By Cody Benthin, MD

Staff Physician, Pulmonary and Critical Care Medicine, Northwest Permanente, Portland, OR

Dr. Benthin reports no financial relationships relevant to this field of study.

Massive hemorrhage with hemodynamic instability or shock may arise from multiple causes and is a medical emergency requiring intensive care. Hemorrhagic shock typically develops with the loss of 30-40% of blood volume. Thankfully, its incidence is likely low, estimated to be 2.5-4.5 per 10,000 person-years.1 Treatment is focused on resuscitative efforts to restore blood volume and stop bleeding. Time is required to locate and secure the sources of blood loss. It is in this setting that resuscitation to maintain oxygen concentration, cardiac output, and circulating blood volume is necessary for survival. Massive transfusion protocols (MTPs) have been developed to provide rapid access to and administration of blood products in these situations.

Massive transfusion is defined as receiving at least 10 units of packed red blood cells within 24 hours. Given the acuity and need for rapid identification, alternative definitions with a shorter time interval, such as three or even four units of packed red blood cells over one hour, may be more meaningful.2 Patients requiring massive transfusions may have baseline coagulopathy due to comorbidities. In addition, these patients may develop secondary coagulopathy due to the activation and consumption of clotting factors from direct tissue trauma (acute traumatic coagulopathy). Further, patients may exhibit reduced factor activity resulting from hypoxia, acidosis, or hypothermia or as a result of the dilutional effects of resuscitative efforts.

In trauma patients, it is estimated that 25% of severely injured patients are coagulopathic from hyperfibrinolysis and endothelial activation resulting from direct tissue damage, hypoperfusion, and inflammation.3

TRAUMA

Most available data regarding critical bleeding and massive transfusion are focused within the trauma literature. Up to 40% of trauma deaths occurring during hospital admission are from massive hemorrhage.4 In the early 2000s, the term “damage control resuscitation” was established to encompass the principles of rapid hemorrhage control with early administration of balanced blood components, prevention of coagulopathy, immediate correction of coagulopathy, and the minimization of crystalloid fluids. It became the standard of care for battlefield resuscitation.

Over the past decade, several retrospective, observational studies in both military and civilian trauma populations have demonstrated increased survival when the amount of plasma and platelets transfused increased comparatively to packed red blood cells.5-9 Changes in these ratios also have shown a reduction in multiorgan failure and postinjury complications, such as pneumonia and abdominal compartment syndrome.10 During this same period, the rate of trauma patients requiring massive transfusion also decreased by 40%.11

In 2015, Holcomb et al published a large multicenter, randomized trial in which they reported that among a civilian trauma population with severe trauma and major bleeding, there was not a significant difference in primary endpoints of mortality at 24 hours (12.7% vs. 17.0% P = 0.12) and 30 days (22.4% vs. 26.1%; P = 0.26) when patients were transfused by ratios of 1:1:1 or 1:1:2 (plasma:platelets:red blood cells).4 Holcomb et al showed that more patients achieved hemostasis, and there were fewer deaths at 24 hours in the 1:1:1 group.

In response to this expanding knowledge regarding the physiology and management of massive hemorrhage in trauma patients, medical professionals developed a protocol-driven concept concerning a fixed-ratio of packed red blood cells to other blood component resuscitation. MTPs have been shown to expedite delivery of blood products, probably through improved communication and planning. When massive transfusion events driven by protocol are compared to those in hospitals without established protocols, there is a significant improvement in survival, as well as reductions in blood product use, waste, and incidence of transfusion-related complications.12

These protocols have been adopted widely across the United States and are now a requirement of several accrediting organizations, such as the American College of Surgeons Trauma Quality Improvement Program and the AABB (formerly the American Association of Blood Banks)/The Joint Commission Patient Blood Management standards. Societal recommendations for the initiation of massive transfusion protocols in trauma patients are variable, but generally include a clinical assessment of both tissue perfusion and the estimated blood loss combined with a validated prediction score.

There are two different prediction scores recommended by separate societies, both of which have been validated. The Assessment of Blood Consumption score is recommended by the American Society of Anesthesiologists and the American College of Surgeons. This simple scoring system considers four variables to predict massive transfusion risk: systolic blood pressure < 90 mmHg, heart rate > 120 beats per minute, positive focused assessment with sonography for trauma (FAST), and penetrating mechanism of injury. A score of 2 is the threshold. The Task Force for Advanced Bleeding Care in Trauma recommends the Trauma Associated Severe Hemorrhage Score, which is a seven-variable score requiring two lab results.

Despite the availability of these scoring systems, it can be challenging to determine which patients will require massive transfusion. Even with a well-established MTP, only 19% of a large trauma center’s annual activations met the historical definition of massive transfusion (> 10 units in 24 hours).13

NONTRAUMA

There are many other causes besides trauma that may result in significant bleeding. In a large U.S. trauma center, MTPs are, not surprisingly, most commonly activated for trauma (77%), but also may be activated for other reasons, such as gastrointestinal hemorrhage (9%), ruptured aortic aneurysm (5%), and unexpected surgical bleeding or medical bleeding in malignancies.13 However, many hospitals provide lower level trauma care and/or routine obstetrical care.

