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Abstract
Objectives Massive transfusion protocols (MTPs) may improve survival in patients with uncontrolled haemorrhage. An MTP was introduced into the Dutch transfusion guidelines in 2011, the ninth edition of the advanced trauma life support course in 2012 and the third version of the European guideline in 2013. This is the first survey of MTPs in Dutch trauma centres.
Methods The aim of the study was to compare MTP strategies in level 1 trauma centres in The Netherlands, and with (inter)national guidelines. A contact in each government assigned level 1 trauma centre in The Netherlands and the Dutch Ministry of Defence was approached to share their MTPs and elucidate their protocol in a survey and oral follow-up interview.
Results All 11 level 1 trauma centres responded. The content of the packages and transfusion ratios (red blood cells/plasma/platelets) were 3:3:1, 5:5:1, 5:3:1, 2:3:1, 4:4:1, 5:2:1, 2:2:1 and 4:3:1. Tranexamic acid was used in all centres and an additional dose was administered in eight centres. Fibrinogen was given directly (n=4), with persistent bleeding (n=3), based on Clauss fibrinogen (n=3) or rotational thromboelastometry (n=1). All centres used additional medication in patients in the form of anticoagulants, but their use was ambiguous.
Conclusion MTPs differed between institutes and guidelines. The discrepancies in transfusion ratios can be explained by (inter)national differences in preparation and volume of blood components and/or interpretation of the '1:1:1' guideline. We recommend updating MTPs every year using the latest guidelines and evaluating the level of evidence for treatment during massive transfusion.
- transfusion
- trauma
- massive
- protocol
- tranexamic acid
- emergency
- surgery
- military
- blood
- platelets
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Key messages
What is already known on this subject
Introduction of hospital specific massive transfusion protocols (MTPs) has increased survival and decreased the total use of blood components during hospital stay. However, 8 years after the introduction of a national guideline for massive transfusion, there is no uniform massive transfusion practice in The Netherlands.
What this study adds
Previous research was mostly restricted to a few hospitals. This study has analysed MTPs in all Dutch level 1 trauma centres and compared the MTPs with the latest edition of the advanced trauma life support course, the European guideline and Dutch national guidelines. In addition, this study provides a detailed overview of the composition of the blood components.
Background
Uncontrollable major haemorrhage after trauma results in 30–40% mortality and requires aggressive volume resuscitation with blood or blood components (ie, red blood cells (RBCs)/plasma/platelets).1 A massive transfusion protocol (MTP) was first described by Malone et al in 2006 and in the ninth edition of the advanced trauma life support (ATLS) course in 2012.2 Over the past decade, MTPs have been implemented and further developed in many countries. Additional medication, such as tranexamic acid (TXA), fibrinogen concentrate (FC)/cryoprecipitate and prothrombin complex concentrate (PCC), have been added to the MTPs for the treatment of fibrinolysis, trauma induced coagulopathy (TIC) and reversal of anticoagulants.3
The Dutch Ministry of Defence (D-MOD) introduced an MTP in 2007 based on early reports by the US military on damage control surgery and transfusion outcomes.2 This introduction resulted in increased early use of platelets and plasma, and a near doubling of survival in trauma patients with massive blood loss in Afghanistan.4 In 2011, The Netherlands introduced national guidelines for transfusion to improve the general use of blood components. The 2011 guidelines included an MTP similar to that described by Malone et al. 3
The recommended transfusion strategy for haemodynamically compensated bleeding in The Netherlands is summarised in box 1. In haemodynamically non-compensated bleeding, a low initial haemoglobin (Hb) concentration is correlated with severe bleeding and an increased risk of requiring a massive transfusion (MT). However, as early measurements are usually unreliable in the acute phase, protocols for administration of blood and blood products based on estimated blood loss are advocated.5 6 Under ideal circumstances, patients should receive blood components in a ratio equivalent to whole blood, and therefore the advice is to use blood components in a 1:1:1 ratio.2 7 However, the exact ratio depends on the component content compared with whole blood content.
