Resident Journal Review: Massive Transfusion Protocols (MTPs) in Traumatic Hemorrhage

1. What is the emerging evidence and possible role regarding inclusion of components such as calcium and factor VIIa in trauma MTPs?
2. What is the ideal blood component ratio for massive transfusion in traumatic hemorrhage?

Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial. JAMA. 2015;313(5):471-82.

Prior to this study, there was a lack of well-designed research to guide transfusions in severe trauma and other major bleeding. The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPRR) was the first large, multicenter randomized control trial to compare the effectiveness and safety of a 1:1:1 to 1:1:2 plasma:platelet:packed red blood cell transfusion ratio. The study was conducted at 12 level-I trauma centers in North America and included non-pregnant patients estimated to be at least 15 years of age or 50 kg or greater who met criteria predicting massive transfusion, who were then transported directly from injury site, in which transfusion of one unit of blood component occurred within one hour of arrival or during transport. The authors excluded those with devastating injuries (expected to die within one hour of admission), need for thoracotomy prior to receiving blood products, significant burns (>20% total body surface area), inhalation injuries, or receiving over five minutes of cardiopulmonary resuscitation prior to arrival or in the ED.

The authors analyzed 11,185 patients for eligibility, 680 of which were included in the study and analysis (338 to the 1:1:1 group and 342 to the 1:1:2 group). Clinicians were blinded to treatment until delivery of blood products. There was no significant difference between groups in the primary outcome of all-cause mortality at 24 hours (12.7% in the 1:1:1 group vs. 17.0% in the 1:1:2 group; p=0.12) or at 30 days (22.4% vs. 26.1%, respectively, p=0.26). Exsanguination as the predominant cause of death within the first 24 hours was significantly lower, however, in the 1:1:1 group (9.2% vs. 14.6%, p=0.03). Patients in the 1:1:1 group also achieved anatomic hemostasis at higher rates (86.1% vs. 78.1%, p=0.006). There was no difference in the secondary outcomes of time to hemostasis, ventilator-free days, ICU-free days, disposition at 30 days, incidence of primary surgical procedures, and functional status at hospital discharge (measured as Glasgow Outcome Scale-Extended Score). The rate of adverse events including acute respiratory distress syndrome, multi-organ failure, venous thromboembolism, sepsis, and transfusion-related complications was high overall (89%) but did not significantly differ between the two groups.

While there was no all-cause mortality benefit at 24 hours or 30 days, 1:1:1 transfusion ratios were associated with decreased death due to exsanguination and greater achievement of hemostasis. Trauma-related deaths generally occur within the first 2-3 hours after injury, leading to the concept of the so-called “Golden Hour” as a key period for life-saving interventions.4 Any potential benefit of a 1:1:1 strategy would theoretically have been more pertinent for this time frame, but at or beyond 24 hours these effects may have been diminished as many of the patients in the 1:1:2 group approached the cumulative ratio of 1:1:1 with the standard care provided after the initial randomized treatment was received. While this study was adequately powered to detect a mortality difference of 10% at 24 hours and 12% at 30 days, it could not detect any smaller benefits. While it would seem and the authors suggest that the 1:1:1 transfusion ratios are safe as compared to the 1:1:2, it should be mentioned that the study was not powered to assess for safety and thus may not be able to detect differences in rarer complications.

Cornelius B, Ferrell E, Kilgore P, et al. Incidence of hypocalcemia and role of calcium replacement in major trauma patients requiring operative intervention. AANA J. 2020;88(5):383-9.

Hypocalcemia is a known complication of blood product transfusion related to the use of citrate, a calcium chelator, as a stored blood anticoagulant. Transfusion-related hypocalcemia has been previously associated with an increased risk of mortality.5 This study was a blinded retrospective analysis from a single level-I trauma center of all trauma activations within a 12-month period. The objectives of this study were to determine the incidence and rate of calcium replacement in major trauma patients requiring operative intervention, as well as to investigate the impact of hypocalcemia on the rate of transfusion and mortality. All patients >18 years of age who were stat trauma activations were enrolled. Patients were excluded if calcium was given prior to arrival, if they were pregnant, or if no operative intervention occurred within the first 24 hours. The patients were divided into 2 groups based on whether they received calcium replacement or not.

