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Massive Transfusion

This module written by Tuan Le, MD, 9/2011


Definition

Before we get into the details of how we manage patients who are undergoing a massive transfusion, it is important that we first step back and make sure that we are all on the same page with the definition of this process.

There are several different settings in which massive transfusions occur most often, including trauma most prominently, but also in cardiovascular surgery (particularly in "re-do" cardiac bypass procedures as well as combination valve replacement/CABG procedures), spinal surgery, hepatic surgery (including transplants), and gastrointestinal hemorrhage, to name a few. Obstetric emergencies also can present with large-scale bleeding that may trigger a massive transfusion. The determination of whether a patient transfused lots of blood qualifies as a "massive transfusion" can be based either on the transfusion of a certain number of RBC units within a particular time period or on the replacement of a portion of a patient's total blood volume.

The following summarizes the standard definitions of the term "massive transfusion."

Massive transfusion definitions

Complications and History

The concept of hemodilution from crystalloid fluid resuscitations and its impact on coagulation began to take hold when surgeons at Denver General Hospital first described the "bloody vicious cycle" in 1982 (Kashuk J, Moore EE, Milikan JS, Moore JB. Major abdominal vascular trauma-a unified approach. J Trauma 1982;22:672-679). The cycle, also known as the "lethal triad," is an apt description of persistent bleeding in vascular trauma patients with hypothermia, acidosis, and coagulopathy. Let's take a look at these issues one-by-one.

Hypothermia
Obviously, when a trauma patient receives an abundance of blood products stored at colder than body temperature, a resultant decrease in core body temperature is not only possible but likely. Hypothermia affects coagulation primarily by depressing platelet function, and the presence of hypothermia correlates with poor outcome in massively transfused trauma patients. As a result, most trauma facilities use FDA-approved blood warmers (which must have appropriate temperature limits and warning systems) as part of their routine practice in transfusing these patients. Hypothermia may occur prior to the patient's arrival at the treating facility, however, and may have already contributed to the vicious cycle mentioned above.

Acidosis
Acidosis in massively transfused patients can occur for one of several reasons. First, when patients lose large quantities of blood, the lack of adequate tissue perfusion can lead to metabolic acidosis through the generation of lactic acid fairly quickly. Significant acidosis upon arrival of a trauma patient to the treating facility correlates with poor survival, so restoring tissue perfusion is one of the main goals of trauma transfusion. In addition, the pH in units of red blood cells declines throughout the course of their storage, and transfusion of "older" units may contribute to the patient's acidosis. Finally, virtually all blood components used in a massive transfusion are anticoagulated with citrate (an acid), which may also add to the downward pressure on the patient's pH.

Coagulopathy
The coagulopathy of trauma is complex and not yet completely understood. What is clear so far is that many patients with trauma actually present with a coagulopathy, which may be due to massive tissue injury and subsequent release of cytokines and other procoagulant factors, as well as widespread activation of endothelial cells. Of course, patients given large quantities of crystalloid for resuscitation, as well as in those given large quantities of red blood cell transfusions (which lack significant quantities of associated coagulation factors or platelets) will suffer from dilutional coagulopathy (this is the main cause of coagulopathy in massively transfused non-trauma patients, such as those having major hemorrhage following an elective procedure, complicated labor and delivery, or gastrointestinal hemorrhage). As with the other members of the vicious cycle, the presence of significant coagulopathy correlates with poor survival in a trauma patient. In addition, the presence of acidosis and hypothermia also contribute to the coagulopathy. We will discuss the various models that attempt to correct and prevent this coagulopathy in the next section and the rest of this module.