Treatment in haemodynamically compensated bleeding
Transfuse red blood cells if haemoglobin concentration:
<4 mmol/L (6.5 g/dL) and low risk (eg, age <60 years, normovolaemic)
<5 mmol/L (8.1 g/dL) and medium risks (eg, age >60 years, fever, acute bleeding age <60 years)
<6 mmol/L (9.7 g/dL) and high risk (eg, septic shock, severe pulmonary disease)
Transfuse plasma if:
The international normalised ratio is >1.5
Transfuse platelets if platelet count:
<100×109/L (in bleeding patients)
<50×109/L (preoperative patients)
<10×109/L (always)
In 2017, 5% (n=4458) of all trauma patients in The Netherlands were severely injured (injury severity score ≥16) and 17% of these patients died in hospital. Severely injured patients are often (68%) transported to one of 11 government assigned level 1 trauma centres in The Netherlands.8 With long term care on site, it is also possible to order supplementary packages of RBCs by ground transportation from a nearby blood transfusion service. The Netherlands has a high density of hospital transfusion services, which makes this logistically feasible. However, timely activation of the MTP is also important to treat haemodynamically uncompensated bleeding.
A previous study showed that MT strategies differ between centres in Europe.9 A study involving all level 1 trauma centres in one country using the same guidelines has never been conducted. Therefore, the aim of this study was to compare MT strategies in level 1 trauma centres in The Netherlands and with (inter)national guidelines.
Methods
Study design
This was a prospective observational study performed between 2017 and 2018. A trauma surgeon or anaesthesiologist involved in compiling the MTP from each level 1 trauma centre was approached to share their current MTP. In addition to civilian hospitals, the D-MOD was asked to share the MT strategy used during missions. Respondents were approached by the authors (TWHR and AB) by telephone and the hospital specific MTP was received by e-mail in November 2017. In addition, respondents were given the opportunity to comment on their MTP in an oral interview using standard questions (see online supplementary appendix S1). The interviews were conducted by the authors (TWHR or AB). MTPs for the 11 level 1 trauma centres were compared, and were also compared with the current Dutch guidelines, the fifth edition of the European guideline and the 10th version of the ATLS course.3 7 10 The main points in the Dutch guidelines regarding MT are summarised in online supplementary appendix S2. The military blood bank shared data obtained from laboratory research over the years on blood components and data from the national blood bank, allowing estimation of the content of (inter)national blood components (online supplementary appendix S3).
Supplemental material
Supplemental material
Supplemental material
Participating hospitals
The Netherlands has 11 government assigned level 1 trauma centres capable of treating severely injured patients: Amsterdam Medical Centre (AMC), Vrije University Medical Centre Amsterdam (VUMC). Erasmus Medical Centre (EMC), Leiden University Medical Centre (LUMC), Radboud University Medical Centre (RUMC), University Medical Centre Utrecht (UMCU), Elisabeth Tweesteden Hospital (ETH), Maastricht University Medical Centre (MUMC), Isala Hospital Zwolle (IHZ), University Medical Centre Groningen (UMCG) and Medical Spectrum Twente (MST).
Outcomes
To provide an adequate overview, we analysed the following topics that are addressed in most MTPs: (1) prehospital transfusion; (2) MTP activation; (3) coagulation monitoring; (4) multicomponent package content; (5) use of TXA; (6) FC (cryoprecipitate); (7) anticoagulant reversal; (8) calcium; (9) recombinant activated factor VII (rFVIIa/NovoSeven); and (10) MTP termination. Results are summarised by absolute numbers per topic. Transfusion ratio is bags (units) per product type.
Patient and public involvement
No patients were involved in the study.
Results
All respondents in the 11 trauma centres and the D-MOD answered our request and sent details of their MTPs. Apart from some reminders, no further action was necessary to achieve full participation for the survey or oral interviews, which were completed in November 2018. All centres had a protocol for massive bleeding which was activated when a patient was suspected of having uncontrollable major bleeding (table 1). Blood supplies for hospitals in The Netherlands are regulated by one blood bank and hence all Dutch hospitals use the same type of blood products. A summary of the Dutch blood components is summarised in online supplementary appendix S4. This provides insight into how the ratio of differently prepared components compares with the transfusion of whole blood, the original intention of the 1:1:1 blood component transfusion ratio.2
Supplemental material
Prehospital transfusion and activation of the massive transfusion protocol
Prehospital transfusion
The Dutch guidelines advise initiation of transfusion in the prehospital environment whereas the 10th edition of the ATLS course and the fifth edition of the European guideline do not mention prehospital transfusion. In all hospitals, the protocol makes no distinction between patients who received prehospital transfusion and those who did not. As shown in table 1, four centres (EMC, VUMC, RUMC and UMCG) are linked to a helicopter emergency medical service. Since January, each helicopter always has 2 u of RBCs on board. The helicopters are located at civilian or military airfields in close proximity to the connected hospital and can rapidly transport patients to any level 1 trauma centre in the country. Data on patient outcome after prehospital transfusion in The Netherlands are currently unavailable.
