The Story of Blood for Shock Resuscitation: How the Pendulum Swings

Abstract

Whole blood transfusion (WBT) began in 1667 as a treatment for mental illness, with predictably poor results. Its therapeutic utility and widespread use were initially limited by deficiencies in transfusion science and antisepsis. James Blundell, a British obstetrician, was recognized for the first allotransfusion in 1825. However, WBT did not become safe and therapeutic until the early 20^th century, with the advent of reliable equipment, sterilization, and blood typing. The discovery of citrate preservation in World War I allowed a separation of donor from recipient and introduced the practice of blood banking. During World War II, Elliott and Strumia were the first to separate whole blood into blood component therapy (BCT), producing dried plasma as a resuscitative product for “traumatic shock.”

During the 1970s, infectious disease, blood fractionation, and financial opportunities further drove the change from WBT to BCT, with few supporting data. Following a period of high-volume crystalloid and BCT resuscitation well into the early 2000s, measures to avoid the resulting iatrogenic resuscitation injury were developed under the concept of damage control resuscitation. Modern transfusion strategies for hemorrhagic shock target balanced BCT to reapproximate whole blood. Contemporary research has expanded the role of WBT to therapy for the acute coagulopathy of trauma and the damaged endothelium. Many US trauma centers are now using WBT as a front-line treatment in tandem with BCT for patients suffering hemorrhagic shock. Looking ahead, it is likely that WBT will once again be the resuscitative fluid of choice for patients in hemorrhagic shock.

Whole blood transfusion (WBT) was introduced at a time when the purging of blood (ie phlebotomy) was thought to have therapeutic advantages.¹ Early physicians presumed the majority of pathophysiology to be related to “humoral imbalance,” and therefore had limited insight into the scientific basis for WBT.² Subsequent rationale and successful application of blood transfusion encompass multiple centuries in the settings of war, clinical practice, and the laboratory. Crossing the threshold from experiment to therapy required generational efforts to establish 3 central tenets of blood transfusion: blood-typing, antisepsis, and preservation (ie the separation in space and time of donor from recipient). It is through this lens that the story of blood and its role in hemorrhagic shock resuscitation begins.

Status quo

Currently, death due to hemorrhagic shock contributes to nearly half of annual trauma-related mortality after hospital admission.³ In the pre-modern era, rationale for transfusing blood was unknown, its risk undefined, and benefit unclear. Richard Lower, a 17^th century English physician was one of the first to see blood as a potential treatment for hemorrhage. In 1666, he performed a successful carotid artery-to-jugular vein transfusion from 1 anesthetized dog into another, making him the first to demonstrate the feasibility of blood transfusion.¹ Several years later, Jean-Baptiste Denys, a French physician to Louis XIV, performed a small volume transfusion from a sheep to a 15-year-old boy for the indication of fever.⁴ Though the boy survived the xenotransfusion, a second patient died after this repeated practice, and Denys was tried for murder. Despite being ultimately acquitted, Denys was restricted from performing any further transfusions by the Parisian Faculty of Medicine.⁵ While these notable efforts suggested the potential for blood transfusion, their failures led society and the church to declare the practice dangerous. Historians Zimmerman and Howell observed, “In view of the complete ignorance of asepsis, of immunology and the process of coagulation, it is indeed fortunate that the pressure of administrative and ecclesiastical disfavor brought about a cessation of further attempts at human transfusion.”⁵

The moratorium on WBT lasted 150 years before an English obstetrician, James Blundell, began some of the first successful transfusions of human blood in 1829. Working at Guy’s Hospital in London, Blundell observed multiple deaths due to postpartum hemorrhage. He concluded that, as a last resort, blood transfusion should be attempted in these patients. Supported by his findings in animal studies, Blundell was credited with the first successful transfusion for severe postpartum hemorrhage (120 mL from husband to wife) via a device of his own creation, named the “Gravitator.” He commented in 1820, “…transfusion by syringe is a feasible and useful operation, and that after undergoing the usual ordeal of neglect, opposition and ridicule, it will hereafter be admitted into general practice.”⁶ Ultimately, he reported 10 successful blood transfusions and presented his work, "Observations on Transfusion of Blood" to the Lancet in 1829 (Fig. 1).⁴

Figure 1.

Dr James Blundell with Gravitator (modified from Baskett,⁴ with permission from Elsevier).