A total of 638 activations were identified. One hundred and ninety-seven patient cases were analyzed with 80 patients receiving calcium and 117 patients not receiving calcium. The majority of patients were male, and blunt trauma was the most common mechanism. There was no difference between groups in the percentage of patients who had received any blood product, but the calcium repletion group contained a higher percentage of MTP activations compared to the no-repletion group (36.3% vs 15.3% respectively, p<0.05), translating to a higher average transfusion of RBCs (8.1 vs. 3.2, p<0.05), FFP (6.4 vs. 2.6, p<0.05), platelets (1.8 vs. 0.98, p<0.05), and cryoprecipitate (0.5 vs 0, p<0.05). There was significantly higher mortality in patients requiring MTP versus not (20.6% vs 6.8%, p<0.005), with a trend towards increased mortality associated with any transfusion requirement compared to none (13.0% vs 3.8%, p=0.051).

While there was no difference across groups in initial ionized calcium level, there was a relatively high incidence of initial and intraoperative hypocalcemia and severe hypocalcemia (defined as a serum <8 mg/dL or ionized <0.9 mmol/L) in patients who required operative intervention. In patients receiving calcium supplementation, the study found no significant difference in mortality between patients who did or did not require MTP activation (31.8% vs 17.9%, p=0.145).

The study has major limitations and the authors acknowledge them: its retrospective nature, the small sample size, the high number of exclusions. They note the lack of current evidence that trauma patients who arrive hypocalcemic have better outcomes after calcium replacement, pointing to the 31.8 versus 17.9% trend in mortality difference, but fail to discuss the potential implication that calcium repletion could possibly mitigate the mortality risk in patients requiring MTP. In truth, the limitations of this study do not allow definitive conclusions to be made and contributions to mortality from trauma severity, hypocalcemia, calcium supplementation, and transfusion cannot be elucidated. This points to the need for future studies; not only examining mortality alone but also to other end-point benefits to determine the role of calcium in MTP.

O’Keeffe T, Refaai M, Tchorz K, et al. A massive transfusion protocol to decrease blood component use and costs. Arch Surg. 2008;143(7):686-90.

Other than the physiological effects of large-volume blood transfusion, the establishment of a massive transfusion protocol has other significant health systems and care delivery effects. The urban, level-1 trauma center at Parkland Hospital in Dallas, Texas evaluated blood product use, costs, delivery times, and outcomes following implementation of a massive transfusion protocol at their institution. Patients receiving massive transfusion for trauma were prospectively enrolled and compared to the retrospective cohort from one year prior to institution of the protocol. The historical patients’ data was collected from a previously established trauma database and using blood bank records including all patients who received more than 10 units of packed RBCs within the first 24 hours. The MTP protocolized the type and number of blood products received based on number of “shipments” required. For example, the shipments included five units of PRBCS and two units of thawed plasma, with platelets added in the third shipment, and cryoprecipitate and recombinant factor VIIa (rFVIIa) added in the fourth.

The pre- and post- MTP implementation groups were similar in patient demographics, injury severity scores, and reported initial blood pressures. Most notably, following establishment of an MTP, providers used significantly less blood products on average, including PRBCS (15.5 vs 11.8, p<0.001), plasma (8.7 vs. 5.7, p<0.02), and platelets (3.8 vs. 1.1, p<0.001). There was no difference in cryoprecipitate administration and higher rFVIIa post-MTP, which was specifically included in the protocol to increase its use. Accordingly, the costs to the blood bank and the overall hospital costs were $2,300 lower on average per patient following initiation of the protocol, despite the increased costs incurred by increasing rFVIIa use. Use of the MTP was associated with decreased time to blood delivery, with average initial time to first blood delivery of nine minutes. Subsequent blood delivery times were reduced in half (p<0.05). Mortality in the retrospective and prospective cohorts were similar, even after stratification by need for operative intervention, time from transfusion, and by injury severity score. There was no increase in thrombotic events associated with increased rFVIIa use.

This study demonstrates that implementation of a well-designed blood delivery protocol for massive transfusion has many systems-based improvements, including reduced costs and more efficient use of limited resources. It is important to note that the institution is a well-established trauma center with significant experience in management of the exsanguinating trauma patient, and that this study took place prior to designation of the widely-accepted 1:1:1 transfusion ratio. As such, this implementation reflects the more efficient delivery of a service and care. These results may not be translatable in all scenarios, and this study was not powered to detect mortality, especially since trauma patients are incredibly heterogeneous in mechanism and salvageability varies greatly despite best efforts. Lastly, recombinant factor VIIA represented an increased expense after protocol implementation and although no change in adverse events were noted, this study is not the correct design to determine its utility.

