Is there one standardized transfusion approach for patients who experience massive bleeding?

Patients in hospitalized settings that experience large amounts of bleeding may warrant use of a Massive Transfusion Protocol (MTP). The traditional massive transfusion (MT) definition is when patients have received > 10 units of red blood cells (RBCs) in a 24-hour period, essentially replacing the patient’s entire blood volume with donor blood. One recent trauma center study validated a definition that assists in capturing patients earlier in the process, that is, those receiving three or more RBCs in six hours.¹ Another recent trauma center study takes the definition even further by identifying a “super” MTP as those patients who’ve received > 30 RBCs in 24 hours.² Perhaps the most widely known, and one of very few prospective studies of trauma patients receiving MTPs, was the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. The PROMMTT study helped further define MT in patients that receive > four units of RBCs per hour.³ Both trauma and non-trauma (including obstetrics) patients who bleed may require use of an MTP as part of their course of treatment.

Most MTP research has been conducted or performed in trauma centers.^4-7 Trauma center research is largely based on military setting experiences, particularly in the Iraq and Afghanistan wars in the 2000s.⁸ Mass amounts of blood products could be needed at any given time at war and in a trauma center, for any patient, and sometimes for several patients at once. Bleeding to death is one of the leading causes of death of trauma patients, the majority of which occur within the first six hours of injury.³ Several studies show that the ideal ratios of red cells to plasma to whole blood derived platelets contained included in an MTP is 1:1:1. In addition, the introduction of plasma products earlier in trauma settings than in the past has been shown to be important in decreasing mortality.⁹ Other studies argue that there is simply not an exact formula of blood products that can be established in an MTP. For example, although a hot topic in recent years, a sixty-year retrospective study disputed that there are not enough random controlled trials to support either high or low plasma to red cell ratios in an MTP.⁴ In addition, one recent study noted that because of a trauma patient pathophysiology, there is a range of plasma to red cell ratio where hemostasis is not possible because of the diluted effect caused by anticoagulants that are contained in blood products.¹⁰ Further, inherent risks of multiple transfusions, like the potential increased transfusion-related acute lung injury (TRALI) incidence, hypocalcemia, hypothermia, and other co-morbidities do exist.¹¹ A recent study from 2019 indicated that women may require less blood products than men in an MTP because of a possible survival advantage due to hypercoagulability.¹² Therefore, research is not clear whether a single ratio-based MTP approach is possible in trauma patient resuscitation.

In addition to trauma, non-trauma patients, including a subset of obstetrical patients, are important groups to consider. In a two-year retrospective analysis of relatively equal amounts of trauma and non-trauma patients using MTP, it was noted that overall blood utilization is not impacted significantly.¹³ In the non-trauma group of patients, MTs are more likely to occur among solid-organ transplant and cardiac surgical patients.⁸

Discussion

Several factors are involved in the development and execution of MTPs that can potentially impact patient outcomes. Some of these factors include: Prediction of which patients may excessively bleed, distance from hospital to the blood supplier, distance from patient location to the blood bank, blood product inventory levels, time from activation to product availability, hemostatic agent use, human and other resources, and training and competency skill sets of staff involved in the process. Although each of these factors are important, there is little research currently available to assist hospitals and transfusion services on implementation and maintenance of an effective MTP.

Who uses an MTP?

In order to discuss and validate if a standard approach to MTPs exists, it’s relevant to have a sense of just how many hospitals already have established MTPs in place. The University of Chicago, Pathology Department, conducted a survey of 107 academic institutions in the U.S. where 56 survey responses were received. The results of this survey were interesting, and somewhat reassuring. One hundred percent of respondents had an MTP in place, 98.2 percent base their MTP on product ratios rather than laboratory result guided therapy, and 69.9 percent use a 1:1 (RBC): plasma ratio.⁹

Other non-blood product factors

Besides blood products themselves, other factors like use of hemostatic agents, and the availability of point-of-care testing (POCT) may contribute to overall MTP effectiveness.

McDaniel discusses the use of hemostatic agents in MTPs, as well as the inherent waste and inefficiency that happens as more institutions expand trauma-center based protocols to non-trauma hospital settings.¹⁶ Most institutions regularly activate MTPs for trauma and non-trauma indications, however, few use validated scoring systems for MTP activation.¹⁷ Although traditional protime (PT) and partial thromboplastin time (PTT) laboratory tests can help guide resuscitation therapy, trauma institutions in particular have used thromboelastography (TEG) as a point-of-care mechanism in or nearby the operating room, as a rapid alternative.

Some trauma institutions have incorporated tranexamic acid, an inexpensive, antifibrinolytic pharmaceutical agent, within three hours of injury into their protocol due to its reduction in mortality in massive hemorrhage.¹⁶ The lack of consistent practices underscores the need for outcome-based studies to guide transfusion practices, which are lacking in current literature.

Who will bleed?