About 30 years after Blundell’s successful cohort, WBT was performed by surgeons Bentley and Fryer in the setting of conflict, with 2 successful cases reported during the American Civil War (1861-1865).⁷ In each instance, transfusion was used as a salvage measure, employing small volumes of blood, in the setting of battlefield sepsis with amputation. Joseph Woodward, a Union Army assistant surgeon, notable for performances of autopsy on Abraham Lincoln and John Wilkes Booth, was recognized during this time for standardization of practices in hospital care. Woodward commented on the unpredictable nature of WBT, stating that he would, “earnestly protest against any general official recommendation of transfusion at present, as likely it will lead to greater mortality than it is intended to prevent.”⁸ While Blundell was able to demonstrate a precedent for WBT, it remained an experimental intervention with unreliable results.

Crossing the threshold

At the turn of the century, 3 major discoveries allowed blood transfusion to cross the threshold from experiment to therapy in the treatment of hemorrhage: blood-typing, antisepsis, and preservation. Karl Landsteiner, a Viennese pathologist, was credited with the discovery of ABO blood types in 1901 at the University of Vienna. After identification of interspecies hemolysis by Landois in 1875, Landsteiner performed serum-mixing studies in 22 human subjects, with description of A, B, and C blood types. Further characterization, performed the following year by Landsteiner’s students, Decastello and Stürli, resulted in the contemporary ABO system. Through these efforts, Landsteiner was awarded the Nobel Prize in 1930 and would later proceed to describe the rhesus (Rh) antigen with Levine and Wiener at the New York Rockefeller Institute for Medical Research in 1940.¹

Evolution in the understanding of sepsis progressed in tandem with these advancements in hematology. Ignaz Semmelweis, a Hungarian obstetrician working at the Vienna General Hospital before Landsteiner, noted increased mortality from postpartum sepsis (ie puerperal fever) in 1 of 2 free clinics he attended. One clinic, staffed by medical students following cadaveric dissection, had an increased incidence of sepsis vs a second clinic staffed by midwives. This observation led to his 1861 publication, asserting reduced mortality in the postpartum period due to handwashing with chlorinated lime.⁹ Semmelweis’ work, while in conflict with prevailing disease models, was the eventual basis for modern germ theory proposed by Pasteur and the development of aseptic surgical technique with carbolic acid by Joseph Lister.

To this point, a blood transfusion required surgical dissection with exposure of the donor and recipient vessels. Conduits between the 2 ranged from a goose quill to a surgical connection of artery and vein, first described as a primary end-to-end anastomosis by Alexis Carrel in 1908.¹ George Crile improved upon the complexity of this design in 1909 with a metallic cannula, through which the vein was coupled with the artery.¹⁰ While functional, these methods transfused unknown volumes of whole blood, placed both patients at risk of vascular injury, and required ligation of artery and vein at the conclusion of the transfusion. At that time, advances in rubberization of natural polymers allowed for the creation of durable, cleanable, and reusable tubing that obviated the need for a vascular anastomosis.¹¹ The heated autoclave, developed by Pasteur, Chamberland, and Koch at the end of the 19^th century, would further revolutionize the practice of surgical instrument sterilization, transforming what was an intricate surgical procedure to a clean and efficient percutaneous needle insertion, laying the groundwork for aseptic blood transfusion.¹²

A remaining barrier to transfusion practice was anticoagulation and the necessity of donor and recipient to be spatially and temporally connected. Previous animal studies in rabbits by Boycott and Douglass at Guy’s Hospital in 1909 revealed that combining phlebotomized blood with citrate, a weak acid, allowed for storage and safe delayed transfusion.¹³ Thereafter, from 1914-1915, Hustin, Agote, Weil, and Lewisohn separately described methods for addition of various concentrations of citrate to whole blood before transfusion in humans.¹³ At the time, Lewisohn’s technique with 30 mL of 2% citrate per 300 mL blood was popularized, allowing for delayed transfusion of whole blood.¹³ Beyond the anticoagulation effect of citrate, an energy source was required for storage of red blood cells (RBC) for longer periods. Peyton Rous, a virologist at the Rockefeller Institute, concluded in 1916 that the addition of glucose to citrate (Rous-Turner solution) maintained cellular integrity for approximately 4 weeks. This early body of work in blood typing, antisepsis, and preservation established a clear foundation upon which future development of large volume blood transfusion could be anchored.