As demonstrated in a separate single academic center study, the pattern in these hospitals may be quite different, with trauma accounting for only 49% of MTP activations, whereas vascular rupture (37%), gastrointestinal bleeding (25%), cardiothoracic surgery (17%), and obstetric bleeding (8%) comprised a much larger percentage of activations.14 Thus, in many hospitals, massive transfusion protocols are activated more frequently in the treatment of nontrauma surgical and critically ill patients.

The use of massive transfusion protocols for the treatment of hemorrhagic shock in nontrauma patients has been supported predominantly by the trauma literature described in this article so far. However, there are distinctions that must be made when comparing these separate patient populations. Nontrauma patients requiring massive transfusion are a heterogeneous group characterized by several comorbid conditions and coagulopathy profiles. They tend to be older, more likely to be on medications that affect platelet function and clotting (such as aspirin or heparin) while in the hospital, and present with a history of liver failure, renal failure, or a malignancy.14

In liver disease, normal coagulation factors are reduced. Also, there is an increased production of abnormal vitamin K-dependent factors that can further inhibit the enzymes of the coagulation pathway. In renal failure, uremia leads to platelet dysfunction by impairing platelet aggregation and adhesiveness through its interaction with fibrinogen and von Willebrand factor. Uremia also can cause an abnormal platelet-endothelial reaction.

Obstetric hemorrhage also is associated with a unique pathophysiology. During pregnancy, there is significant plasma volume expansion and dilutional anemia. In addition, routine pregnancy is a prothrombotic state. The placenta expresses a tissue factor that becomes active when there is vascular endothelial disruption, placental trauma, or necrosis. This is a cofactor for the coagulation cascade and clot formation. Disseminated intravascular coagulation may occur when this cascade overwhelms offsetting effects of the anticoagulant proteins, leading to depletion of the coagulation factors and platelets. Thrombocytopenia may result from alternate causes such as gestational thrombocytopenia, HELLP syndrome, immune thrombocytopenia, antiphospholipid syndrome, dilutional thrombocytopenia, or myeloproliferative neoplasm. Major obstetric hemorrhage (> 2.5 L blood loss or > 5 units transfused) complicated 3.7 per 1,000 births in the United Kingdom in the late 2000s. Postpartum hemorrhage accounts for 25% of maternal deaths worldwide.15

Data evaluating nontrauma patients treated with massive transfusion are limited. Within an obstetric population, blood taken predelivery for in vitro testing of effects of blood component ratios revealed that a ratio of 1:1:1 resulted in optimal clot strength with significant strengthening from the addition of platelets.15

A retrospective, observational, single-center study conducted to compare transfusion ratios in a nontrauma, massively bleeding population from 2011-2015 revealed that there was no difference in 30-day mortality when patients were transfused above a 1:2 ratio of plasma to red blood cells or platelets to red blood cells.16 However, the secondary endpoint of 48-hour mortality showed a significant improvement in the > 1:2 platelet to red blood cell group. The mean red blood cell transfusion requirements administered during a massive transfusion episode are similar with gastrointestinal hemorrhage (6.1 units), ruptured abdominal aortic aneurysm (5.7 units), and trauma (7.1 units).13

Massive transfusion protocols have been shown to be overactivated 53% of the time in nontrauma patients. Despite this, no unique disadvantage of resource allocation was identified, as there was no difference in product waste when compared to trauma activations, with platelet waste decreasing from 14% to 2%.17 Currently, there is no validated prediction score for nontrauma patients to assess the need for massive transfusion.

CONCLUSIONS

Hemorrhagic shock requires a concerted effort to reach stability and prevent death. It is a common endpoint of many etiologies, with trauma by far the most widely studied. Through numerous investigations on massive hemorrhage in both military and civilian trauma, we have gained crucial knowledge regarding the pathophysiology of acute traumatic coagulopathy, which results from direct tissue damage, hypoperfusion, and inflammation leading to fibrinolysis and endothelial activation.

The concept of damage control resuscitation focuses on rapid hemorrhage control with balanced blood component transfusions to correct acute traumatic coagulopathy, preserve oxygen-carrying capacity, and avoid dilutional coagulopathy. Massive transfusion protocols are employed widely and activated for trauma as well as massive hemorrhage from nontrauma causes.

Causes of massive hemorrhage other than trauma are a heterogeneous group associated with different comorbidities and abnormalities in coagulation. Special considerations must be made in certain cases, such as with hepatic and renal failure and obstetric hemorrhages. In these situations, it is difficult to predict who will require activation of the MTP because of the variability within the population. This decision currently requires a clinical assessment of tissue perfusion and blood loss.

In contrast to a trauma population, where prediction scores have been validated, it will be more challenging to develop a prediction tool that could be universal across the nontrauma population. Using the shock index as a variable has been considered. MTPs allow for the rapid delivery of blood components and are beneficial to patient survival. Further research in these areas will help define how treatment may be more effective.

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