombinar or Thrombogen or Thrombostat) ) OR AB ( (Evithrom or Floseal or Hemopatch or Gel‐Flow or Gelfoam or Gelfilm or Recothrom or Surgifoam or Surgiflo* or "rh Thrombin" or Thrombi‐Gel or Thrombi‐Pad or Thrombin‐JMI or Thrombinar or Thrombogen or Thrombostat) )           

S58      TI ( (porcine gelatin or bovine collagen or bovine gelatin or nu‐knit or arista or hemostase or vita sure or thrombin‐jmi or thrombinjmi or avicel or vivagel or lyostypt or tabotamp or arterx or omnex or veriset) ) OR AB ( (porcine gelatin or bovine collagen or bovine gelatin or nu‐knit or arista or hemostase or vita sure or thrombin‐jmi or thrombinjmi or avicel or vivagel or lyostypt or tabotamp or arterx or omnex or veriset) ) 

S59      TX (polysaccharide NEXT (sphere* or hemostatic powder))       

S60      (MM "Polyethylene Glycols")   

S61      (MH "Hydrogel Dressings")       

S62      (MH "Polyurethanes/AD/AE/TU/ST/DE")

S63      TI ( ((polymer‐derived elastic* or polymer tissue adhesive* or elastic hydrogel* or glutaraldehyde or PEG‐based or polyurethane‐based tissue or polyethylene glycol* or polyvinyl alcohol‐based tissue or PVA‐based tissue or natural biopolymer* or polypeptide‐based or protein‐based or polysaccharide‐based or chitosan or poliglusam or cyanoacrylic or cyanoacrylate or cyacrin or dextran‐based or chondroitin sulfate‐based or mussel‐inspired elastic* or glycol hydrogel or polymer‐based) N3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste* or powder*)) ) OR AB ( ((polymer‐derived elastic* or polymer tissue adhesive* or elastic hydrogel* or glutaraldehyde or PEG‐based or polyurethane‐based tissue or polyethylene glycol* or polyvinyl alcohol‐based tissue or PVA‐based tissue or natural biopolymer* or polypeptide‐based or protein‐based or polysaccharide‐based or chitosan or poliglusam or cyanoacrylic or cyanoacrylate or cyacrin or dextran‐based or chondroitin sulfate‐based or mussel‐inspired elastic* or glycol hydrogel or polymer‐based) N3 (glu* or seal* or adhesive* or topical* or local* or matrix or matrices or spong* or fleece* or foam* or scaffold* or patch* or sheet* or bandag* or aerosol* or dressing* or paste* or powder*)) ) 

S64      (MH "Cellulose/TU")    

S65      TI ( (absorbable cellulose or resorbable cellulose or oxidi?ed cellulose or carboxycellulose or oxycellulose or cellulosic acid or oxycel or oxidi?ed regenerated cellulose) ) OR AB ( (absorbable cellulose or resorbable cellulose or oxidi?ed cellulose or carboxycellulose or oxycellulose or cellulosic acid or oxycel or oxidi?ed regenerated cellulose) )       

S66      TI ( (BioGlue or Progel or Duraseal or Coseal or FocalSeal or ADAL‐1 or AdvaSeal or Pleuraseal or Angio‐Seal or Avitene or Instat or Helitene or Helistat or TDM‐621 or Dermabond or Tissueseal or PolyStat or Raplixa or Spongostan or Surgicel or Surgilux or Tachosil or Traumstem) ) OR AB ( (BioGlue or Progel or Duraseal or Coseal or FocalSeal or ADAL‐1 or AdvaSeal or Pleuraseal or Angio‐Seal or Avitene or Instat or Helitene or Helistat or TDM‐621 or Dermabond or Tissueseal or PolyStat or Raplixa or Spongostan or Surgicel or Surgilux or Tachosil or Traumstem) )          S67      TI ( (collagen‐thrombin or thrombin‐collagen or gelatin‐fibrinogen or fibrinogen‐gelatin or gelatin‐thrombin or thrombin‐gelatin or fibrinogen‐thrombin or thrombin‐fibrinogen or collagen‐fibrinogen or fibrinogen‐collagen or microfibrillar collagen or CoStasis or "GRF Glue" or GR‐Dial or Algosterile or TraumaStat or HemCon or ChitoFlex or Celox or QuikClot or WoundStat or Vitagel or TachSeal or TachoComb or Cryoseal) ) OR AB ( (collagen‐thrombin or thrombin‐collagen or gelatin‐fibrinogen or fibrinogen‐gelatin or gelatin‐thrombin or thrombin‐gelatin or fibrinogen‐thrombin or thrombin‐fibrinogen or collagen‐fibrinogen or fibrinogen‐collagen or microfibrillar collagen or CoStasis or "GRF Glue" or GR‐Dial or Algosterile or TraumaStat or HemCon or ChitoFlex or Celox or QuikClot or WoundStat or Vitagel or TachSeal or TachoComb or Cryoseal) )

