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1
New York Blood Center, New York, NY, USA
2
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
3
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
* Corresponding author. E-mail: bshaz@nybloodcenter.org
& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA Pham and Shaz
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Massive transfusion management BJA
of 65%, and a platelet count of 90 000 ml21.37 In addition, if
Coagulopathy
storage defects are taken into account, then this mixed
product would have a haematocrit of 26%, coagulation
Acidosis
factor activity of 40–50%, and platelet count of 90 000
Tissue
ml21.37 Furthermore, any attempt to increase the concentra-
Severe trauma Bleeding
hypoxia tion of one component would lead to dilution of the other two.
Hypothermia The administration of RBC:plasma:platelets at 1:1:1 ratio
Colloid and
Dilution of was first proposed by the US military and subsequently sup-
coagulation factors
crystalloid infusion and platelets ported by military and then civilian studies. The rationale for
Massive RBC the 1:1:1 ratio is that it more closely resembles whole blood,
transfusion which would help to treat and prevent ETIC. A retrospective
review of patients receiving MTat a US combat hospital demon-
Fig 1 Pathogenesis of haemostasis abnormality in MT. Dilutional strated reduced mortality from 66% to 19% when the
coagulopathy, activation of inflammatory mediators, hyperfibrinoly- RBC:plasma ratio decreased from 8:1 to 2:1.38 Then, Johansson
sis, thrombocytopathy, and metabolic abnormalities (hypothermia, and Stensballe39 demonstrated that high plasma and
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BJA Pham and Shaz
Table 3 Sample adult MTP. Modified from Table 2 in Cushing and Shaz,44 with permission from Minerva Anestesiologica, Edizioni Minerva Medica
S.p.A. RBC, red blood cell; SDP, single-donor platelets; Cryo, cryoprecipitate; rFVIIa, recombinant activated factor VII; AB, blood type AB
between different clinical services. When developing an MTP, is associated with improved survival to hospital discharge by
determining quality indicators will enable clear parameters to decreasing death from bleeding.51 Thus, monitoring fibrinogen
track and trend, such as the time for products preparation and level and/or early transfusion of fibrinogen concentrate or cryo-
issue, product wastage, laboratory turnaround time, laboratory precipitate could be potentially beneficial.
values, and indications for MTP in order to continuously The military uses fresh whole blood when apheresis platelet
improve the MTP. An MTP should have the following components: products are not available. In the recent military experiences
in Iraq and Afghanistan, whole blood transfusion compared
(i) When and who should initiate MTP. with RBC, plasma, and apheresis platelet use reduced pulmonary
(ii) Notification of the transfusion service and laboratory and tissue oedema, which decreased the ventilation time and
regarding start and stop of MTP. also allowed closure of the abdomen with minimal delay.52 Fur-
(iii) Laboratory testing algorithm [prothrombin time (PT), thermore, retrospective analysis suggested that patients who
activated partial thromboplastin time (aPTT), fibrino- received both fresh whole blood and component therapy had
gen level, blood gas, and complete blood count], and better clinical outcomes compared with those who received
thromboelastography if available. only component therapy.53 However, concern for transfusion-
(iv) Blood product preparation and delivery (i.e. pre- transmitted infections and transfusion-associated graft vs host
determined transfusion packages). disease remains.54 55
(v) Other patient care needs (such as blood warmers,
nursing care). Paediatric MTPs
The data on paediatric MTPs are limited, and thus practices vary
MTPs can include preparation and administration of blood
significantly among institutions.56 57 Owing to logistics, it is a
products based on laboratory test results, predetermined
challenge for hospitals that are not free-standing children’s
transfusion packages [see Table 3 (adult MTPs) and Table 4
hospitals to have both adult and paediatric MTPs. In the major-
(paediatric MTPs), for examples), or integration of both.42 Al-
ity of institutions, a single MTP is used for both adult and paedi-
though the number and timing of blood component delivery,
atric patients.4 Two published studies on paediatric MTPs did
laboratory testing algorithms, and other aspects of the MTPs
not show improvement in mortality in the group receiving
varies between institutions, most current MTPs use pre-
blood products according to the institutional MTP compared
determined transfusion packages.42 MTPs vary in their pre-
with the historical control58 or the group receiving blood pro-
determined transfusion packages, but all include platelet and
ducts at physician discretion (Table 4).59 Despite obtaining
plasma units with RBC units (Table 3).43 – 48 Furthermore,
null results in both studies, probably due to small sample
patients with obstetrical haemorrhage should also be moni-
sizes,58 59 it was suggested that implementation of MTP to in-
tored closely for fibrinogen level, because it has been shown
crease the plasma:RBC ratio is feasible in paediatric patients.58
that women with fibrinogen level .400 mg dl21 did not
develop post-partum haemorrhage. Similarly, data from neur-
ology and cardiac surgery showed that there is increased Considerations for MTP development
bleeding tendency if the fibrinogen level is ,150 –200 mg When developing an MTP, it is important that an institution
dl21.49 50 Moreover, a retrospective review from a US Army hos- establishes policies for emergency release and delivery of
pital demonstrated that increasing the ratio of fibrinogen:RBC blood products. There should also be protocols for administration
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Massive transfusion management BJA
Table 4 Sample paediatric MTPs.4 Modified from Table 2 in Diab et al,4 with permission from British Journal of Haemotology, John Wiley and Sons.