McQuilten ZK, Crighton G, Engelbrecht S, et al. Transfusion interventions in critical bleeding requiring massive transfusion: A systematic review. Transfus Med Rev. 2015;29(2):127-37.

The authors of this systematic review aimed to identify new data as well as remaining evidence gaps in the investigation into benefit of specific components for inclusion in massive transfusion protocols. The authors were able to identify 19 papers to include in qualitative analysis, however they were unable to perform any meta-analysis due to the heterogeneity of interventions in the studies identified. As we are addressing MTP for trauma other causes of hemorrhage will not be discussed here.

Only three studies were found examining the component ratios and timing. Among these studies, none were powered to detect differences in mortality, but one noted greater plasma wastage with the fixed 1:1:1 ratio. In the discussion they look to the then-impending PROPPR trial (discussed above) to provide more robust data. On the topic of specific components in addition to RBCs and plasma, three systematic reviews were evaluated. Those looking at fibrinogen concentrate were only in bleeding elective surgical patients but showed no change in mortality or increase in thrombotic episodes. The meta-analysis looking at FFP identified plasma to RBC ratios >1:3 to be associated with reduced mortality, with the caveat that this data is low evidence as it was based on observational data. No quality studies on platelet, prothrombin complex concentrate transfusion, or cryoprecipitate for fibrinogen repletion were identified.

The strongest evidence discussed is that regarding factor VIIa. The authors cited civilian trauma randomized controlled trials and systematic reviews, although these reviews included non-trauma patients. In the RCTs evaluating trauma patients, one demonstrated no difference in RBC transfusion regardless of trauma mechanism. Another, the CONTROL trial, was halted early due to high likelihood of futility and low mortality, although they did see a reduction in the number of units transfused in the factor VIIa arm.

Overall, this review identifies the significant lapses in evidence for the details of massive transfusion protocols. While most large societies advocate for a protocol based, structured transfusion plan for life-threatening hemorrhage, the evidence for the specifics of these plans are lacking, specifically related to inclusion of adjunctive therapies that could potentially further decrease mortality and/or resource utilization.

Conclusion

The above studies and others in the literature support the role of MTP to standardize blood administration and conserve resources in the care of the critically ill trauma patient. As mentioned, the guidelines from the American College of Surgeons are broad, but do support a red blood cell to plasma transfusion ratio between 1:1 and 1:2, as well as one pool of platelets for every six units of red blood cells. There is no sufficient data to contravene their statement against the routine use of recombinant factor VIIa in trauma, and further studies are needed to determine how important stringent calcium repletion is in the setting of major trauma and massive transfusion.

Answers:

1. What is the emerging evidence and possible role regarding inclusion of components such as calcium and factor VIIa in trauma MTPs?
   Robust data on the optimal inclusion of calcium repletion in MTPs and use of adjuncts such as recombinant factor is lacking and requires further study.
2. What is the ideal blood component ratio for massive transfusion in traumatic hemorrhage?
   A definitive ideal ratio of blood products requires further study but the best current evidence is for a 1:1:1 ratio of plasma:platelets:packed red blood cells, and is consistent with the American College of Surgeons Best Practice Guidelines for Massive Transfusion in Trauma.2

References

1. Holcomb JB, Wade C, Michalek J, et al. Increased Plasma and Platelet to Red Blood Cell Ratios Improves Outcome in 466 Massively Transfused Civilian Trauma Patients, Ann Surg. 248(3):447-58.
2. MASSIVE TRANSFUSION IN TRAUMA. ACS TQIP Best Practice Guidelines. https://www.facs.org/-/media/files/quality-programs/trauma/tqip/transfusion_guildelines.ashx?la=en. Published October 2014. Accessed January 5, 2021.
3. CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 376(9734):23-32.
4. Newgard CD, Schmicker RH, Hedges JR, et al. Emergency medical services intervals and survival in trauma: assessment of the “golden hour” in a North American prospective cohort. Ann Emerg Med. 2010;55(3):235-246.e4.
5. Giancarelli A, Birrer KL, Alban RF, et al. Hypocalcemia in trauma patients receiving massive transfusion. J Surg Res. 2016 May 1;202(1):182-7.