Clinical review: Canadian National Advisory Committee on Blood and Blood Products - Massive Transfusion Consensus Conference 2011: report of the panel

In June 2011 the Canadian National Advisory Committee on Blood and Blood Products sponsored an international consensus conference on transfusion and trauma. A panel of 10 experts and two external advisors reviewed the current medical literature and information presented at the conference by invited international speakers and attendees. The Consensus Panel addressed six specific questions on the topic of blood transfusion in trauma. The questions focused on: ratio-based blood resuscitation in trauma patients; the impact of survivorship bias in current research conclusions; the value of nonplasma coagulation products; the role of protocols for delivery of urgent transfusion; the merits of traditional laboratory monitoring compared with measures of clot viscoelasticity; and opportunities for future research. Key findings include a lack of evidence to support the use of 1:1:1 blood component ratios as the standard of care, the importance of early use of tranexamic acid, the expected value of an organized response plan, and the recommendation for an integrated approach that includes antifibrinolytics, rapid release of red blood cells, and a foundation ratio of blood components adjusted by results from either traditional coagulation tests or clot viscoelasticity or both. The present report is intended to provide guidance to practitioners, hospitals, and policy-makers.

Advisory Committee on Blood and Blood Products [8]. A summary of the Proceedings of the Consensus Conference, including synopses of the public presentations of each speaker, will be published separately.
Each question posed to the panel was discussed in faceto-face meetings conducted during the 3-day conference. Panel members had access to the presentations of the speakers. Each panel member had an equal voice. For each response created by the panel, the degree of consensus was noted with a minimum requirement of 70% agreement required for consensus. Strong consensus required >90% agreement. Any concern or objection raised by a panel member was included in the report. Th e panel considered issues of patient equity and access to healthcare services in Canada, but was not asked to address blood support of trauma in neonates or small children. Pediatric trauma thus represents an important area for future consensus. Th e Consensus Conference Panel's response to each of the six key questions follows. Question 1. Formula-driven resuscitation as the standard of care: is there suffi cient evidence to justify 1:1:1 formula-driven resuscitation as the standard of care for bleeding trauma patients?
Th e panel reviewed the quality and generalizability of current evidence; methodological challenges in existing reports; risk-benefi t balance; cost-benefi t balance; alternatives to 1:1:1 ratio-driven resuscitation; and equity and access for Canadians. Currently, evidence for benefi t is limited to retrospective and historical control-case series with no prospective randomized trials addressing ratio-based blood support. Retrospective, nonrandom ized, or not properly controlled analyses comparing survival and other outcomes among patients who have received diff erent ratios of blood components determined post hoc have signifi cant fl aws in methodology [9]. Th ere is no high-quality information to form a confi dent assess ment of the risk-benefi t ratio surrounding ratio-driven blood resuscitation applied prospectively to cohorts of patients at risk for massive hemorrhage. Th ere are no costeff ectiveness studies on this subject. Th ere is insuffi cient investigation of the potential for an increased rate of adverse outcomes following formula-driven resus citation, especially among patients who ultimately do not require massive blood transfusion. Application of a 1:1:1 blood component strategy in the absence of clear benefi t will place demands on blood inventories with potential negative consequences for nontrauma patients. Alternatives to a formula-driven blood resuscitation strategy exist.

Recommendation of the Consensus Panel
As a result of the above considerations, especially the limited scientifi c evidence, the panel concluded that 1:1:1 formula-driven care cannot be recommended as a national standard of care for Canada. Practice recommendations for transfusion support are off ered in the Discussion. See Each study of formula-driven resuscitation reviewed by the panel was found to be susceptible to survivorship bias [10]. Two reports that attempted to correct for survivorship bias by treating the blood component ratio as a time-dependent covariate [11,12] found no benefi t on mortality. Th e relationship between blood ratios and survival rates is not linear [13,14], although reported comparisons may have assumed linearity. Moreover, current studies of ratio-driven blood support are further complicated by other sources of bias, including those commonly found in retrospective studies, registry studies, and studies without random allocation. Th ese methodologic concerns include secular trends, poor generalizability of single-site studies, selection bias, and imbalance of measured and unmeasured confounders [9].
Failure to adequately address survivorship bias is a serious impediment to the interpretation of retrospective studies of blood ratios and has probably contributed substantially to the observed interpretation and uptake of results. It is unlikely that further retrospective studies will overcome survivorship bias or resolve questions regarding the value of ratio-driven resuscitation.
While treating blood ratios as a time-dependent covariate may improve analysis, this analytic approach assumes that the risk of mortality is constant over the period of observation. Exclusion of early deaths from analysis, while partially accounting for survivorship bias, excludes the key subpopulation with the highest, and perhaps modifi able, mortality. Randomized controlled trials will require a very large sample size in order to demonstrate any statistically signifi cant eff ect. In the absence of randomized controlled trials, better organized observational studies in which the exact timing of blood infusions is captured may allow analysis that partially corrects for survivorship bias. Studies based on a cluster randomized trial design or a before-after design would have the advantage that each participating site need only follow one protocol.
Panel consensus: unanimous agreement.