MTP activation
The Dutch guidelines use an ATLS shock classification ≥III to initiate an MTP, whereas the 10th edition of the ATLS advises starting an MTP with a shock classification of IV. The fifth European guideline advises utilising a combination of clinical evaluation, shock index, and lactate and haemoglobin concentration.
All centres have clearly described initiation criteria for the MTP (table 1). None use just the Dutch guidelines and only one centre uses the ATLS shock classification for initiation. The majority of centres use other criteria: combination of a low systolic blood pressure and tachycardia, non-response to initial fluid resuscitation, penetrating injury and focused assessment with sonography in trauma. Following the patient’s arrival, the surgeon, anaesthesiologist or emergency physician assesses the patient and, if necessary, activates the MTP. Based on the clinical view, it is possible for the helicopter emergency medical service and the ambulance crew to initiate the inhospital MTP before arrival at the hospital.
Coagulation monitoring
The fifth European guideline and the 10th edition of the ATLS course advise the use of standard coagulation tests in combination with viscoelastic measurement (VEM) to monitor the patient’s coagulation status. In the Dutch guidelines, only the use of standard coagulation parameters is advocated.
At all centres, coagulation monitoring is performed as soon as possible by standard coagulation tests, such as prothrombin time, activated partial thromboplastin time, platelet count and fibrinogen levels, and use similar target values (table 1). In addition to these standard laboratory tests, most hospitals use VEM such as rotational thromboelastometry (n=6), thromboelastography (TEG) (n=1) or both (n=1). The interviews gave no insight into the actual use of VEM.
Multicomponent package content
Based on product volumes and the number of donors in the pool, the Dutch guidelines from 2011 advise using a 3:3:1 ratio of RBCs/plasma/platelets for the MTP, while the 10th edition of the ATLS course advises using a 1:1:1 ratio with standard US blood components. The fifth European guideline advises transfusing with a 2:1 ratio of RBCs/plasma and platelets only if platelet count is <100×109/ L.
Dutch hospitals use the standard blood components provided by the national blood bank (see online supplementary appendix S4) but differ in quantity per package (table 2). As shown in figure 1, according to the Dutch guidelines, packages (3:3:1) contain 300 mL less plasma compared with packages in the ATLS guidelines (1:1:1). Less plasma volume per package is the result of the change in single donor apheresis plasma (fresh frozen plasma, 300 mL) to pooled donor plasma (OctaplasLG, 200 mL) in 2014 and the change to platelets in platelet additive solution. As shown in figure 2 and table 2, only one centre complied with the ATLS course, two centres complied with the Dutch guidelines in both package content and ratio whereas one centre used the same ratio but with larger packages. None of the centres followed the European guideline. The total volume of each MTP package varied enormously, from 1460 to 2685 mL but the interviews gave no definite answer as to whether this amount was actually transfused. In addition to blood components, each centre specific MTP states that the use of crystalloids or colloids should be limited.
Transfusion ratio and package content
Red blood cells (RBCs) and fluid content of massive transfusion protocol package. AS, additive solution; DEC, deep frozen erythrocyte concentrate; DFP, deep frozen plasma; D-MOD, Dutch Ministry of Defence; DTC, deep frozen thrombocyte concentrate; FFP, fresh frozen plasma; PAS, platelet additive solution; PLT, platelet; PRP, platelet rich plasma; WB, whole blood.