Battlefield expansion

The onset of World War I (1914-1918) introduced massive casualty trauma care and subsequently, large volume transfusion. Whereas experiments within the research laboratory allowed for demonstration of concepts among healthy human and animal subjects, the over-whelming volume of critically ill warfighters provided physicians and scientists with new challenges to expansion of life-saving transfusion practices.

Oswald H Robertson was a London-born American physician who attended medical school at Harvard and conducted research in Peyton Rous’ laboratory. He joined the military medical services in 1917 and was ultimately stationed at the Number 3 Casualty Clearing Station (CCS), a forward-positioned facility, in Grévillers, France. In his 1918 publication, “Transfusion with preserved red blood cells,” he described the difficulty in “procuring sufficient blood under rush conditions…[reducing] the number of transfusions which can be given.”¹⁴ To overcome this challenge, Robertson selected a large volume container (the Winchester bottle, 2,000 mL capacity) into which he added 500 mL of whole blood to the preservative solution described by Rous and Turner (850 mL, 5.4% dextrose; 350 mL, 3.8% citrate) (Fig. 2). Bottles were stored in double walled boxes, insulated with sawdust and packed with ice. A period of 4-5 days was required for sedimentation of the hematocrit. The supernatant plasma, containing high concentrations of citrate, would be siphoned off. The RBC sediment would be volume-reconstituted to 1 L with gelatin (ie Hogan’s solution) or normal saline. With this innovation, Robertson reported outcomes of 22 transfusions in 20 patients. On average, recipients were given relatively small volumes (500 mL to 1 L), all from type O donors. Eleven patients were discharged to base and 8 ultimately died, due to gangrene. He recorded no hemolytic reactions and reported a 4-week limitation for storage. For his work, Robertson was awarded the Distinguished Service Order for his meritorious service during wartime combat in 1919.^13,15

Figure 2.

Dr Oswald Robertson with Winchester bottle (modified from Robertson,¹⁴ with permission from BMJ).

Despite these remarkable innovations, further improvements to wartime preservation practices were needed. In the Winchester bottle, the only usable component was volume-reconstituted RBCs (800—900 mL), which could be transfused only after a 4-5 day period of cold (1-3°C) sedimentation. In response to this challenge, Rous observed a “great and urgent need” for an RBC transfusion replacement in the setting of hemorrhage. He would further conclude that, though RBC transfusion may be desirable, “it is not essential to supply blood corpuscles in ordinary cases of acute hemorrhage.”¹⁶ Rous’ rationale was based on a rabbit controlled hemorrhage model in which animals were phlebotomized between 25% and 50% of their blood volume. He demonstrated that the animal would survive as long as there was replacement by plasma with return of normal blood pressure. By comparison, he noted an unsustained physiologic response with crystalloid, stating, “it leaves the vessels for the tissues” shortly after injection.¹⁶ While this controlled hemorrhage model did not fully represent the pathophysiology of the battlefield, further enthusiasm for plasma transfusion was shared by Captain Gordon R Ward of the Royal Army Medical Corps. In a 1918 British Medical Journal correspondence, Ward noted that the challenges of RBC transfusion logistics might be circumvented by transfusing only “citrated plasma,” as this was the component of whole blood that conferred a survival advantage.¹⁷

Evolution and failure

After a brief interbellum period, by 1939, the world was in massive conflict once again. Fast and portable transfusion was made all the more critical as the mechanisms of war had changed. What previously was a series of entrenched battles became the Blitzkrieg (“Lightning War”) of World War II (1939—1945), defined by rapidly mobile artillery divisions and strategic air bombardment. Innovation during this time came from the unlikely figure of John Elliot, a naval laboratory technician. While he had no formal medical training, Elliott made modifications to Robertson’s Winchester bottle in 1936, resulting in a much smaller vacuum bulb tube that contained citrate, termed the "TransfusoVac" (Fig. 3).¹⁸ After establishment of a relationship with Baxter Laboratories, Elliot’s TransfusoVac replaced open-container blood bottles in domestic hospitals and was an efficient mechanism for blood collection, component separation, and plasma transfusion on the battlefield.

Figure 3.

Dr John Elliott with TransfusoVac (modified from Schmidt¹⁹ with permission from Wiley).