Question 2. In addition to plasma, is there a role for other blood components and products in the resuscitation of massively bleeding patients?
Question 2a. What is the role for goal-directed or formuladriven platelet transfusion, fi brinogen use, cryoprecipitate transfusion, fi brinogen concentrate and factor XIII, prothrombin complex and activated recombinant factor VII and tranexamic acid?
Because adequate tissue oxygenation is essential for survival in massively bleeding patients, the fi rst principle of blood resuscitation remains the re-establishment of an adequate blood volume and cardiac output, and the optimization of oxygen-carrying capacity. Platelet transfusions are of presumed benefi t for trauma patients with thrombocytopenia, but there is no evidence of benefi t for nonthrombocytopenic patients who have taken antiplatelet agents. Hypofi brinoginemia occurs in some patients with massive bleeding, and when present should be treated. Th ere are insuffi cient data, however, to support the routine use of cryoprecipitate or fi brinogen concentrate in patients with fi brinogen levels >150 mg/dl [15].
Th ere is evidence from more than one randomized controlled trial to support the lack of utility with the use of recombinant activated factor VII (rVIIa) for the treatment of bleeding in blunt trauma or penetrating trauma patients [16][17][18]. rVIIa is not licensed for nor recom mended for the prevention or management of hemorrhage in trauma patients. In contrast, a large randomized controlled trial has supported the use of tranexamic acid in trauma patients, especially if given in the fi rst 3 hours after injury [19,20].
Topical control of bleeding sites -including ligature or resection, endovascular occlusion, packing with or without topical hemostatics, electrocautery, and proximal tourniquets -is expected to have the highest benefi t-torisk ratio of any hemostasis therapy. Nevertheless, there is insuffi cient infor mation regarding the benefi t of topical application of blood components (for example, cryoprecipitate, fi brin sealants) or topical pharmacologic agents (for example, antifi brinolytics, collagen) to make defi nitive recommendations.
Panel consensus: unanimous agreement. Two retrospective studies, conducted in patients undergoing abdominal aortic aneurysm surgery, examined outcomes related to blood transfusion ratios [21,22]. No studies have specifi cally addressed the use of ratio-driven blood resuscitation in cardiovascular surgery, upper gastrointestinal bleeding, burn surgery, liver transplan tation, or obstetrical bleeding. Th ese patients have comorbidities, clinical features, and hemostatic disorders very diff erent from those of trauma patients. Moreover, toxicities resulting from the high volume of blood components that are given in 1:1:1 blood resuscitation protocols may be diff erent in nontrauma patients compared with trauma patients.

Recommendation of the Consensus Panel
Overall, the literature for ratio-driven blood resuscitation applied to nontrauma patients is insuffi cient to recommend that this transfusion support strategy be directly applied to nontrauma patients with major bleeding.
Panel consensus: unanimous agreement. Th ere is evidence that clinical pathways in healthcare tend to improve the consistency and quality of care [23], and it is widely expected that a predetermined plan for transfusion support of trauma patients with critical bleeding will improve patient outcomes [24]. However, evidence that such plans improve patient outcomes is based on a limited number of before-after studies [25][26][27][28][29].
Activation of urgent and large-volume transfusion plans are meant to focus attention on the critically ill patient. Th ese plans can divert attention away from other patients, however, and unnecessary activation of massive transfusion plans may adversely aff ect the care of other patients. Develop ment of a working policy for treatment of life-threatening massive hemorrhage is challenging, and survey data suggest there is wide variability of practice [7,30]. Challenges and practical considerations are listed in Table 1.