Detailed content of transfusion packages. AMC, Amsterdam Medical Centre; AS, additive solution; ATLS, advanced trauma life support; D-MOD, Dutch Ministry of Defence; EMC, Erasmus Medical Centre; ETH,Elisabeth Tweesteden Hospital; IHZ, Isala Hospital Zwolle;LUMC, Leiden University Medical Centre; MST, Medical Spectrum Twente; MUMC,Maastricht University Medical Centre; PAS, platelet additive solution; RBCs, red blood cells; RUMC, Radboud University Medical Centre; UMCG, University Medical Centre Groningen; UMCU, University Medical Centre Utrecht; VUMC, Vrije Universiteit Medical Centre.
Tranexamic acid
The CRASH-2 trial, the fifth European guideline and the 10th edition of the ATLS course advise the early use of 1 g TXA followed by an infusion of 1 g over 8 hours.11 The Dutch national guidelines suggest that TXA might reduce mortality based on the CRASH-2 trial but that TXA only should be used in an experimental setting.11
Although the Dutch national guidelines from 2011 only recommend TXA use in an experimental setting, it is administered in all participating centres soon after trauma but the quantity and additional dose in the following hours differ. With the exception of two centres, all gave 1 g of TXA as soon as possible but at least within 3 hours (table 3).
Addtional medication during massive transfusion
Fibrinogen concentrate/cryoprecipitate
The Dutch national guidelines advise the use of fibrinogen based on laboratory values (<1.5 g/L) whereas the 10th edition of the ATLS course recommends the use of cryoprecipitate or FC when levels decrease to <1.8 g/L. The fifth European guideline advises using an initial supplementation of fibrinogen (3-4 g) in the early phase during resuscitation followed by laboratory based supplementation (<1.5 g/L).
All civilian hospitals have FC available; the D-MOD does not use FC. The MTPs describe direct administration of 2 g FC (n=6), 1 g (n=1) or based on laboratory results (n=4) (table 3).
Anticoagulant reversal
The fifth European guideline and the 10th edition of the ATLS course are unambiguous about reversal of anticoagulants. The Dutch guidelines are similar except that advice on dabigatran reversal is missing because this medication was not available in 2011. PCC is advised for coumarin reversal, protamine for heparin reversal, platelets for antiplatelet medication reversal, and in the fifth European guideline and the ATLS course, idarucizumab for dabigatran reversal.
Dutch hospitals generally use additional medication during MT for the same purpose. PCC is given directly in one centre, for coumarin reversal in nine centres and in two centres PCC is not part of the MTP. Desmopressin is part of the MTP in four centres and protamine in eight centres. Iarucizumab is used for dabigatran reversal and available in all centres but only described in five MTPs (table 3).
Calcium
The Dutch national guidelines advise the use of calcium only when large amounts of citrate containing blood components are transfused. The 10th edition of the ATLS course and the fifth European guideline advise infusion of calcium based on calcium levels (below the threshold of 1.1 mmol/L in the fifth European guideline). In participating hospitals, calcium was mostly administered based on laboratory values (n=8). In two centres, calcium was given immediately, and in two centres after 5 or 10 u of RBCs (table 3).
Recombinant activated factor VII
The use of recombinant activated factor VII (rFVIIa/NovoSeven) is no longer recommended in the 10th edition of the ATLS course or the fifth edition of the European guideline. The Dutch guidelines only recommends rFVIIa as a last resort. In 9 of the 11 participating centres, rFVIIa is available and used in the event of persistent bleeding despite transfusion of multiple packages (table 4).
Transfusion ratio compared with whole blood
MTP termination
The 10th edition of the ATLS course and the Dutch guidelines advises stopping the MTP and switching to laboratory based transfusion when bleeding control is achieved and the patient is haemodynamically stable. The fifth European guideline advises switching to goal directed therapy with VEM as early as possible. In all hospitals, transition from protocol administration of blood and blood components to laboratory based transfusion took place after bleeding control was achieved and the bleeding was haemodynamically compensated by the patient.
Discussion
Early recognition of major haemorrhage and activation of the MTP is important to reduce mortality in patients with uncontrolled bleeding.4 12 This study analysed MTPs in 11 level 1 Dutch trauma centres and the D-MOD, and compared these MTPs with (inter)national guidelines. Differences in transfusion ratio and package content, use of VEM and use of additional medications were found between hospitals and inter (national) guidelines, despite the introduction of a national guideline in 2011.