Additional Complications
Citrate toxicity can manifest in several ways, including the direct contribution to metabolic acidosis mentioned above. In addition, however, through citrate's avid binding to calcium, marked hypocalcemia may occur in massively transfused patients. This hypocalcemia may have negative effects on cardiac and neural function, and may lead to hyperventilation as well. Indeed, to address hypocalcemia and the need for intravenous calcium replacement, most massive transfusion protocols include the use of ionized calcium levels along with traditional coagulation tests to ensure optimal clotting factor replacement. Potassium abnormalities, either hyperkalemia or hypokalemia, can also cause significant problems in massively transfused patients. Stored red cells leak potassium into the supernatant fluid in increasing quantities as the cells age, and when most blood bankers think of potassium abnormalities in massive transfusion, we worry most about resulting hyperkalemia when older blood is transfused. However, this is not often an issue, as the actual amount of residual plasma is so small in modern red cell preparations. Hypokalemia, on the other hand, secondary to the potassium-starved transfused red cells soaking up the body's free potassium, may be a bigger issue. Finally, air embolism can occur with the inadvertent introduction of air into the infusion set or through intraoperative salvage techniques. While uncommon, such a complication may be fatal.

The evolution in the management of massive transfusion in the U.S. can be traced to lessons learned from the various military involvements in its history.

Military conflicts and transfusion lessons

Recent transfusion practices from U.S. military action in Iraq and Afghanistan and the impetus to translate military trauma management into the civilian setting culminated in the call for a common massive transfusion protocol by Debra Malone and colleagues in 2006 (Malone DL, Hess JR, and Fingerhut A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. Trauma 2006;60:S91-S96).

Models

MTP can be generally pigeonholed into two working models: The laboratory-driven (pull) vs. formula-driven (push) model. Both models aim at stopping the "bloody vicious cycle," and both are summarized below and in the figure below.

Laboratory-driven (pull) MTP:
This model depends on laboratory parameters and transfusion triggers to guide transfusion management during a massive bleeding event.

Formula-driven (push) MTP:
This model uses a prearranged delivery system of blood products or "trauma packages" in various mixture of red cells, plasma, platelets, and cryoprecipitate to stabilize a hemorrhagic patient prior to or in the absence of laboratory data.

The two main MTP models

A sample Blood Delivery protocol

Certainly, both models have their supporters as well as their critics. Let's look at a few of both the positive and negative thoughts on each model:

Lab-driven (pull) MTP +/-:
This is the traditional model, obviously. In this model, the surgeons, hopefully in concert with the transfusion service or other wise consultants, uses laboratory values to aid in the selection of various appropriate blood products based on laboratory results. This model could be considered more reactive, and sometimes more consultative. However, this approach is countered by the poor turnaround times of the traditional coagulation panels (e.g. PT,PTT, fibrinogen, platelet count) combined with potential delays in thawing FFP or PF24 based on waiting to exceed lab-based transfusion triggers.

Formula-driven (push) MTP +/-:
In this approach, the patient gets an appropriate mix of blood products without anyone having to think too much about it. Theoretically, this results in the patient receiving a physiologically appropriate mix of blood products. However, the advantages of using a high plasma and/or platelet to red cell transfusion ratio and minimizing delays with a set delivery schedule of blood products is offset by the lack of randomized controlled trials in support of these protocols, as well as the potential issue of plasma overuse.

The currently available studies are mainly retrospective in nature. The National Heart, Lung, and Blood Institute State of the Science Symposium in Transfusion Medicine has identified the "PROPPR study" (Prospective Randomized Optimum Plasma to PLT Ratios) as crucial to determine the survival advantage, if any, in the use of high plasma/platelet to red cell transfusion ratios (Transfusion 2011;51:828-841). The PROPPR study aims to screen over 3000 patients who receive at least 1 RBC unit in the ED, enroll approximately 580 massive transfusion patients, and involve at least 12 study sites over a 3.5 year period.

Hot Topic Studies

The following studies serve to highlight the current issues and debates that the PROPPR trial will attempt to resolve:

Zink KA et al. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Amer J Surg 2009;197:565-570.

  • Retrospective review of the transfusion ratios in the first 6 hours with correlated survival outcome in 466 massive transfusion trauma patients at 16 level 1 trauma centers.
  • Improved 6-hour survival was noted in the groups receiving high plasma to red cells and high platelets to red cell transfusion ratios (e.g. for plasma:RBC ratio= 2% mortality seen with transfusion ratio of >1:1 vs. 37.3% mortality in transfusion ratio of <1:4).
  • Criticisms of this study include:
    • The study is retrospective
    • The 16 level 1 trauma centers used different MTP hence significant there was inter-center variability with issues of heterogeneous patient demographics and transfusion practices
    • While patients who received the higher plasma and platelet transfusion ratios had increased survival at 6 and 24 hours, the patients who received the lower transfusion ratios had similar survival rates to those with the higher transfusion ratios when one evaluates the 30 day mortality data.
    • Evaluating the data with the view that platelets also contain plasma, the patient group receiving the 1:2 plasma to RBC transfusion ratio had the worst outcome.