Recommendation of the Consensus Panel
Despite these signifi cant challenges, the panel recommended that all hospitals in Canada that supply blood transfusion services should have a local procedure in place for urgent blood transfusion. Th e details of the procedure should be formulated in the context of locally available resources at the facility. Smaller hospitals should be encouraged to participate in regional or provincial trauma systems, to optimize local resources, to establish criteria for referral of care, and to establish pathways for communication and expeditious transfer for defi nitive trauma care.
Pan el consensus: strong agreement.

Question 5. Usefulness of laboratory tests: what do coagulation laboratory tests help (or not help) in massively bleeding patients?
Question 5a. What do thromboelastography and rotational thromboelastometry add to the management of massive hemorrhage? Question 5b. What are the strategies to reduce the turnaround time for laboratory results to allow for goal-directed resuscitation?
Although hemodilution remains a concern during prolonged trauma resuscitation, recent evidence suggests that the acute coagulopathy of trauma is not related to dilution of clotting factors. Rather, the acute coagulopathy of trauma is related to activation of a systemic injury response, including release of tissue-type plasmino gen activator with conversion of plasminogen to plasmin, and systemic endothelial activation leading to activation of protein C [31][32][33][34]. Th is pathophysiologic model might suggest a potential disadvantage to early administration of fresh frozen plasma, which provides an infusion of plasminogen and protein C, both substrates for anticoagulant pathways. More research is needed to distinguish causes, rather than markers, of coagulopathy. As already noted in patients with severe head trauma [35], treatments will be ineff ective if directed at abnormal coagulation tests that are only markers of association and not the cause of adverse outcomes.

Traditional laboratory testing
Serial measurements of a limited number of traditional laboratory tests (hemoglobin, platelet count, prothrombin time/International Normalized Ratio, fi brinogen, ionized Ca 2+ , pH, and electrolytes), if made available with a turnaround time that allows them to refl ect the clinical situation, are a useful adjunct to the clinical assessment of bleeding in patients undergoing massive transfusion [36,37]. Th e turnaround time for selected tests can be substantially shortened by attention to the processing details and policies [36]. Although point-of-care, wholeblood coagulation tests off er promise, results for the prothrombin time/International Normalized Ratio and fi brinogen may be dependent on the hematocrit and diffi cult to standardize for samples with abnormal values [38]. Key factors that need to be considered in the execution of traditional laboratory tests with rapid turnaround time are listed in Table 2.
Experi ence in trauma patients has identifi ed specifi c parameters of TEG™ and ROTEM™ that can be used as a guide to blood component treatment [41,[46][47][48]. In trauma patients, however, results correlated poorly (r 2 = 0.22 to 0.28) with those obtained using traditional laboratory tests [49]. Moreover, a Cochrane review found lack of evidence that transfusion guided by TEG™ or by ROTEM™ improved morbidity or mortality in patients with severe bleeding [50]. Point-of-care testing introduces challenges of standardization, quality control, and staffi ng, especially in programs with less frequent trauma cases.

Recommendation of the Consensus Panel
Th ere have been no substantial direct comparisons of clinical outcomes in a cohort of patients randomized to receive resuscitation guided by TEG™ or ROTEM™ versus traditional testing. For example, although both traditional laboratory coagulation tests and tests of clot viscoelasticity can be used to determine fi brinogen levels, published data are not suffi cient to decide whether clinical outcomes are improved by using one method versus another as a guide to fi brinogen replacement. Either traditional laboratory tests or tests based on clot viscoelasticity, or combinations of these tests, despite their Access to high-quality science upon which to design a transfusion policy. Clinical studies are needed to rapidly and reliably predict which patients will need large-volume transfusion support; and to evaluate laboratory-guided versus ratio-based transfusion.
• Access to resources needed for creating, implementing, monitoring, and updating the protocol.
• Access to information technology resources needed to execute rapid, large-volume transfusion.
• Access to resources required to train and educate a wide variety of staff including physicians, nurses, operating room and blood bank staff , and administrators. Ongoing training is needed especially in areas where trauma care is not a routine occurrence.
• Access to equipment required for delivery of urgent large-volume transfusion.
• Access to suffi cient blood supply. Smaller hospitals may not be able to stock suffi cient blood for large-volume resuscitation. The distance from the regional supplier may cause depletion of local blood stocks and threaten appropriate blood support of other patients. Transfusion policies that assign O-negative red blood cells and AB plasma to trauma patients may deplete regional reserves of these uncommon blood groups.
• Governance/agreement between multiple parties with diff erent perspectives. Policies need hospital executive support and agreement by a variety of stakeholders from diff erent departments. Clinicians involved in policy-making need a systems perspective in addition to that representing individual patient care.

