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British Journal of Anaesthesia 113 (S2): ii3–ii8 (2014)

doi:10.1093/bja/aeu379

CRITICAL CARE

Role of the massive transfusion protocol in the management


of haemorrhagic shock
J. H. Waters

Department of Anesthesiology, Magee Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, USA
E-mail: watejh@upmc.edu

The concept of rapid delivery of multiple blood products to the bedside of


Editor’s key points a massively haemorrhaging patient seems to be a logical approach to the
† Retrospective data from victims of severe military management of the massively bleeding patient. However, controversy
trauma have led to fixed blood component ratio exists in the use of fixed blood component ratios. Assessing the extent
therapy in trauma. of the coagulopathy through point-of-care testing might provide

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† Close inspection of these studies reveals important patients with product administration as needed, and avoid excessive
limitations in their interpretation including a transfusion and its associated complications.
prominent effect of survivor bias.
Keywords: blood component transfusion; consumption coagulopathy;
† Point-of-care viscoelastic testing of whole blood erythrocytes; trauma
coagulation provides an individualized approach to
therapy to reduce unnecessary plasma transfusion. Accepted for publication: 29 September 2014

From the experience gained during the Iraq and Afghanistan support hospital. Massive transfusion was defined as .10
conflicts, a concept of damage control resuscitation has RBC units in 24 h. They separated 246 patients into three
arisen. Within the context of damage control resuscitation is groups, depending on the ratio of RBCs to plasma. High
the incorporation of the massive transfusion protocol, which plasma patients who received high ratios of plasma units to
dictates that blood is delivered expeditiously to the bleeding RBCs had higher survival rates compared with those who
patient, generally in a fixed ratio. The protocol is intended received a low ratio of plasma units to RBCs. From this non-
to provide blood to the patient bedside in a rapid fashion. randomized, retrospective analysis, the authors concluded
At the author’s institution for example, 10 units of O+ uncross- that a higher ratio of plasma to erythrocytes contributed to a
matched packed red blood cell (RBC) units, 6 units of AB better outcome. What seems to have been neglected in the
plasma, and 2 bags of platelets are provided. analysis was that the patients who received the high ratio
The importance of the ratio of these products is where had lower rates of thoracic and head injuries; had haemoglobin
controversy arises. Some evidence, which will be discussed, concentrations on presentation to the combat hospital that
implies that these products should be administered in a were 1.5 gm dl21 higher than the low ratio group; had
fixed ratio of 1 unit of packed erythrocytes to 1 unit of reduced base deficit (8 compared with the low ratio group
plasma to 1 unit of platelets (generally termed the 1:1:1 with a base deficit of 13); and had a lower International nor-
transfusion ratio). Most of these studies focus primarily on malized ratio (INR) of 1.54 compared with the low ratio group
the erythrocyte to plasma ratio so in reality, this discussion whose INR was 1.78. So, the low ratio group was more acidotic,
primarily entails a 1:1 erythrocyte:plasma transfusion ratio. more coagulopathic, and more anaemic than the high ratio
In 1982, the phrase ‘viscious circle of trauma’ was coined, group. In addition, for the patients who died in the low ratio
which refers to the acidosis, hypothermia, and coagulopathy group, they did so at an average of 2 h from arrival into the
of trauma.1 The intent of aggressive plasma use is to address combat facility; whereas, the patients in the high ratio group
the coagulopathy of trauma at an early stage. The following dis- died on average at 37 h and died more commonly from
cussion is an unsystematic review of literature related to the sepsis, multi-organ failure, and central nervous system injury.
fixed ratio plasma to red cell transfusion strategy. A number of studies similar in study design followed the
Borgman study (see Table 1). In 2008, a retrospective civilian
Fixed ratio transfusion study involving 16 level I trauma centres and 467 patients
The evidence for a 1:1 transfusion ratio derives from a number was published,5 which also found improved survival with
of studies. The landmark study that started this practice was by higher ratios of plasma and platelets. This study appeared to
Borgman and colleagues in 2007.2 This was a retrospective be the catalyst for many trauma surgeons to adopt the 1:1
chart review of massive transfusion at a US Army combat transfusion strategy. Like the Borgman study, there were

& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
BJA Waters

stark differences in time-to-death between the patients that Part of this minimal effect relates to the variable pro-
received high ratios of plasma and platelets. If the time of coagulant potency of transfused plasma. The INR of trans-
death and the average number of blood products administered fused plasma ranges from ,1 to .1 based on the donor
to the patients who died in each group are used to estimate and the effect of storage. Some plasma can have an INR as
rates of blood product administration between ratio groups, high as 1.3.23 So, if an INR level is ,1.3, there is a good
stark differences in patient populations appear to exist in this chance that plasma transfusion will raise the INR. In addition,
study also. Patients who were categorized in a low plasma, correction of an INR is not linear and at low INR values,
low platelet group, received erythrocytes at a rate of 5.25 plasma has little effect.24 25 If plasma is given to raise
units per hour before death whereas for the high plasma, coagulation factor concentrations by 10%, the effect will be
high platelet group erythrocytes were given at a rate of 0.63 very different depending upon the starting INR. For instance,
units per hour (Table 2). Additionally, the mechanism of if the INR is 1.5 and enough plasma is given to raise factor
injury was truncal and head injury in 58% of the low ratio concentrations by 10%, then the result will be to correct it
patients and 23% in the high ratio patients. While this study to 1.4. A similar change in 10% when the INR is 3.0 will
has been highly influential, caution would be suggested in result in a new INR of 2.3, so the effect is much greater at
translating these findings to civilian trauma. higher INRs. Recent evidence suggests that conventional la-
Each of the studies outlined in Table 1 has flaws associated boratory tests of coagulation are insensitive in detection
with their retrospective study design. Most prominently, sur- acquired coagulopathy as in trauma, or in guiding procoagu-
vivor bias has been a repetitive source of error in these 1:1 lant therapy.26 27
ratio studies. Survivor bias is associated with having survived With the understanding that varying effects of plasma

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long enough to receive a particular therapy. A nice example transfusion are seen at varying INR values, what is necessary
to illustrate this bias is shown in Figure 1. In Figure 1A, four to raise the INR level by 10%? First, each plasma unit varies in
erythrocyte units are administered to a patient followed by a volume depending on how it is collected and the haematocrit
plasma unit, at which point the patient dies. In Figure 1B, the of the donor. In general, each unit contains 250 ml with each
same pattern of blood administration occurred; however, the millilitre of plasma containing one unit of procoagulant activ-
patient did not die and was given further plasma units before ity. Since the procoagulant content of a unit of plasma is
the end of resuscitation. So, the short survival patient in diluted by anticoagulant and since some activity is lost in pro-
Figure 1A received an erythrocyte:plasma ratio of 4:1 (low cessing, a 250 ml unit of plasma might be expected to provide
ratio); whereas the surviving patient in Figure 1B received a 200 units of procoagulant activity on average. Recovery of
1:1 ratio of erythrocyte to plasma (high ratio). This illustrates procoagulant factors in plasma is not 100%, however, and
survivor bias in that the only real difference is that the may be as low as 20 –40%. Thus, in a 70 kg patient with a
patient in Figure 1A simply died earlier whereas the therapy 3000 ml plasma volume, transfusion of one 250 ml unit of
was identical up until that point. plasma might be expected to increase most factors by
To assess the effect of survivor bias, Snyder and colleagues12 2.5% (or 0.025 U ml21). Transfusion of four units would
looked at the impact of a high ratio of plasma to RBCs com- raise levels by 10%. The 1:1 RBC: plasma ratio is predicated
pared with a low ratio (Table 3). In this study, 40% of the high on correction of one arm of the lethal triad of trauma (acidosis,
ratio patients died while 58% of the low ratio patients died. hypothermia, and coagulopathy). Administration of 1 unit of
However, if one looks at the time of death, there is clearly a plasma to treat mildly abnormal INR elevations would be
difference between groups. Like the aforementioned studies, anticipated to have little to no effect on coagulation function
the low ratio group patients died much earlier in their care. while exposing the patient to the adverse effects of plasma.
When Snyder and colleagues looked at the relative risk of
death with a time-varying covariate, the survival advantage
of the added plasma disappeared, thus confirming the exist- Adverse effects of aggressive plasma use
ence of this bias. Logically, it would seem that more plasma would facilitate re-
suscitation early in the hospital course of a trauma patient, but
the question must be asked as to whether such aggressive
Effect of plasma on coagulation function plasma use simply facilitates resuscitation that could be
Many of the studies outlined in Table 1 report average INR achieved with a different colloid solution such as albumin. If
values that are mildly or slightly elevated, generally around this better resuscitation is facilitated, is there harm that
an INR of 1.8. While there is no debate that trauma is asso- could potentially arise from aggressive plasma use compared
ciated with coagulopathy, there is substantial evidence that with an alternate therapy.
transfusing plasma in circumstances where the INR is mini- Several investigators have attempted to answer this ques-
mally elevated has a minimal effect on the INR.15 – 17 While tion. Perel and colleagues,28 in a secondary analysis of the
minimal effect on INR occurs, it does expose the patient to CRASH-2 (clinical randomization of an antifibrinolytic in sig-
risks associated with plasma transfusion.18 These risks pri- nificant haemorrhage 2) trial data (a study to assess the
marily relate to acute allergic reactions,19 transfusion related impact of tranexamic acid in trauma patients), found that
acute lung injury,20 21 and transfusion associated circulatory transfusion increased the survival in a patient population
overload.22 where 50% of the patients were predicted to die; whereas