In the U.S., there is no established scoring system to predict whether patients may massively bleed in the first place. One trauma-center evaluated MTP activations for one year after implementing their MTP program. Their goal was to determine if patients were missed in that an MTP should have been activated, but for whatever reason, was not. The four criteria where patients were included for an MTP activation, whether activated or not, were:

1) Patient required uncrossmatched blood transfusions;

2) patient required tranexamic acid;

3) transfusion of four or more RBCs in one hour; and

4) transfusion of ten or more RBCs in 24 hours.

Patients who met these four criteria were included in the study, which showed that there were more deaths in the non-MTP group than in the MTP group.²²

Transfusion medicine role

In order to provide the blood products for immediate patient care, the transfusion service, or hospital laboratory blood bank, plays a key role in the execution of an MTP. The blood bank is comprised of hospital staff members who prepare and dispense blood products to all patients who require transfusion therapy as prescribed by their physician, including the subset of patients involved in an MTP.

To have an efficient MTP, a consistent process must be followed, by all staff, 24 hours a day, 365 days per year. Hospital blood banks must maximize patient outcomes by helping to establish MTPs based on evidence-based research, however limited it may be.¹³

Three areas of blood-bank related areas will be reviewed in this discussion:

1) Timing;

2) amount of products dispensed; and

3) the use of liquid plasma.

1. Timing

Timing is everything for patients who are exanguinating. Just how fast can an MTP be prepared? One article in the literature review discussed timing of the initial cooler of blood products provided in a trauma-center and offered a target level of ten minutes.¹⁸ This time frame may seem reasonable to accomplish in most hospitals. There are several key factors that may impact being able to get blood to the patient’s bedside this quickly, however. For example, the location proximity of the blood bank to the patient’s location at time of MTP could be a five-minute walk, not to mention the time it takes for the blood issue (dispense) process, and any required checks prior to handing off the products. In addition, many hospitals have just enough blood product for a limited amount of time (a few days or one week), and therefore an MTP could quickly deplete all stock of a particular patient’s blood type). Further, the resources available in the patient’s location, in the lab, or both, may not be sufficient to be able to allow for a ten-minute or less turnaround time (TAT).  

Some of the questions to consider when developing or fine-tuning the MTP with respect to blood-bank operations are: Does initiation of an MTP require an electronic order or is the request placed by phone call? What is required (paperwork, etc.) to pick up the blood? If there is no sample in the blood bank, is there a separate process to be followed if uncrossmatched (Emergency Release) RBCs vs type specific (compatible) RBCs are dispensed? What is required for the dispense step? What is required for the delivery process to the patient location? Does the person assigned to pick up (or deliver) the blood products know the exact location of the patient (or blood bank)?

2. Product amount

The amount of blood products contained in an MTP, regardless if the patient is trauma or non-trauma, is essentially the same.¹³ This information is helpful so that the hospital transfusion service can ensure that all staff are trained and knowledgeable on a single process with regard to the number of products prepared and dispensed for an MTP. A standardized approach used by all blood bank staff can streamline operations and help to maximize patient outcomes.

3. Liquid plasma use

The use of liquid plasma can help the transfusion service streamline the MTP process for quicker patient care. Liquid plasma is plasma that is never frozen and expires 26 days after collection from a volunteer blood donor. Gaining popularity in the U.S. in recent years, liquid plasma has been proven beneficial in order to more rapidly meet the quick TAT, at least in the initial round of MTP products.² This is because the product requires no manipulation (thawing) prior to transfusion, and is therefore readily available, as opposed to most plasma in the frozen state, which must be thawed prior to transfusion.

In addition, liquid plasma availability has helped transfusion services minimize plasma outdating. Blood centers may typically supply group AB (universal plasma type) or group A liquid plasma, which has been proven to be safely transfused to any adult patient in an emergency, contrary to what many blood bankers may have learned during their studies. Allen, et al. noted that use of liquid plasma seems to improve ratios toward earlier use of plasma in an MTP.² As with many articles found in this review of the current literature, more studies are needed in relation to patient outcomes to determine effectiveness of liquid plasma.

Trauma patients

Most MTP research has been primarily focused on trauma center patients studied retrospectively. The PROMMTT study was the first of its kind in that it was a prospective study which led to a new definition of MT with early identification of patients who may have been missed using the traditional definition. This study showed that mortality is significantly greater in those patients receiving > four units of RBCs per hour. The authors concluded that a new MTP definition be instituted. This new definition would predict MT patients earlier, rather than the traditional one, as defined as receiving 10 units of RBCs in 24 hours. The traditional definition, the authors note, introduces survival bias because it excluded patients who died prior to receiving 10 units. In addition, the traditional definition included patients who, while not exsanguinating, did require transfusions in a 24-hour period.²³ Trauma patients are in a unique state because a good amount, 25 percent in fact, are in a coagulopathic state at the time of presentation, which is believed to be related to direct tissue trauma.¹⁶ Combining coagulopathy with the impacts of hypothermia and acidosis causes a “lethal triad” scenario in these patients.