Practical considerations
• Communication between the clinical team, the blood bank, the laboratory, and treatment locations (emergency room, operating room, interventional radiology suite, and so forth) of critical stages in the patient's treatment.
• Rapid assessment of patients who are at risk for critical bleeding.
• Effi cient and useful mechanisms for notifi cation of key hospital services required for delivery of urgent transfusion support.
• Proper patient and specimen identifi cation for unconscious patients.
• Policy for immediate release of uncrossmatched red blood cells.
• Rapid delivery of a properly labeled patient sample for ABO/Rh.
• Policy for waiving restrictions on special blood component attributes (for example, irradiated blood or cytomegalovirus-seronegative blood).
• Organized, sequential delivery of additional red blood cells, fresh frozen plasma, and platelets to the patient's location.
• Laboratory, nursing, and messenger staff allocations.
• Rapid turnaround systems for laboratory testing of hematology, coagulation, and critical metabolic parameters.
• Plan for inventory restocking with regional blood supplier.
• Development of predefi ned guidelines on when to withdraw support.

Process improvement
• Inclusion of all relevant participants including nonclinical participants (for example, porter services, managers of equipment and supply).
• Practice runs that simulate as much as possible actual trauma events.
• Periodic process review, critique, and change.
• Data collection including blood product wastage, especially O-negative red blood cells and AB plasma.
• Periodic assessment of spillover eff ects upon nontrauma patients whose transfusion care is altered as a consequence of the policy used to support trauma patients with critical bleeding. limitations, can provide serial information for the initiation and ongoing blood component therapy and resuscitation in massive hemorrhage due to trauma. Th ere is currently insuffi cient evidence to favor either approach to laboratory testing.
Panel consensus: unanimous agreement.

Question 6. Future research: what research is needed to improve the outcome of massively bleeding trauma patients and the use of blood and blood products?
Th e term 'massive transfusion' has several shortcomings, including: defi ning a medical condition by its treatment; treating a continuous variable (red blood cells (RBCs) transfused) as if it was dichotomous; and fostering retrospective analyses. Because of its limitations, the Con sensus Panel felt that the continued use of the term 'massive transfusion' should be discouraged except to describe an outcome of clinically important bleeding. Th e term 'acute coagulopathy of trauma' requires better defi nition using laboratory tests that refl ect the underlying physiology, have useful predictive performance characteristics, and are reproducible across diff erent institutions. New risk-scoring systems that would include physiologic markers associated with the acute coagulopathy of trauma would also be welcome.
Clinical studies on transfusion support in trauma need to be hypothesis driven with clearly defi ned inter ventions, defi ned populations for study, meaningful outcomes, specifi c capture of treatment-related toxicities, and a suffi cient follow-up period. Study designs will need to address the diffi cult challenges of patient selection, consent, enrollment, randomization, treatment masking, sample size, data collection, and adverse event capture and reporting [16].

Panel recommendations
Th e panel identifi ed fi ve categories of specifi c research opportunity in the topic of trauma, critical bleeding, and transfusion (see Table 3). Finally, the panel noted that better research on healthcare cost is needed for all categories of trauma-related blood component resuscitation. Analysis of proposed treatment strategies can consider cost-eff ectiveness and cost utility, and can perform sensitivity analyses to better understand the key drivers of cost to the national healthcare system. Considerations of cost are essential to balance societal investment in both the treatment of trauma and the prevention of injury.

Discussion and panel recommendations
Th e Consensus Conference process has several important strengths, including full public access to the process, broad participation, and a goal of reasonable consensus based on the current evidence. Th e consensus process generates an opinion based on presented evidence and with considera tion of equity and access to patients in both rural and urban settings. Th e panel was selected with a goal of broad independent representation. Th e panel did not formulate the questions and had no infl uence on the content presented at the meeting.
Th e Consensus Conference process also has weak nesses. Th e panel was not asked to conduct a formal systematic review of the literature or to provide a grading of the quality of prior published literature. Th e views of the panel therefore represent expert independent opinion.