*Difference from protocol in Diab and colleagues4 comparing with protocol from Hendrickson and colleagues.58 Hendrickson and colleagues’58
protocol does not contain emergency release package. RBC, red blood cell; Cryo, cryoprecipitate
of D-positive RBCs to a D-negative or unknown patient, issuing of group O RBCs and AB plasma. However, if type-specific pro-
ABO-incompatible plasma, and administration of antigen- ducts are administered, adequate patient identification steps
positive or untested RBCs to a patient with the corresponding should be in place to ensure ABO mistransfusion does not occur.
red cell alloantibody. It is also important to follow patient identi- The frequency of anti-D formation after transfusion of
fication protocols in order to avoid ABO incompatible transfusion D-positive blood products to a D-negative patient is about
errors. In many trauma situations, there is excessive blood loss, 20% for RBCs and ,4% for platelets (likely lower for apheresis
and transfusion is needed before the ability to perform pre- platelets).61 – 63 It is especially important to prevent anti-D for-
transfusion testing. In these cases, group O RBCs and AB mation in females of childbearing potential because anti-D can
plasma products should be given until the patient’s blood type cause haemolytic disease of the fetus and newborn in future
can be determined. Alternatively, it has been demonstrated pregnancies. Therefore, females of childbearing potential
that using group A plasma products in trauma patients should receive D-negative RBCs. However, institutions may
needing emergency plasma transfusion due to limited supply transfuse D-positive RBCs to a D-negative/D-unknown female
of group AB plasma did not result in an increase in mortality or in- of childbearing potential after a certain number (such as 8
cidence of complications, such as haemolytic reaction.60 It is im- units) of D-negative RBCs have already been transfused given
portant to obtain and test a patient sample as soon as possible the balance of available inventory and the likelihood of survival.