Non-trauma patients

Non-trauma patients have unique considerations when it comes to survival and may be the largest group of patients in consideration of MTP support. Surgical patients, often times those having solid-organ transplants or heart surgery, will need transfusion support. In addition, obstetrical patients may need support due to excessive bleeding during or after labor and delivery. It goes without saying that these patients may also need an MTP activation. A retrospective analysis of non-trauma patients experiencing hemorrhagic shock over a four-year period noted that over half of patients survived; this is believed to be related to the younger age of survivors, and also that they were less acutely ill.¹ An eight-year study in the U.S. showed that increased FFP:RBC ratios were associated with better survival in these patient groups.¹⁹

Obstetrics patients

Obstetrics patients have their own challenges. The mortality rate of mothers who die after childbirth has risen 50 percent in the U.S., compared with the previous generation.²⁵ Maternal mortality rates have doubled in the U.S. over the last 25 years. Therefore, an increased effort has been made in recent years by groups to help improve health of mothers before, during, and after childbirth. Part of this effort is to reduce the amount of unnecessary cesarean section procedures, which are known to increase both maternal morbidity and mortality, including hemorrhage and death. As recent as 2014, only 80 percent of U.S. academic obstetric anesthesia units had an established protocol in place for postpartum hemorrhage.¹²

Lab result vs. ratio based MTP

Historically, MTPs were largely lab results guided. This meant that clinicians would decide to activate an MTP after receiving the patient’s lab results—a process which could take several hours. Waiting for lab results can cause delays in patient care, and so in recent years, many facilities have moved toward a ratio based MTP. When changing from a lab-results-guided to a ratio based MTP, one trauma-center noticed no change in frequency, nature, or duration of coagulopathy.⁶ Nascimento, et al. noted that when comparing arms of a fixed-ratio vs lab-result- guided MTP in severe trauma patients, 28-day mortality and number of respiratory distress free days were statistically similar, however plasma wastage was higher in the ratio group.¹⁴

The practice of using ratio-based, roughly equal amounts of red blood cells, plasma, and whole blood derived platelets (1:1:1 ratios), and possibly increasing plasma amounts in an MTP, is not without controversy. An obstetrician colleague of mine once put it very simply, “If we bleed out whole blood, then whole blood should be returned.”

Critics of the 1:1:1 ratio argue that: (1) 1:1:1 may lead to abuse of FFP and platelets; (2) increased transfusion-related acute lung and organ injuries may ensue; (3) observational studies contain survivor bias; (4) there has been no randomized controlled trial (RCT) validation; and (5) its use might not precisely address the different hemostatic defects encountered in trauma-induced coagulopathy.11 In addition, the AABB points out that in a trauma setting, there is no statistical difference in the ratios of plasma and platelets to red cells used (1:1 or 1:2) , but also that research is lacking on whether use of these protocols actually improves patient outcomes.¹⁵ Further research is needed to continuously study and/or validate previous studies to substantiate specific ratios that are now widely used, and in edition, the early use of plasma or platelets.

Evaluation of effectiveness

Since no standardized process exists across the U.S., once established, the effectiveness of MTPs can be evaluated by each facility to determine if patient outcomes are benefited or if any modifications are needed. This particular aspect of MTP use is lacking in current literature. Broxton, et al. compared data for one year after a MTP was implemented at one Level 1 trauma hospital. Findings concluded there were more deaths in the non-MTP group then the MTP group. Results concluded that only 16 percent of patients who experienced massive bleeding were managed using the MTP. This article clearly helps to reinforce the need for institutions to evaluate their respective MTPs to check if they are being utilized appropriately.²⁰

Decision support

This review also helped bring to light decision support mechanisms that can aid in fine-tuning MTPs to help meet performance improvement measures and minimize protocol failures. Enticott, et al. noted that four human factors were identified in MTP requirements: environment, human, machine, and task. Although this article focused on trauma patients, the strategies could be theoretically incorporated into any hospital’s MTP program with regularity, including guidance, evaluation, drills, and feedback.²¹

Conclusion

An MTP requires an all-hands-on-deck approach in the hospital blood bank as well as in the patient care areas. In interdepartmental approach is necessary to provide timely product delivery and immediate care for the patient to ensure the best chance at positive patient outcomes. Since all patients are unique, the science is not fully understood, and all hospitals do not have the same resources, diagnostic tools and equipment. Current research shows that it may not be feasible to have a fully standardized MTP throughout the U.S.²⁴ In addition, little research has been performed to predict which patients may bleed, or measure patient outcomes after receiving a MTP. Although MTPs can be partially standardized in the blood bank with regard to the kinds and amounts of blood products used, it is clear that more research is needed to determine if a fully standardized transfusion approach for MTPs is feasible in this country, given that there are many uncontrollable, yet important, variables to consider.

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