Prevention of trauma is cost-eff ective
Th ere can be little doubt that many injury-prevention measures, already implemented, are more cost-eff ective than the treatment of trauma; and this fact should weigh heavily on decisions regarding allocation of government funding to promote wider acceptance of prevention programs [51,52]. Despite prevention eff orts, injuries related to motor vehicles [53], self-infl icted trauma including suicide [54], and use of alcohol or drugs [53,55] remain common preventable causes of injury. Opportunities thus remain for further reduction of serious injury and death from motor vehicle accidents, falls, and trauma related to fi rearms, alcohol and drug abuse, and depression.

Only a very small percentage of trauma patients can have survival directly aff ected by changes to current transfusion strategies
Th e great majority of trauma victims do not experience massive hemorrhage. Among fatally injured patients 40

Table 2. Laboratory considerations for urgent care patients with critical bleeding
• Commitment of the laboratory and hospital administration to re-engineer standard processes with special emphasis on rapid turnaround time of a few selected tests important in trauma-related critical bleeding.
• Rapid analytical tests or use of in-laboratory point-of-care technology.
• Direct reporting of results to the patient care area and to the blood transfusion laboratory.
• Policies that allow early release of preliminary values that would otherwise require reverifi cation or duplicate runs if tested under less urgent conditions.
to 60% die at the scene or in transit, with higher fatality rates in rural settings [56][57][58][59]. A review of trauma fatalities from a Canadian level 1 trauma program found that 15% died from hemorrhage and that 16% of these deaths were deemed preventable [60]. Among the preven table deaths, the root cause was delayed recognition in hospital of bleeding rather than preventable death due to blood transfusion strategies. An additional 11% died from a combination of bleeding and severe central nervous system injury where transfusion practice has less impact on overall survival. Similar estimates were found at another Canadian level 1 trauma center (RS Morad Hameed, personal communication, Vancouver General Hospital, 2011). If 40-60% of trauma fatalities occur prior to admission to hospital, and if 15% of hospitalized trauma cases die from hemorrhage, then even if 20% of hospitalized trauma cases could be saved by alternative strategies of transfusion support, only 1% to 3% of all trauma fatalities could be directly addressed by changes in transfusion practice. Because some fatal bleeding outcomes result from extensive and uncorrectable anatomic injury, the percentage of preventable bleeding deaths that can be directly addressed by changes in blood transfusion practice is likely to be even lower. Th ese estimates are relevant to the importance of injury prevention, for considerations of the cost-eff ectiveness of transfusion strategies, and for determining the required size of prospective clinical trials focused on transfusion. When indiscriminately applied as part of a standard protocol, expensive transfusion interventions will not be cost-eff ective due to the small number of individuals who actually benefi t from the intervention. Reducing prehospital deaths through injury prevention remains an area with high opportunity for saving lives. Nevertheless, for trauma patients who experience massive blood loss, hemorrhage is a common cause of death [61].

Civilian trauma and military trauma are not the same
Treatment of battle casualties represents an important area for the exploration of new treatments of trauma patients. Some aspects of trauma seen among soldiers and noncombatants wounded in theaters of war have similarities to trauma seen in civilian settings (for example, burns, gunshot wounds). However, substantial diff erences exist between civilian trauma and military trauma [62]. Th ese diff erences include the characteristics of the underlying population, the nature of the trauma, and the treatments available. For example, 93% of trauma in Canada is blunt trauma, with only 5% penetrating trauma and 2% burns [53]. In military trauma these proportions are reversed. Th e panel felt that obser vations, clinical reports, policies, and practice patterns obtained in and relevant to the theater of war, while of potential benefi t to civilian healthcare [63], should not be Table 3