after admission so that type-specific products can be adminis- Each institution should have a policy determining the use of
tered when available. This helps to preserve the inventory of D-positive products in D-negative or D-unknown patients, in-
group O RBCs and AB plasma, and minimizing potential for ABO cluding the use of D-positive products for men and women
typing discrepancies when a patient has received multiple units past childbearing age (usually .50 yr old), and after a set
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BJA Pham and Shaz
number of D-negative RBC units. In addition, Rh immune Prothrombin complex concentrate (PCC) has been used to
globulin (RhIG) might be considered to prevent anti-D alloim- treat congenital coagulation disorders and for warfarin rever-
munization in D-negative patients receiving D-positive blood sal in patients with active bleeding or undergoing urgent proce-
products. The practice of giving RhIG is more common when dures. PCC contains factors II, VII, IX, and X, and proteins C and
D-positive platelets are given to D-negative patients. The risk S, with variations in the amount of factors between different
of haemolysis needs to be weighed against the benefit of products; thus, it is important to know which PCC product is
prevent alloimmunization, especially when RhIG is given to a available at the institution. PCC can be three-factor, such as
patient receiving more than 1 or 2 D-positive RBC units. Profilnine SD (Grifols Biologicals, Los Angeles, CA, USA)
Another important consideration is availability of thawed (lacking factor VII), or four-factor, such as Kcentra (CSL
plasma units for patients requiring MT. It takes about 20 min Behring, King of Prussia, PA, USA). To date, there has not been
to thaw frozen plasma. Expedited plasma transfusion in any prospective randomized controlled trial to evaluate the ef-
patients requiring MT can result in reduced overall transfusion ficacy and safety of PCC in massively bleeding patients. In add-
requirement and mortality.64 Hence, in order to facilitate ition, PCC might be associated with thromboembolic risk as
early transfusion of plasma in the resuscitation process, shown in animal studies.74 75 Hence, it is advisable to discuss
many institutions keep some units of thawed plasma available the risks and benefits of using PCC as an adjunctive therapy
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Massive transfusion management BJA
values upon intensive care unit admission, increased cryopre- detect accurately the coagulopathies in massively bleeding
cipitate or fibrinogen concentrate use is indicated during patients in a timely manner. Conventional coagulation
MTP. A metabolic panel should be used to monitor metabolic assays, such as PT, aPTT, and fibrinogen levels, are likely not
abnormalities during MT, such as hyperkalaemia and hypocal- available in real-time fashion. In addition, these tests do not
caemia. Point-of-care arterial blood gases measurement is detect some haemostatic abnormalities, such as platelet dys-
helpful in monitoring oxygenation. function, hyperfibrinolysis, and factor XIII deficiency. They also
Monitoring haemostasis in patients with MT is challenging do not quantify the relative contribution of pro-coagulant and
because there is no validated coagulation assay that can anti-coagulant factors.91 92 Although these conventional co-
agulation assays do not predict the future need for MTP and
have limited utility to direct ongoing blood component
therapy in real time because of slow turnaround times,93
Coagulation Fibrinolysis
they should be ordered and retrospectively reviewed to help
alpha angle (a) in correcting any abnormalities occurring during the resuscita-
tion and to continuously improve the institutional MTP.
Recently, it has been suggested that point-of-care haemo-
Table 5 TEG/ROTEM parameters, interpretations, and management of haemostatic abnormalities.4 Modified from Table 3 in Diab and colleagues,4
with permission from British Journal of Haemotology, John Wiley and Sons. R, reaction time; CT, clotting time; K, kinetics time; CFT, clot formation
time; a, alpha angle; MA, maximum amplitude; MCF, maximum clot firmness; LY, lysis; ML, maximum lysis
TEG ROTEM Definition Haemostatic phase Aetiologies for abnormalities Potential management
parameter parameter
R CT Time from the start of Initiation of Prolonged R/CT: factor deficiencies Plasma for prolong R/CT
the test till the first sign coagulation or anticoagulants. Shortened R/CT:
of clot formation plasma hypercoagulability
K CFT Time from the start of Amplification of Prolonged K/CFT: factor Cryoprecipitate
clot formation to the coagulation deficiencies, hypofibrinogenaemia,
time when the curve dysfibrinogenaemia,
reaches amplitude of 20 thrombocytopenia, or platelet
mm dysfunction
a a Angle between the Propagation of Low a: factor deficiencies, Cryoprecipitate
baseline and the coagulation (i.e. hypofibrinogenaemia,
tangent to the curve ‘thrombin burst’) dysfibrinogenaemia,
through the starting thrombocytopenia, or platelet
point of coagulation dysfunction
MA MCF Amplitude measured at Propagation of Low MA/MCF: factor XIII deficiency, Platelets might consider
the maximum curve coagulation (i.e. hypofibrinogenaemia, plasma or cryoprecipitate for
width ‘platelet¼fibrin dysfibrinogenaemia, factor XIII deficiency if
interaction’) thrombocytopenia, or platelet ongoing bleeding and
dysfunction persistently low MA/MCF
LY ML Reduction in area under Fibrinolysis Increased LY/ML: hyperfibrinolysis Anti-fibrinolytic medication
the curve (LY) or in
amplitude (ML) from
time MA/MCF is achieved
until 30 or 60 min after
MA/MCF
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BJA Pham and Shaz
combination with clinical assessment for the decision-making the use of TEG/ROTEM to monitor and direct component therapy
process.95 Secondly, these assays can detect hyperfibrinolysis, in patients with MT.