S68      S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 OR S53 OR S54 OR S55 OR S56 OR S57 OR S58 OR S59 OR S60 OR S61 OR S62 OR S63 OR S64 OR S65 OR S66 OR S67 

S69      TI ( (((haemosta* or hemosta* or antihaemorrhag* or antihemorrhag* or anti haemorrhag* or anti‐hemorrhag*) N5 (drug* or agent* or treat* or therap*)) or ((coagulat* or clotting) NEXT factor*)) ) OR AB ( (((haemosta* or hemosta* or antihaemorrhag* or antihemorrhag* or anti haemorrhag* or anti‐hemorrhag*) N5 (drug* or agent* or treat* or therap*)) or ((coagulat* or clotting) NEXT factor*)) )         

S70      S31 OR S35 OR S38 OR S41 OR S44 OR S68 OR S69        

S71      (MH Clinical Trials+)     

S72      PT Clinical Trial

S73      TI ((controlled trial*) or (clinical trial*)) OR AB ((controlled trial*) or (clinical trial*))       

S74      TI ((singl* blind*) OR (doubl* blind*) OR (trebl* blind*) OR (tripl* blind*) OR (singl* mask*) OR (doubl* mask*) OR (tripl* mask*)) OR AB ((singl* blind*) OR (doubl* blind*) OR (trebl* blind*) OR (tripl* blind*) OR (singl* mask*) OR (doubl* mask*) OR (tripl* mask*)) 

S75      TI randomi* OR AB randomi*   

S76      MH RANDOM ASSIGNMENT      

S77      TI ((phase three) or (phase III) or (phase three)) or AB ((phase three) or (phase III) or (phase three))        

S78      ( TI (random* N2 (assign* or allocat*)) ) OR ( AB (random* N2 (assign* or allocat*)) )     

S79      MH PLACEBOS 

S80      MH META ANALYSIS     

S81      MH SYSTEMATIC REVIEW          

S82      TI ("meta analys*" OR metaanalys* OR "systematic review" OR "systematic overview" OR "systematic search*") OR AB ("meta analys*" OR metaanalys* OR "systematic review" OR "systematic overview" OR "systematic search*")          

S83      TI ("literature review" OR "literature overview" OR "literature search*") OR AB ("literature review" OR "literature overview" OR "literature search*")           

S84      TI (cochrane OR embase OR cinahl OR cinhal OR lilacs OR BIDS OR science AND citation AND index OR cancerlit) OR AB (cochrane OR embase OR cinahl OR cinhal OR lilacs OR BIDS OR science AND citation AND index OR cancerlit)       

S85      TI placebo* OR AB placebo*    
S86      MH QUANTITATIVE STUDIES     

S87      S71 or S72 or S73 or S74 or S75 or S76 or S77 or S78 or S79 or S80 or S81 or S82 or S83 or S84 or S85 or S86

S88      (MH "Blood Coagulation Factors") OR (MH "Prothrombin")       

S89      TI ( (prothrombin N5 (complex* or concentrate*)) ) OR AB ( (prothrombin N5 (complex* or concentrate*)) )       

S90      TI ( (PCC* or 3F‐PCC* or 4F‐PCC* or Beriplex* or Feiba* or Autoplex* or Ocplex* or Octaplex* or Kcentra* or Cofact or Prothrombinex* or "Proplex‐T" or Prothroraas* or Haemosolvex* or Prothromplex* or "HT Defix" or Facnyne* or Kaskadil* or Kedcom* or Confidex* or PPSB or Profil?ine* or Pronativ* or Proplex* or Prothar* or ProthoRAAS* or Protromplex* or "Pushu Laishi" or "Uman Complex") ) OR AB ( (PCC* or 3F‐PCC* or 4F‐PCC* or Beriplex* or Feiba* or Autoplex* or Ocplex* or Octaplex* or Kcentra* or Cofact or Prothrombinex* or "Proplex‐T" or Prothroraas* or Haemosolvex* or Prothromplex* or "HT Defix" or Facnyne* or Kaskadil* or Kedcom* or Confidex* or PPSB or Profil?ine* or Pronativ* or Proplex* or Prothar* or ProthoRAAS* or Protromplex* or "Pushu Laishi" or "Uman Complex") )   