. Specifi c research opportunities in the fi eld of trauma, critical bleeding, and transfusion
Strategies for blood resuscitation of trauma patients with critical bleeding • Prospective randomized head-to-head comparison trials of goal-directed, ratio only, or combination strategies for blood support in trauma patients.
• Immune consequences of exposure to large quantities of incompatible group A and group B soluble antigens found in ABO-compatible but nonidentical plasma.
• Prospective randomized studies that examine eff ects of colloid versus crystalloid resuscitation.
• Studies of clinical hemostatic effi cacy and adverse eff ects of stored thawed plasma compared with plasma thawed within 24 hours, including the effi cacy and adverse eff ects on nontrauma patients who might receive such products.
Other blood therapies • Studies comparing triggers for fi brinogen supplementation, diff erent sources of fi brinogen, and methods to monitor eff ect of transfusion of fi brinogencontaining products.
• Preclinical studies of the eff ect of novel inhibitors of the protein C pathway on the acute coagulopathy of trauma.
Conditions other than trauma • Identifi cation of features common to all patients receiving sustained high rates of transfusion as well as research designed to identify clinical, laboratory, and treatment features unique to critical bleeding in trauma, cardiac surgery, obstetrics, and pediatrics.
Clinical pathways for delivery of transfusion support in trauma complicated by critical bleeding • Studies of the value eff ect of massive transfusion protocols.
• Studies addressing the diffi culty and the process of withdrawing therapy among patients with negligible physiologic chance of survival.
• Studies of access to massive transfusion strategies in remote healthcare settings.
Coagulation testing and the acute coagulopathy of trauma • Studies of the value of various specifi c laboratory tests to support the transfusion of massively bleeding trauma patients. These to include both classical tests of hemostasis and thromboelastography/rotational thromboelastometry testing.
• Well-designed, controlled investigation of topical hemostasis therapy including topical application of blood components and the topical application of procoagulant drugs/agents. considered immediately transferrable to civilian trauma patients.

Practice recommendations for transfusion support of critical bleeding in trauma patients
Trauma care is complex, and outcomes depend on timing, the nature of the injury, patient age and comorbidities, geographic location and transport times, surgical and anesthesia expertise, intensive care services, physiologic and laboratory assessment, and transfusion support. Practitioners can fi nd valuable information from several sources, listed in Table 4 and in recently published guidelines [64][65][66]. Th e initial approach to the care of the injured patient should be in keeping with current principles -such as those detailed in the Advanced Trauma Life Support guidelines, which are regularly updated [67,68]. Direct control of bleed ing with defi nitive management by surgery or interventional radiology remains the mainstay of therapy. Th e most important step in the transfusion support of trauma patients is the development of a local, agreed-upon practice approach to blood support.

Red blood cells and tissue oxygenation
Tissue oxygenation remains the fi rst goal of blood therapy. Because of the direct link between tissue ischemia, disordered hemostasis [31,69], and mortality, the most important blood component for prevention and treatment of coagulopathy is packed RBCs. Local policies should clearly provide for the rapid delivery of uncrossmatched RBCs. Life-saving RBC transfusion should not be delayed. Venous access of suffi cient size for rapid blood infusion should be established without delay. Although higher concentrations of hemoglobin are associated with improved hemostasis [70], the optimal target hemoglobin concentration for patients undergoing resuscitation from traumatic injury is not well established. Intraoperative blood salvage, when select ively used for cases involving large-volume blood loss, can provide a ready source of ongoing erythrocyte support for trauma patients. Devices designed for rapid blood infusion and blood warming can facilitate transfusion support and can mitigate complications of hypothermia.

Pharmacologic support of hemostasis
A large multicenter prospective trial has established that early use of an antifi brinolytic (tranexamic acid) reduced overall mortality in trauma patients, especially if administered within 3 hours of injury [19,20]. Th e incremental cost of tranexamic acid per life-year gained was just $64 [71]. In contrast, when tested in trauma trials, even multiple doses of rVIIa did not improve survival  [17,18] and may have worsened outcomes due to an increased risk of arterial thrombosis [72][73][74]. Th e lack of clinical eff ectiveness and the extremely high cost of rVIIa relative to RBCs translate into a negligible cost-eff ectiveness for rVIIa.