an important component of haemostatic abnormalities in
patients with MT that cannot be detected by PT and aPTT
assays.94 Thirdly, unlike the PT and aPTT that can only test sec- Complications from MT
ondary haemostasis, whole blood assays assess all phases of Besides the risk of transfusion reactions that occur with single
coagulation, such as the contribution of platelets to primary unit transfusions, patients with MT are at risk of other adverse
haemostasis and factor XIII to cross-linking the fibrin clot. events due to large transfusion volumes, such as hypocalcae-
Fourthly, TEG/ROTEM can be performed at the patient’s true mia and acidosis due to citrate and hypothermia due to cold
temperature, which makes it more sensitive for detection of storage (Table 6).4 The patient should be monitored closely
coagulopathy due to hypothermia.96 TEG/ROTEM has been for these complications because they might contribute
shown to reduce the transfusion requirement and need of MT further to coagulopathy. Paediatric patients, patients with pre-
in patients undergoing cardiovascular and liver transplantation existing cardiac, hepatic, and renal disease, or older patients
surgery.97 – 100 Nonetheless, a Cochrane review suggested that are more at risk for having these complications.
there is no evidence that TEG/ROTEM reduced the morbidity and
Table 6 Complications from MT.4 Modified from Table 1 in Diab and colleagues,4 with permission from British Journal of Haemotology, John Wiley
and Sons. *Adverse events more likely, due to rapid infusion of a large amount of blood products in a short period of time
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Massive transfusion management BJA
of red cell storage age and patient outcome. A recent 3 Malone DL, Hess JR, Fingerhut A. Massive transfusion practices
meta-analysis investigating the effect of storage lesions of around the globe and a suggestion for a common massive trans-
RBCs suggested that using older stored RBC units was asso- fusion protocol. J Trauma 2006; 60: S91– 6
ciated with increased mortality.102 However, the majority of 4 Diab YA, Wong EC, Luban NL. Massive transfusion in children and
neonates. Br J Haematol 2013; 161: 15 –26
data in this meta-analysis was from retrospective observation-
5 Seghatchian J, Samama MM. Massive transfusion: an overview of
al studies. A recent large randomized controlled trial done in
the main characteristics and potential risks associated with sub-
premature, very low-birth-weight infants (the ARIPI trial) did stances used for correction of a coagulopathy. Transfus Apher Sci
not find an association between using fresh RBCs and improved 2012; 47: 235–43
mortality.103 Several other trials (such as the RECESS trial) are 6 Deaths and Mortality. Centers for Disease Control and Prevention,
ongoing at the time of writing to investigate the storage 2010. Available from http://www.cdc.gov/nchs/fastats/deaths
effect of RBCs, on clinical outcome of transfusion (see Cohen .htm (accessed 13 August 2013)
and Matot,104 this issue, for further discussion). 7 Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma
deaths: a reassessment. J Trauma 1995; 38: 185– 93
8 Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation:
Conclusions directly addressing the early coagulopathy of trauma. J Trauma
i79
BJA Pham and Shaz
26 Watts DD, Trask A, Soeken K, Perdue P, Dols S, Kaufmann C. Hypo- 45 Dente CJ, Shaz BH, Nicholas JM, et al. Improvements in early mor-
thermic coagulopathy in trauma: effect of varying levels of hypo- tality and coagulopathy are sustained better in patients with blunt
thermia on enzyme speed, platelet function, and fibrinolytic trauma after institution of a massive transfusion protocol in a civil-
activity. J Trauma 1998; 44: 846– 54 ian level I trauma center. J Trauma 2009; 66: 1616– 24
27 Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differen- 46 Nunez TC, Young PP, Holcomb JB, Cotton BA. Creation, implemen-
tial effects on fibrinogen synthesis and breakdown in pigs. Ann tation, and maturation of a massive transfusion protocol for the