In 1937, the American Red Cross began its first blood transfusion program under the medical directorship of William DeKleine.¹⁹ After a period of correspondence, DeKleine travelled to Salisbury, NC to see Elliot’s work with liquid plasma transfusion techniques. DeKleine was excited by the potential of this technology and provided Elliott an opportunity to present at the national American Medical Association (AMA) meeting in 1940, where he met Captain (later Brigadier General) Douglas Kendrick. Kendrick embraced Elliott’s ideas for liquid plasma transfusion, and their collaboration resulted in ongoing research at the newly established Blood Research Unit at Walter Reed Army Hospital in Bethesda, MD.¹⁸

In July 1940, Britain requested liquid plasma from the American Red Cross during the German Blitzkrieg of London (the Plasma for Britain program). Though Elliot was considered to lead this initiative, Charles Drew, a surgeon and blood product researcher from Columbia University, was appointed project director. Drew, a protégé of John Scudder, had partnered with his mentor to form a blood bank at New York Presbyterian hospital and published extensively on blood preservation.²⁰ The program was enormously complex, recruiting 14,000 volunteers from 8 hospitals with nonstandard equipment, supplies, and procedures. Pooled specimens were centrally processed and subsequently transported via overseas shipping to London. Fraught with logistical challenges, the program was discontinued when DeKleine visited London, finding none of the plasma had been transfused due to concerns of bacterial contamination, evident during the sea voyage, in 1941.¹⁸ The success of the program was in Drew’s subsequent 86-page report that detailed handling of the blood donations, paving the way for the 14 million collections received by the American Red Cross for World War II.²⁰

Lessons learned from the Plasma for Britain program ultimately led the military and American Red Cross to seek alternatives to liquid plasma. Max Strumia, a physician scientist working at the Philadelphia Bryn Mawr Hospital, developed a process for freezing liquid plasma and drying it under a vacuum.²¹ Interestingly, he was also present during the 1940 AMA meeting and presented his technique to Captain Kendrick at that time.

Thereafter, Strumia received funding from the military and American Red Cross for production of several hundred units of plasma for testing by the Army and Navy.¹⁸ His dried plasma transfusion kit underwent thorough evaluation and development in coordination with Captain Kendrick and Commander Lloyd Newhouser (Fig. 4), seeing first combat action at Pearl Harbor (December 7, 1941).²² Dried plasma was subsequently produced by 8 companies over the course of the war, generating more than 6 million packages, and it served as a mainstay of resuscitation in all environments, including prehospital use by medics during the D-Day invasion of Normandy on June 6, 1944.²²

Figure 4.

Standard military 250 cc plasma package. (A) Front of box; (B) back of box; (C) tops removed from cans of distilled water and plasma, with contents showing and ready for removal; (D) contents removed from cans. Pictured on the right are (E) Dr Max Strumia, (F) Captain Douglas Kendrick, and (G) Commander Lloyd Newhouser (modified from Kendrick and Coates²²).

The ease and ubiquity of dried plasma led to a reevaluation of WBT. Colonel Edward Churchill, a cardio-thoracic surgeon and Consultant in Surgery to the 5^th US Army in Northern Africa, was charged with the assessment of WBT necessity and delivery in 1943. He concluded: 1) whole blood should remain the agent of choice for most battlefield casualties; 2) whole blood was the only agent that could adequately prepare the seriously injured soldier for an operation; 3) whole blood reduces mortality and wound infection; and 4) plasma should be considered a first aid measure, a supplement to whole blood, but not a replacement for WBT.²² After being rebuffed by the US Army senior medical leaders, (including the Surgeon General), Churchill effectively publicized his position on WBT via the lay press, endorsing the military’s need for blood banks to the New York Times.²³ He commented, “There is need for whole blood transfusions in the treatment of a significant proportion of the wounded. Plasma is not an adequate substitute in these cases.”²³ The effectiveness of his campaign led to the shipment of refrigeration units to the Army Medical Corps mobile hospitals in Northern Africa for storage of whole blood.²⁴

This period of history witnessed the early innovations and ongoing obstacles of transfusion science. Churchill’s work during WWII established WBT as the mainstay of resuscitation for hemorrhagic shock—a strategy that would guide efforts into the subsequent Korean and Vietnam wars.²⁵ However, despite its desirability, whole blood was limited in its durability, labor intensive, and quickly exhausted in circumstances of massive casualty. Red blood cells, though capable of being stored, proved to be a cumbersome resuscitative fluid. Subsequently, several iterations of dried plasma preparation addressed the logistical problems of the battlefield, but were an incomplete substitute for WBT. Importantly, large scale calls for civilian blood donation at home and abroad were undertaken during this time through the newly established British and American Red Cross programs. These initiatives resulted in 13 million pints of blood collected between 1942 and 1945, the majority of which were converted to plasma.¹⁸ Taken together, the conflicts of the early 20^th century were not only critical to advances in transfusion science, but established the early processes and infra-structures of modern blood banking.