S91      S88 OR S89 OR S90      

S92      S70 OR S91

S93      S27 AND S87 AND S92

TRANSFUSION EVIDENCE LIBRARY

Clinical Specialty: Critical Care/Trauma  

AND

Subject Areas: Alternatives to Blood/Antifibrinolytics OR Alternatives to Blood/Fractionated Blood Products OR Alternatives to Blood/Recombinant Coagulation Factors

ClinicalTrials.gov

1. Other terms: randomized or randomised OR randomly OR random AND Condition: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster AND Intervention: hemostatic OR antifibrinolytic OR tranexamic OR EACA OR aminocaproic OR aprotinin OR desmopressin OR DDAVP OR factor viia OR novoseven OR aryoseven OR fibrinogen OR haemocomplettan OR Riastap OR Fibryna OR Fibryga OR factor XIII OR Tretten AND Study Type: Interventional Studies (Clinical Trials)

2. Other terms: randomized or randomised OR randomly OR random AND Condition: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster AND Intervention: sealant OR adhesive OR collagen OR cellulose OR gelatin OR glue OR matrix OR sponge OR fleece OR foam OR scaffold OR patch OR sheet OR gelfoam OR chitosan OR hydrogel OR polyethylene glycol OR tachocomb OR BioGlue OR Surgicel OR Veriset AND Study Type: Interventional Studies (Clinical Trials)

3. Other terms: randomized or randomised OR randomly OR random AND Condition: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster AND Intervention: Evithrom OR Floseal OR Tachosil OR Cryoseal OR Hemopatch OR Progel OR Duraseal OR Coseal OR FocalSeal OR Algosterile OR TraumaStat OR HemCon OR ChitoFlex OR Celox OR QuikClot OR WoundStat OR Vitagel OR TachSeal AND Study Type: Interventional Studies (Clinical Trials)

4. Other terms: randomized or randomised OR randomly OR random AND Condition: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster AND Intervention: iniprol or kontrikal OR CloSys OR Glubran OR Gluetiss OR Ifabond OR Indermil OR LiquiBand OR Octafil OR Octanate OR Optivate OR Quixil OR Tisseel OR Tissucol OR TissuGlu OR Thrombi‐Gel OR Vivostat OR Voncento OR Wilate OR Wilnativ OR Wilstart AND Study Type: Interventional Studies (Clinical Trials)

5. Other terms: randomized or randomised OR randomly OR random AND Condition: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster AND Title: hemostasis OR hemostatic OR antifibrinolytic OR factor OR fibrinogen OR thrombin OR collagen OR gelatin OR cellulose AND Study Type: Interventional Studies (Clinical Trials)

6. Other Terms: randomized or randomised OR randomly OR random AND Title: trauma OR polytrauma OR injury OR injuries OR wound OR wounds OR casualty OR stabbing OR laceration OR shooting OR gunshot OR accident OR assault OR disaster OR cranial OR cerebral OR craniocerebral OR intracranial OR intracortical OR subcortical OR subdural OR extradural OR subarachnoid OR intraparenchymal OR intraventricular OR periventricular or cerebellum OR cerebrum OR corpus callosum OR posterior fossa OR hemisphere AND Study Type: Interventional Studies (Clinical Trials) AND Condition: bleeding OR haemorrhage OR hemorrhage OR blood loss OR bloodloss OR hematoma OR haematoma OR coagulopathy

7. 1 OR 2 OR 3 OR 4 OR 5 OR 6 [N.B. combined and de‐duplicated in EndNote]

Contributions of authors

VPE: protocol development and content expertise (clinical).

AN: protocol development and content expertise (clinical).

VNG: protocol development and content expertise (clinical).

RC: protocol development and content expertise (methodological).

JS: protocol development and content expertise (methodological).

CD: protocol development and developing the search strategy.

AH: protocol development and content expertise (clinical).

RM: protocol development and content expertise (clinical)

SJB: protocol development and content expertise (methodological).

LJE: protocol development and content expertise (clinical and methodological).

 

 

 

Sources of support

Internal sources

• NHS Blood and Transplant, Research and Development, UK

  Funded the work of the Systematic Review Initiative (SRI), UK

External sources

• Cochrane Injuries Group, UK

  Provided editorial review, and co‐ordinated peer review

• NIHR, UK

  Provided funding for a one‐year Fellowship post that supported Vishakha Erasu's involvement in this review 

Declarations of interest

VPE: none known.

AN: none known.

VNG: funded by an NIHR Cochrane Programme Grant.

RC: funded by an NIHR Cochrane Programme Grant.

CD: none known.

AH: none known.

RM: none known.

JS: none known.

SJB: none known.

LJE: none known.

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