Authors: Evan G. Pivalizza, M.B.Ch.B., FFASA et al

Key Points:

■ Retrospective evidence exists for successful use of whole blood (WB) in military scenarios.

■ Early reports of civilian center experience with WB are encouraging.

■ Implementation of a WB program requires education, coordination between stakeholders and compliance with regulatory requirements.

■ Post-WB implementation monitoring for transfusion safety will be essential until further safety data accumulates.

Current standard-of-care civilian trauma resuscitative practices have been forged upon military data and concepts. This includes blood component ratios in massive transfusion protocols (MTPs) which, apart from a large civilian study with potential benefit, are limited by their retrospective nature and potential selection or survival bias.¹ Successful use of WB has been reported over the last decade in military scenarios and is being slowly instituted in several large civilian trauma centers in the United States.² Herein, we briefly review WB, potential applications in civilian trauma care and suggestions for administrators at institutions that wish to develop a WB strategy.

Although WB in military use is warm and fresh, WB available for civilian trauma will be cold (stored at 1-6 degrees Celsius) with added CPDA anticoagulant. The current FDA-approved shelf-life (up to 35 days, although many centers are using only up to 21 days) is shorter than traditional RBC component storage (42 days). Both in vitro and in vivo data confirm numerous potential advantages of WB:

■ Less anticoagulant and preservative in a single unit of WB (+60 ml) than combinations of RBC, fresh frozen plasma (FFP) and platelets (+200 ml) with less overall dilution and potential hemostatic impact.

■ Hemostatic function is better preserved in WB for up to one to two weeks, even with refrigeration.³

■ Accumulating evidence suggests that cold-stored platelets (similar to cold WB) have preserved function even with cold-induced changes in platelet shape and a shorter potential life span, while continuing to be adequate for acute hemorrhagic control.³

Supportive mathematical modelling has shown increased availability of all cell types in a single unit of WB than the sum of availability when given as individual blood components.⁴

However, theoretical and logistical disadvantages of WB include:

Cost considerations for WB use require close collaboration with blood suppliers.

Possible risk of immunogenicity in emergency trauma situations; group O WB contains both anti-A and anti-B antibodies; so if used as a universal donor, testing is necessary to ensure the absence or low dose of anti-A or anti-B antibodies. A range of acceptable titers from 1:50 to 1:256 is described in the literature and will be related to the local donor community.⁵

Rh-negative WB should be reserved for females of reproductive age and other patients with known Rh-negative status.

Military Data

The military has used WB transfusion since World War I for multiple reasons. A forward-operating hospital may have logistical issues getting resupplied by the theater blood banking unit if a single patient requiring massive transfusion requires a large percentage of the stored products. The walking blood bank – a system for collecting fresh whole blood at the time it is needed – offers a relatively large supply of blood in a short time. Spinella described as little as 25 minutes under optimum conditions from activation of the blood drive to delivery of WB to the patient.⁶ Available evidence from both military and civilian casualties in recent Middle Eastern conflicts suggests a positive (or at minimum, equivalent) survival benefit when WB is added to component therapy resuscitation, although data are subject to the inherent bias associated with retrospective studies. Many comparison groups are of unequal size, although injury severity is similar (and occasionally worse in the WB group) and WB is not isolated as a discrete signal (usually <30 percent of the transfused total products). These signals include improved survival and preservation of platelet and coagulation function.^7,8 These data have been sufficiently robust to support official recommendation for fresh WB as the priority fluid of first choice in military casualties with hemorrhagic shock.⁹

Modern Civilian Data

Several large trauma centers have recently reported their initial WB experiences. The Houston group prospectively investigated modified WB (mWB = 1 RBC + 1 FFP, with platelets added after six units) in 107 patients and found a beneficial effect of mWB on all individual and total products transfused only after sensitivity analysis excluding patients with severe brain injury.¹⁰ In Pittsburgh, a feasibility study in 47 male trauma patients who were emergently transfused up to two units of uncrossmatched O positive WB was successful, with no adverse safety signal, but was not powered to investigate outcome effects of WB transfusion.¹¹ The same group also found no abnormal markers of hemolysis (lactate dehydrogenase, total bilirubin, haptoglobin, creatinine, serum potassium) up to 48 hours post-transfusion in 44 patients.⁵ Until more robust prospective evidence arises, military data and small civilian studies are reassuring for absence of a significant hemolytic effect on uncrossmatched O positive WB, supporting ongoing experience and analysis.