Paradigm shift

The increased enthusiasm for plasma transfusion in battlefield resuscitation required the creation of pooled plasma repositories. However, lack of screening for communicable diseases, notably hepatitis, led to the observation of post-transfusion infection (termed “serum hepatitis”). As the assays for hepatitis B and C would not be developed until the 1960s and 1980s, respectively, the infectious consequences of plasma transfusion hampered blood product resuscitation domestically (in cardiac surgery) and abroad during the Korean War.^18,26 Ultimately, applying blood fractionation techniques, pioneered by Cohn, contaminated plasma stores had an opportunity for salvage in the form of heat-treated human serum albumin, which increased in popularity among resuscitative practice.^1,18

During this time, concerns for infection and the advancement of blood fractionation for various diseases (factor deficiencies, isolated cytopenias during chemotherapy, etc) further drove the change from WBT to BCT for hemorrhagic shock, with few supporting data.^1,26,27 Moreover, misconceptions existed regarding blood typing, processing, and storage of whole blood.²⁷ Specifically, requirements for ABO-specific vs low titer group O, whole blood, overemphasis of leukoreduction, which historically depleted platelets, and 3) the perception that cold-storage reduced the functionality of platelets compounded its limited availability.²⁷ In contrast, the enthusiasm for component therapy was a boon to blood banking. While the first civilian blood bank, credited to Bernard Fantus at Cook County Hospital in 1937, largely relied upon the storage techniques developed by Lewisohn and Robertson, its maturation to a sophisticated industry for complex isolation and processing of blood components presented significant financial incentives.^28-30 Taken together, the medical community from the 1960s to the 1980s moved away from the routine use of WBT as the primary resuscitative agent for hemorrhagic shock in favor of BCT.

C James Carrico and G Tom Shires, influential surgeons and researchers at Parkland Hospital in the 1960s and 1970s, wrote extensively on the use of crystalloid solutions as an adjunct for replacement of the extracellular space in hemorrhagic shock.³¹ This was based on controlled-hemorrhage animal experiments with radiolabeled sulfur ion, considered to reflect acute changes in the extracellular fluid (ECF) volume. They observed that prolonged (>2 hours) hemorrhagic shock was accompanied by a distributional loss of ECF greater than that explained by hemorrhage alone. They concluded that, if phlebotomized whole blood and a balanced crystalloid were infused, then there was no reduction in the functional or total ECF at any experimental time point. For clinical practice in hemorrhagic shock, they recommended resuscitation with a balanced salt solution (lactated Ringer’s) in addition to WBT for restoration of the ECF and durable maintenance of blood pressure.

These physiologic models, based in the controlled hemorrhage of the laboratory, were translated to the uncontrolled hemorrhage of human shock resuscitation with little investigation. As Sondeen and colleagues³² would later describe, fundamental physiological differences exist between uncontrolled and controlled hemorrhage when matched for pressure or volume loss, concluding that such influences must be thoroughly understood before a reliable application of preclinical strategies may occur.³² Nonetheless, evolution of the concepts developed by Carrico and Shires resulted in the misappropriated paradigm of “supranormal resuscitation,” promoted by Shoemaker in the 1980s, during which trauma and surgical patients received large volumes of crystalloid transfusion and BCT.³³ In 1967, recognizing that their research had been misrepresented to endorse volume overload, Shires commented, “…we are enthusiastically agreed that no conceivable interpretation of these data would justify the use of such excessive volumes of balanced salt solution for early replacement in hemorrhage…The objective of care is restoration to normal physiology…[which] can never be accomplished by inundation.”³⁴