Surg 2007; 246: 831– 5 exsanguinating trauma patient. J Trauma 2010; 68: 1498–505
28 Stanworth SJ, Morris TP, Gaarder C, et al. Reappraising the concept 47 O’Keeffe T, Refaai M, Tchorz K, Forestner JE, Sarode R. A massive
of massive transfusion in trauma. Crit Care 2010; 14: R239 transfusion protocol to decrease blood component use and
29 Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM, Young PP. costs. Arch Surg 2008; 143: 686– 90; discussion 90–1
Predefined massive transfusion protocols are associated with a re- 48 Riskin DJ, Tsai TC, Riskin L, et al. Massive transfusion protocols: the
duction in organ failure and postinjury complications. J Trauma role of aggressive resuscitation versus product ratio in mortality
2009; 66: 41– 8; discussion 8–9 reduction. J Am Coll Surg 2009; 209: 198– 205
30 Cancio LC, Wade CE, West SA, Holcomb JB. Prediction of mortality 49 Gerlach R, Tolle F, Raabe A, Zimmermann M, Siegemund A,
and of the need for massive transfusion in casualties arriving at Seifert V. Increased risk for postoperative hemorrhage after intra-
combat support hospitals in Iraq. J Trauma 2008; 64: S51– 5; dis- cranial surgery in patients with decreased factor XIII activity:
i80
Massive transfusion management BJA
64 Radwan ZA, Bai Y, Matijevic N, et al. An emergency department (ROTEM)-guided administration of fibrinogen concentrate and pro-
thawed plasma protocol for severely injured patients. JAMA Surg thrombin complex concentrate. Crit Care 2010; 14: R55
2013; 148: 170– 5 81 Innerhofer P, Westermann I, Tauber H, et al. The exclusive use of
65 Mehr CR, Gupta R, von Recklinghausen FM, Szczepiorkowski ZM, coagulation factor concentrates enables reversal of coagulopathy
Dunbar NM. Balancing risk and benefit: maintenance of a and decreases transfusion rates in patients with major blunt
thawed group A plasma inventory for trauma patients requiring trauma. Injury 2013; 44: 209–16
massive transfusion. J Trauma Acute Care Surg 2013; 74: 1425– 31 82 Tanaka KA, Esper S, Bolliger D. Perioperative factor concentrate
66 Goodnough LT, Spain DA, Maggio P. Logistics of transfusion support therapy. Br J Anaesth 2013; 111(Suppl. 1): i35–i49
for patients with massive hemorrhage. Curr Opin Anaesthesiol 83 Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on
2013; 26: 208– 14 death, vascular occlusive events, and blood transfusion in trauma
67 Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as ad- patients with significant haemorrhage (CRASH-2): a randomised,
junctive therapy for bleeding control in severely injured trauma placebo-controlled trial. Lancet 2010; 376: 23 –32
patients: two parallel randomized, placebo-controlled, double- 84 Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Ap-
blind clinical trials. J Trauma 2005; 59: 8 –15; discussion 15– 8 plication of Tranexamic Acid in Trauma Emergency Resuscitation
68 Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: (MATTERs) study. Arch Surg 2012; 147: 113–9
efficacy and safety of recombinant activated factor VII in the 85 Roberts I, Shakur H, Afolabi A, et al. The importance of early treat-
i81
BJA Pham and Shaz
100 Coakley M, Reddy K, Mackie I, Mallett S. Transfusion triggers in 102 Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of
orthotopic liver transplantation: a comparison of the thrombo- older stored blood and risk of death: a meta-analysis. Transfusion
elastometry analyzer, the thromboelastogram, and convention- 2012; 52: 1184– 95
al coagulation tests. J Cardiothorac Vasc Anesth 2006; 20: 103 Fergusson DA, Hebert P, Hogan DL, et al. Effect of fresh red blood
548 – 53 cell transfusions on clinical outcomes in premature, very
101 Afshari A, Wikkelso A, Brok J, Moller AM, Wetterslev J. Thrombelas- low-birth-weight infants: the ARIPI randomized trial. J Am Med
tography (TEG) or thromboelastometry (ROTEM) to monitor hae- Assoc 2012; 308: 1443– 51
motherapy versus usual care in patients with massive transfusion. 104 Cohen B, Matot I. Aged erythrocytes—a fine wine or sour grapes?
Cochrane Database Syst Rev 2011; CD007871. Br J Anaesth 2013; 111(Suppl. 1): i62–i70
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