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MTP in haemorrhagic shock
Table 1 Studies advocating 1:1 transfusion ratios. PRBC, packed red blood cells. NR, not reported; FFP, plasma; PRBC, erythrocytes; TEP, transfusion exsanguination protocol; MT, massive transfusion;
MTP, massive transfusion protocol; LOS, length of stay; MOF, multiple organ failure; ARDS, acute respiratory distress syndrome.

Author, year Study design Follow-up Interventions Control Outcomes


Borgman, 20071 Retrospective, cohort NR FFP:PRBC ratios from 1:8 to FFP:PRBC ratio 1:1.4 High FFP, lower death
1:2.5
Cotton, 20083 Non-randomized pre- post- 30 days TEP (PRBC:FFP:Plts 10:4:2) No TEP less FFP, also needed TEP reduced death
.10 units PRBC in first 24 h
Cotton, AAST, 20083 Non-randomized pre- post- NR TEP (PRBC:FFP 3:2) No TEP, less FFP TEP reduced MOF
Gunter, 20084 Non-randomized pre- post- 30 days PRBC:FFP 3:2 or greater PRBC:FFP 3:2 or less High FFP, lower death
Holcomb, 20085 Retrospective cohort 30 days High plasma to PRBC≥1:2 Low plasma to PRBC.1:2 High FFP, lower death
Duchesne, 20086 Retrospective cohort Death High plasma to PRBC.1:2 Low plasma to PRBC.1:2 High FFP, lower death
Kashuk, 20087 Retrospective cohort Death, or LOS FFP:PRBC ratios from 1:1 to 1:4 FFP:PRBC ratio 1:5 No benefit
Moore, 20088 Prospective cohort, Death, or LOS MT protocol, subgroups of early, No MT MT provides better outcomes
retrospective control late death, survivors
Scalea, 20089 Prospective, cohort Death, or LOS Transfusion, stratification by No transfusion No benefit
ratio
Sperry, 200810 Prospective, cohort Death, or LOS PRBC:FFP ,1:1.5 PRBC:FFP.1:1.5 High FFP, lower death, higher
ARDS
Dente, 200911 Prospective, cohort 30 days MTP 1:1:1 No MTP Reduces short-term
mortality but no difference at
30 days
Snyder, 200912 Retrospective , cohort Death, or LOS Survivors Non-survivors PRBC:FFP ratio predictive of
death but survival bias
negated effect
Zink, 200913 Retrospective, cohort 30 days PRBC:FFP 1:1 PRBC:FFP.1:1 Survival better in 1:1
Teixeira, 200914 Retrospective, cohort Death, or LOS PRBC:FFP 1:1 PRBC:FFP in lower ratios Survival better in 1:1

BJA
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BJA Waters

Table 2: Blood component transfusions by plasma and platelet ratios. Reproduced with permission from Holcomb and colleagues.2
RBC = erythrocytes; FFP = Plasma; rFVIIa = recombinant factor VIIa