Transfusion ratio and package content
Differences in transfusion ratio may be because not all hospitals adjusted this ratio after the product changes in 2014 and 2018. An unadjusted ratio results in a reduction in plasma transfusion per package. As balanced resuscitation leads to faster haemostasis and reduced 24 hour mortality due to exsanguination, it is important that hospitals adjust the packages for changes in plasma volume.6 Also, most centre specific MTPs are based on more recent literature than the 2011 Dutch guidelines.
Viscoelastic measures
VEM such as rotational thromboelastometry and thromboelastography can be useful to detect TIC and it is suggested that it can be used to guide transfusion therapy.13 14 However, evidence that its use reduces blood transfusion or mortality in MT is lacking. Most of the participating centres described the use of VEM in their MTP but target values were unclear and information on how often VEM was actually used or preferred over standard laboratory techniques was lacking.
Additional medication
Blood components may not be transfused early enough to prevent or treat TIC.15 International guidance on the efficacy of additional medication during MT is rapidly evolving. This may explain why additional medication such as TXA, FC, prothrombin complex concentrate and rFVIIa are mentioned in most MTPs and intended quantity and timing of administration differ. For all additional agents, except TXA and anticoagulant reversal, international evidence to support their standard use in trauma is still absent or of low grade.3 16 The differences can be explained by the fact that MTPs were initially based on the Dutch guidelines that do not recommend its standard use. Whether the difference in dose is clinically relevant is currently unknown. It is expected that the now outdated Dutch guidelines will be updated and will advise using TXA.
Although low plasma fibrinogen is associated with an increased risk in mortality in blunt trauma patients, there are only a few studies that showed a survival benefit for trauma patients receiving additional FC.17 18 Whether additional FC during the MTP contributes to survival in trauma patients with major haemorrhage may be learnt from the results of the CRYOSTAT-2 International Clinical Trials Registry Platform identifier: ISRCTN14998314 and the PRooF-iTH trial.18 However, in this trial, the transfusion protocols differ between participating institutions which may affect interpretation of the results.
In The Netherlands, the use of oral anticoagulants (n=437 000) or direct oral anticoagulants (n=49 000) is particularly common in the elderly population.19 This group of elderly patients has an increased risk of inhospital mortality.8 19 Patients’ electronic records are currently not being exchanged between hospitals in The Netherlands. As a result, it is not always clear which anticoagulant the patient is receiving. Timely reversal of anticoagulants can reduce the time required to restore haemostatic function.20 All centres use procoagulants in their MTPs but indication, timing and quantity differ. The interviews and analysis of the MTPs showed that differences are possibly the result of MTPs based on the outdated national guidelines. rFVII is still used during resuscitation, despite the fact that there is a lack of evidence and that there is a significant increased risk of thromboembolic events.21
Crystalloids
Despite the restrictive policy in each centre, a recent Dutch study showed that an average of 4–5 L crystalloids is given to trauma patients in the first 8 hours after admission.22
Limitations
Although MTPs differed across the different level 1 medical centres, it is not clear if this resulted in different numbers of blood components transfused, amount/type of medications administered and/or patient outcomes. To identify an acceptable common ratio that is similar to current practice, the actual ratio, timing and frequency of blood component transfusions in MTPs in The Netherlands will be addressed in a future study (online supplementary appendix S5).
Supplemental material
Conclusion
MT strategies in Dutch level 1 trauma centres differ from (inter)national guidelines in transfusion ratio and additional medication, which could be explained by differences in the interpretation of the 1:1:1 ratio, changes in components and following outdated Dutch national guidelines. Whether these differences in MTPs lead to different patient outcomes will be determined from data currently being collected by this study group. An update of the Dutch national guidelines may help to achieve uniformity concerning MT. We recommend checking and updating MTPs using the latest guidelines and evaluating the level of evidence for each advocated treatment in the MTP at least once a year.
Acknowledgments
We would like to thank VLIJ van der Kruit for narrative and editorial support.
References
Footnotes
Contributors TWHR and FN conducted the research and wrote the manuscript. All authors read and approved the final manuscript.
Funding This study and the future clinical trial (the MAssive transfusion of Frozen bloOD (MAFOD)) is fully funded by the Dutch Ministry of Defence and the Dutch Army Health Insurance Foundation (SZVK).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.