Considerations for Initiation of a WB Program

Extensive experience with development of a WB program from Mayo Clinic exists.¹² Based on their regulatory and pathology recommendations, we offer pragmatic recommendations for institutions with similar desires:

Institutional Education

Concerted and coordinated multi-disciplinary education must precede any planned WB use. At an institutional level, approval should be obtained from the chief medical officer and multi-disciplinary patient blood management committee. Physicians and nurses in the emergency medicine, surgical, anesthesiology and pathology departments as well as medical technicians require education. Initially, WB should be available on medevac helicopters (up to two units) and in trauma bays (up to four units) with a clearly distinctive label (Figure 1). Known contraindications should be publicized, accepting that these may not be identifiable in acutely injured patients, including known allo-antibodies, non-O blood groups, or patients with known malignancy or bone marrow transplantation requiring irradiated products.
Coordination With Local Blood Supplier

A WB program cannot be successful without support from blood suppliers. The Gulf Coast Regional Blood Center is providing group O blood from male-only donors with a 21-day expiration, no leukoreduction, and low anti-A and B titers (< 1:200). It is incumbent on the institution to facilitate management and stewardship of these valuable products to avoid unnecessary WB expiration and waste.
Regulatory Requirements

WB transfusion is under the review of the American Association of Blood Banks, or AABB, and the Food and Drug Administration. AABB approval is necessary for “variance use” (Standards for Blood Banks and Transfusion Services. 2015, AABB, Bethesda, MD, 30th edition), given current recommendation for ABO-group specific transfusion. Revisions to this AABB standard are forthcoming (31st edition, personal communication, Yu Bai, blood bank, Memorial Hermann Hospital, Texas Medical Center).

Conclusion

Current interest in cold WB for resuscitation in acute civilian trauma victims follows compelling, although retrospective, data from the military medical community where fresh WB has been successful in combination with component therapy. Initial reports from several large level 1 trauma centers in the United States build on these potential applications, and a low incidence of hemolytic and other adverse effects to date support continued exploration.² Stay tuned for additional prospective investigations on the efficacy, safety and cost analysis of WB to ascertain whether the return of this therapy is indeed sustained.

References:

Haider AH, Piper LC, Zogg CK, et al. Military-to-civilian translation of battlefield innovations in operative trauma care. Surgery. 2015;158(6):1686–1695.

Spinella PC, Pidcoke HF, Strandenes G, et al. Whole blood for hemostatic resuscitation of major bleeding. Transfusion. 2016;56 Suppl 2:S190–S202.

Strandenes G, Austlid I, Apelseth TO, et al. Coagulation function of stored whole blood is preserved for 14 days in austere conditions: a ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S31–S38.

Mays JA, Hess JR . Modelling the effects of blood component storage lesions on the quality of haemostatic resuscitation in massive transfusion for trauma. Blood Transfus. 2017;15(2):153–157.

Seheult JN, Triulzi DJ, Alarcon LH, Sperry JL, Murdock A, Yazer MH . Measurement of haemolysis markers following transfusion of uncrossmatched, low-titre, group O+ whole blood in civilian trauma patients: initial experience at a level 1 trauma centre. Transfus Med. 2017;27(1):30–35.

Spinella PC, Perkins JG, Grathwohl KW ; for 31st CSH Research Working Group. Fresh whole blood transfusions in coalition military, foreign national, and enemy combatant patients during Operation Iraqi Freedom at a U.S. combat support hospital. World J Surg. 2008;32(1):2–6.

Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB . Warm fresh whole blood is independently associated with improved survival for patients with combat-related injuries. J Trauma. 2009;66(4 Suppl):S69–S76

Perkins, JG, Cap, AP, Spinella, PC et al; for 31st Combat Support Hospital Research Group. Comparison of platelet transfusion as fresh whole blood versus apheresis platelets for massively transfused combat trauma patients (CME). Transfusion. 2011;51(2):242–252.

Baker BL, Powell D, Riesberg J, Keenan S . Prolonged field care working group fluid therapy recommendations. J Spec Oper Med. 2016;16(1):112–117.

Cotton, BA, Podbielski, J, Camp, E et al; for Early Whole Blood Investigators. A randomized controlled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions. Ann Surg. 2013;258(4):527–533.

Yazer MH, Jackson B, Sperry JL, Alarcon L, Triulzi DJ, Murdock AD . Initial safety and feasibility of cold-stored uncrossmatched whole blood transfusion in civilian trauma patients. J Trauma Acute Care Surg. 2016;81(1):21–26.

Stubbs JR, Zielinski MD, Jenkins D . The state of the science of whole blood: lessons learned at Mayo Clinic.

Is Whole Blood Poised for a Return in Civilian Trauma?

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