Kashuk JL, Moore EE, Johnson JL et al. Postinjury life threatening coagulopathy: Is 1:1 fresh frozen plasma:packed red cells the answer? J Trauma 2008;65:261-271.

  • Retrospective review of the transfusion ratios in the first 6 hours correlated with survival outcome in 133 patients at a single level 1 trauma center between 2001-2006.
  • Although data suggests the 1:1 plasma to RBC transfusion ratio reduced coagulopathy, a U-shaped survival curve was noted with the lowest mortality probability correlated with the transfusion ratios in the range of 1:2 to 1:3 even when penetrating trauma was excluded.
  • Criticisms of this study include:
    • Retrospective
    • Single institution experience by one group of trauma surgeons
    • No consistent MTP over the 5 year review
    • Chart review contained incomplete data collection
    • Study focused on acute bleeding and coagulopathy and did not include deaths from multiorgan failure, a known late complication of massive transfusions.

Since the call for a common MTP by Debra Malone and colleagues in 2006 (Trauma 2006;60:S91-S96), most trauma centers have implemented an MTP even though the protocols are variable and only about 50% of those surveyed used a plasma:RBC transfusion ratio of 1:1 (Transfusion 2010;50:1545-1551). More recently, a retrospective study of 438 massively transfused adult patients found a correlation between survival and the correction of plasma deficit within the first two hours of resuscitation. The study highlights the efficacy of plasma replacement instead of the plasma transfusion ratio as the potential key step in the disruption of trauma-induced coagulopathy (de Biasi A et al. Blood product use in trauma resuscitation: Plasma deficit versus plasma ratio as predictors of mortality in trauma. Transfusion 2011;51:1925-1932).

Because of a lack of best practice guidelines related to the optimal transfusion resuscitation of trauma patients (which the PROPPR trial will be attempting to answer), variation in transfusion ratios are being implemented along with the controversial, off-label use of recombinant factor VIIa in the MTP. In contrast to the rFVIIa controversy, the CRASH-2 study showed that antifibrinolytic therapy may play an important and cost-effective role in reducing the risk of death in bleeding trauma patients. The CRASH-2 study was a randomized, placebo-controlled trial that evaluated the use of tranexamic acid in 10,096 adult trauma patients from 274 hospitals in 40 countries (Lancet 2010:376:23-32). Besides showing a survival advantage with the use of tranexamic acid in bleeding traumas, the study also revealed an incremental cost per life year saved ranging between $48 (Tanzania) and $66 (India) depending on the cost of the drug in different countries. While the limited survival impact of an MTP implementation can be sobering (Arch Surg 2008;143:686-691), the potential or temptation to apply a high plasma: RBC transfusion ratio outside the setting of massive transfusion can result in an increase in ARDS, MOF, pneumonia, and sepsis as highlighted by a recent retrospective study of 1,716 patients (J Am Coll Surg 2010;210:957-965).

Measuring Coagulation

Enhancing or improving the turnaround times (TAT) of laboratory assessment of coagulation might be one of the deciding factors in resolving the debates between a laboratory-driven ("pull") vs. formula-driven ("push") model of MTP. A small but interesting study comparing the prothrombin time assay with a point of care (POC) instrument versus a central laboratory device revealed a TAT of 5 minutes for the POC test while the central lab had a median of 88 minutes! Perhaps more disturbingly, the range of TAT for the PT from the central lab was 29 minutes to 235 minutes (Toulon P et al. Point-of-care versus central laboratory coagulation testing during haemorrhagic surgery-a multicenter study. Thrombosis Haemo 2009;101:217-241). Obviously, such long TAT make the lab-driven model impractical at best and dangerous at worst, since the patient's current status may be dramatically different from that reflected in a lab value drawn over an hour previously! Reducing the TAT of coagulation tests has provided the impetus of assessing other assays in the transfusion management of massively bleeding patients. Some of these assays include:

Thromboelastography or TEG (see description):
TEG parameters have been previously used to guide transfusions during heart surgery or liver transplants. This whole blood cell-based clotting assay can provide a snapshot of not only the formation of a blood clot but also the breakdown of that clot from fibrinolysis. Although coagulopathy assessment based on TEG parameters has been incorporated in the practice guidelines by the American Society of Anesthesiologists (Anesthesiology 2006;105:198-208), the implementation of TEG beyond the OR and into the ED or other areas of the hospital potentially involved in the management of massive transfusions (e.g. Labor and Delivery, ICU, interventional radiology) is a more complex question. Such areas would have to consider numerous issues such as the strict sample handling and specimen requirements required for this test, along with an analysis of who will perform the interpretation of TEG results.

Rotational Thromboelastometry or ROTEM:
This viscoelastic whole blood clotting assay has been used in Europe and recently received US FDA approval (8/16/11). The ROTEM hemostasis parameters have been reportedly used in the management of bleeding patients (Ogawa S et al. Transfusion 2011 Epub 7-14-11). Because of similarities in the assessment of clot formation and breakdown between the ROTEM and TEG assays, a working group from Europe, the U.S., and Israel has been formed to standardize methodologies, parameters and diagnostic nomenclatures (Chitlur M et al. Standardization of thromboelastography: a report from the TEG-ROTEM working group. Haemophilia 2011;17:532-537).

New Research and Products

The perceived need for earlier plasma intervention in the correction of the "bloody vicious cycle" or trauma-induced coagulopathy and the resultant demand from a transfusion service/blood bank inventory have prompted the evaluation of the use of both traditional and unconventional blood components. The development of MTP has facilitated new areas of research including:

Whole blood transfusion:
The U.S. Armed Services Blood Program has used a "walking blood bank" program to provide fresh whole blood as part of its MTP and in situations where specific blood components are not available. The "walking blood bank" donors consist of the in-hospital personnel, a collection of "walking wounded" but otherwise healthy soldiers, and U.S. government support personnel within or near a combat service hospital area. Using this program, the first unit of fresh whole blood is reportedly available within an hour of a surgeon's request. The experience of the use of fresh whole blood within an MTP at the 31st Combat Service Hospital in Baghdad was reported by Thomas Repine and colleagues (Repine TB et al. The use of fresh whole blood in massive transfusion. J Trauma 2006;60:S59-269). The role of fresh whole blood and its application in the civilian U.S. setting has been discussed (Brinsfield K. Reserve donor strategies). In addition, the role of stored whole blood as a part of a trauma resuscitation strategy is organized as a phase IV clinical trial.

Freeze-dried plasma:
Breakage of frozen plasma units and the logistic burden of product wastage have prompted the evaluation of the provision of plasma products in the battlefield. (see Lelkens CCM et al. Transfusion and Apheresis Science 2006;34:289-298). The options to transport plasma products efficiently and have coagulation factors available at the frontline for massive transfusion support are a few appeals of lyophilized or freeze-dried plasma. The French army has used freeze-dried plasma since 1994 (see Daban JL et al. Freeze-dried plasma-a French army specialty Critical Care 2010;14:412) and Octapharma has provided freeze-dried solvent/detergent-treated plasma in its collaboration with the German Red Cross (LyoPlas). The U.S. Army Research Materiel Command is developing freeze dried plasma in collaboration with HemCon Medical Technologies.

Stem-cell derived red blood cells:
Although not being developed specifically for MTP, the potential production of O-negative RBC from a stem cell source might address the inventory demand of having a universal RBC type within a trauma blood product package. In the U.S., Cleveland-based Arteriocyte was awarded funding from the Defense Advanced Research Projects Agency (DARPA) in 2008 to produce O-negative RBC units from the ex vivo expansion of stem cells. The high cost of "pharming" RBC from stem cells (estimated to be ~ $5,000/unit) along with the need for clinical trials are barriers to the availability of these types of blood products.