Transfusion support of hemostasis
Th e Consensus Panel felt that neither a strategy of transfusion support based solely on laboratory testing nor a strategy based solely on blood component ratios was demonstrated to result in optimal transfusion support for all trauma patients. A potential shortcoming of laboratorydirected therapy, as the only strategy for blood support in massive hemorrhage, is the potential to fall behind. Th is can result from reliance on assays with low sensitivity and predictive value for the hemostatic derangements among trauma patients, or from delays in test turnaround time. A potential short-coming of ratio-driven blood support, as the only strategy of transfusion care, is overtransfusion with plasma and platelets resulting either in no benefi t [75,76] or in added toxicity (especially pulmonary) [13,[76][77][78]. Th e evidence supporting a 1:1:1 transfusion strategy in civilian trauma was not suffi ciently strong to overcome concerns about its toxicity to patients, nor to recommend it as a standard of care in Canada. Th ere was insuffi cient evidence to favor a panel of traditional tests over TEG™/ROTEM™ tests or vice versa for guiding therapy. Th ere was also insuffi cient information to favor point-of-care testing versus centralized testing. Because patients receiving large-volume transfusion support vary greatly in the nature and degree of injury, the panel wished to emphasize the importance of individual tailored therapy over rigid protocols of blood transfusion support. In addition, treatment guidelines appropriate for severe trauma patients do not apply to elective surgery patients who experience signifi cant hemorrhage. Patients undergoing elective surgery without shock, acidosis, and signifi cant tissue injury do not experience the same degree of hemostatic breakdown observed in severe trauma.

Suggested blood component support of the critically bleeding trauma patient
Given the current available knowledge, practical management of blood support for the trauma patient with critical bleeding should give consideration to a combination of up-front hemostatic support, a foundation ratio of blood component release, and goal-directed adjustment of transfusion therapy. A specifi c example of the combination of these three strategies -suitable for a defi nitive-treatment center and applied to patients who are identifi ed as at high risk for massive hemorrhage -is shown in Figure 1.

Platelet concentrates
At the University of Maryland program, <3% of patients with an Injury Severity Score >15 had an admission platelet count <100,000/μl [79]. Th rombocytopenia will generally not develop until at least one blood volume of resuscitation has occurred. Th ere is currently no highquality evidence to support the use of up-front platelet transfusions. Th ese platelet transfusions do not reverse antiplatelet agents such as clopidogrel and there is no evidence to support use of platelet transfusions to improve outcomes in patients who have recently taken antiplatelet agents [80]. Retrospective studies in both trauma patients and nontrauma patients with intracranial hemorrhage have found no benefi t from platelet transfusions given to patients who are taking antiplatelet agents [81][82][83].

Fibrinogen
Because a decline in fi brinogen concentration is seen in hyperfi brinolysis, consumption coagulopathy, disseminated intravascular coagulation, and hemodilution, and because a decline in fi brinogen is observed in massively injured patients, specifi c attention to fi brinogen may be of merit in transfusion support of critical bleeding [45]. Fresh frozen plasma and thawed plasma contain physiologic levels of fi brinogen. Higher concentrations of fi brinogen are found in cryoprecipitate and in fi brinogen concentrates. Current evidence does not support the superiority of one source of fi brinogen over another [15].

Prothrombin complex concentrates
Whether or not infusion of prothrombin complex concen trates used either as a substitute for plasma or as a supplement to plasma is safe or improves outcomes beyond that which would be observed without their use has not been adequately studied (a lack of data).

Transfusion and trauma care in both small, rural and large, urban healthcare facilities
Canadians residing in rural and remote locations have been shown to be at increased risk of sustaining severe injuries, and to have decreased access to defi nitive trauma care once injuries occur [58]. Despite the greater challenges to care, smaller hospitals not specializing in trauma can apply early treatments of proven value such as tranexamic acid. Because no single approach to transfusion support of trauma patients is of proven superiority, there is no requirement that specifi c practices regarding blood products be imposed as an absolute standard of care. Improved communication within existing regional trauma systems should provide valuable guidance for the initial care of critically injured patients and supports the principle of equitable delivery of care [84][85][86][87]. Large, urban hospitals off ering level 1 trauma care have the opportunity to establish centers of excellence and use their vantage point to pursue, in a collaborative way, welldesigned prospective trials intended to answer specifi c questions regarding best practice in trauma.
Competing interests AWK has served on an Advisory Panel discussing the use of ultrasound contrast media for Lantheus Medical Corp, Boston, MA, USA. WHD, MAB, DF, MH, BH, TK, SL, RS, SS, CM and BM declare that they have no competing interests.
Authors' i nformation BM is Acting Vice-Chair of the National Advisory Committee on Blood and Blood Products. AWK is the immediate Past-President of the Trauma Association of Canada.