High plasma, High High plasma, low Low plasma, high Low plasma, low P
Platelets platelets platelets platelets
Plasma (units) 17 (12) 16 (10) 7 (5) 6 (6) ,0.001
Platelets (units) 20 (16) 5 (6) 18 (10) 4 (6) ,0.001
RBC (units) 22 (17) 21 (12) 21 (11) 21 (12)
Crystalloid (L) 14 (10) 13 (7) 17 (12) 11(10) ,0.001
FFP:RBC ratio 0.8 (0.3) 0.8 (0.3) 0.3 (0.1) 0.2 (0.1) ,0.001
Platelet:RBC ratio 0.9 (0.4) 0.2 (0.2) 0.9 (0.4) 0.1 (0.2) ,0.001
Crystalloid:RBC 0.8 (0.5) 0.8 (0.6) 0.9 (0.6) 0.6 (0.5) ,0.001
ratio
Received rFVIIa (%) 34 (22) 11 (11) 21 (25) 15 (12) 0.006

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A Death B
Survivor

Time Time

Fig 1 Survivor bias. (A) a theoretical patient receives 4 erythrocyte units followed by a plasma unit and subsequently dies, so a 4:1 ratio results. (B), a
theoretical patient receives 4 erythrocyte units followed by 4 plasma units but doesn’t die resulting in a 1:1 ratio. The therapy is identical with the
exception being the death of the patient.

Table 3: Group sizes* and numbers of deaths in low (,1:2) and high (.1:2) FFP:PRBC ratio groups by time interval of hospitalization. Reproduced
with permission from Snyder and colleagues.12

≤30 >30 –60 >60 – 90 >90 – >2 –3 >3 –4 >4–5 >5–6 >6–12 >12 – 18 >18– 24 >24 Total
min. min. min. 120 min. hrs. hrs. hrs. hrs. hrs. hrs. hrs. hrs.
,1:2 (low ratio)
No. pts in group 86 102 103 102 95 91 85 87 74 73 74 74 74
No. deaths 0 0 8 10 9 3 2 1 2 2 0 6 43
during interval
.1:2 (high ratio)
No. pts in group 1 6 13 20 34 39 46 46 60 61 60 60 60
No. deaths 0 0 0 0 0 2 1 0 7 1 0 13 24
during interval

plasma transfusion increased the risk of death in a cohort of colleagues30 found an increased risk of multiple organ
patients that had a predicted risk of death ,20%. Similarly, failure when patients were transfused aggressively with
Inaba and colleagues29 found an association between plasma. These authors suggested that caution is warranted
plasma use and overall complications in non-massively trans- when empirically transfusing plasma. These three studies
fused patients (defined as patients receiving ,10 units of suggest that in the bleeding patient, more plasma might
PRBCs during the first 24 h of their hospitalization). In a retro- have unpredictable results when given using a fixed ratio
spective review of 1440 trauma patients, Johnson and strategy.

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MTP in haemorrhagic shock BJA
Laboratory-guided plasma use risks increase with escalating plasma exposure, thus affecting
patient safety. Assessing the extent of coagulopathy through
In order to avoid excessive or overzealous administration of
conventional laboratory testing cannot help guide bleeding
blood products, several investigators now suggest that transfu-
management, but minor derangements in routine coagulation
sion be guided by laboratory testing. In a randomized study,
tests can be used to avoid excessive allogeneic blood transfu-
Nascimento and colleagues31 compared a fixed transfusion
sions including plasma and its associated complications.
ratio with transfusion guided by laboratory data every 2 h.
Future prospective research is warranted to assess the poten-
This study enrolled 78 patients with the primary aim being to
tial benefits of rapid delivery of plasma in a fixed ratio to
assess the feasibility of doing a larger study of this topic. They
RBC concentrates compared with laboratory testing guided
found a trend towards worse outcomes with the fixed ratio
plasma without a fixed ratio to other blood products compared
strategy of care compared with laboratory-guided plasma
with individualized coagulation management based on point-
and platelet use, but concluded that a larger study size was
of-care coagulation monitoring.
needed in order to show statistical significance. Regardless,
the authors make a significant leap in sophistication from the
recipe of giving blood products in a fixed ratio to one that is
Declaration of interest
guided by laboratory data. None declared.
Traditional laboratory testing provides slow information
by which to make a care decision but the concept of point- References
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