Despite their efforts, the ensuing 3 decades (1970—2000) after Carrico and Shires’ experiments witnessed a proliferation of large-volume crystalloid and BCT transfusions. The military experience in the Vietnam War described the pulmonary complications (“shock lung” syndrome or “Da Nang Lung”) of these resuscitative strategies. Victims of hemorrhagic shock and non-thoracic trauma were noted to experience progressive pulmonary decompensation during their hospitalization. Proctor and colleagues,³⁵ from the US Navy Station Hospital Da Nang, observed that, in the first 24 hours after admission, volumes of crystalloid, whole blood, RBC, and plasma averaged over 17 L for severely injured warfighters, leading them to postulate: “Thus fluid retention still remains a possible etiologic factor to explain the observed alterations.”³⁵ These clinical findings would later be described as acute respiratory distress syndrome (ARDS). Other patterns of edema-related, end-organ failure include myocardial dysfunction/arrhythmia, ileus, abdominal and extremity compartment syndromes, and coagulopathy.³³ It is now known that large volume crystalloid-based resuscitation and fluid overload in hemorrhagic shock increases inflammation and worsens clinical outcomes.¹⁷ Though these adverse effects after massive resuscitation remain a contemporary challenge, current practice guidelines are designed around the development of balanced resuscitative strategies.

Balanced resuscitation

In the years after high-volume resuscitation, the pendulum began to swing. In 1994, a US Army emergency medicine physician, William Bickell, published one of the first trials on hypotensive resuscitation in penetrating trauma. An observation originally made by Cannon and Beecher in World War I and World War II, respectively, was that normalization of blood pressure in the absence of definitive surgical care may reactivate bleeding, worsening outcomes.³⁶ Bickell and coauthors³⁷ recognized the clinical equipoise in balancing end-organ perfusion with the crystalloid-associated risk of thrombus disruption, increased coagulopathic bleeding, and decreased survival. Subsequently, they demonstrated, that in 598 adults with penetrating chest trauma and systolic blood pressure ≤90 mmHg, standard of care prehospital crystalloid infusion vs hypotensive resuscitation (2,478 mL vs 375 mL, p < 0.001, respectively) resulted in a decreased incidence of survival to discharge. They concluded that aggressive fluid resuscitation should be delayed until the time of operative intervention. Moreover, the authors specified that their results did not conflict with the work of Carrico and Shires, but rather the “broad interpretation…[of] volume, timing and extent of that resuscitation for certain patients.”³⁷

Evolving from this approach came the concepts of damage control resuscitation (DCR) and the acute coagulopathy of trauma (ACOT).^38-40 The tenants of these strategies hold that, in the setting of hemorrhagic shock, early administration of blood products in a balanced ratio, reapproximating whole blood, with minimization of crystalloid and prevention and/or immediate correction of coagulopathy, leads to improved outcomes in hemorrhagic shock. These conclusions are supported by an extensive body of literature, including the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study and the Pragmatic Randomized Optimal Platelet and FFP Ratios (PROPPR) trial, establishing similar mortality outcomes, but greater successful hemostasis in the 1:1:1 vs 1:1:2 group (plasma, platelets, and red blood cells), and the Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial, revealing a mortality and coagulopathy benefit with pre-hospital plasma transfusion.^3,41,42 As a result, contemporary civilian and military resuscitative strategies for trauma use a blood product transfusion ratio of 1:1:1 in the setting of over-whelming hemorrhage.^43-45

With these balanced ratios in mind, there are multiple benefits of WBT as a resuscitative strategy that make it preferable to reapproximation with BCT. Whole blood contains a higher concentration of coagulation factors, platelets, and hematocrit, reduced additive volumes, and the logistical advantages of a simplified and expeditious delivery to achieve balanced resuscitation.⁴⁶ Consequently, higher concentration of hemoglobin and fibrinogen may be achieved in a reduced volume of transfusion.^47,48 Recent reviews of fresh WBT practices at Role 2, or limited capability, hospitals in Afghanistan, from 2008-2014, show a 2.8-times increased risk of death for critically injured warfighters who did not receive fresh whole blood.⁴⁹ Furthermore, the associated mortality benefit for those receiving fresh WBT was observed at 6 hours after admission to the Role 2 facility.⁵⁰ Civilian evaluation supports these military experiences, suggesting that transfusion of low titer (low anti-A/anti-B antibody) group O whole blood (LTOWB) correlates with an increased 30-day survival in multivariate logistic regression.⁴⁷ Moreover, transfusion of LTOWB appears safe in the emergent setting, with similarly low incidences of transfusion reactions and hemolysis compared to BCT.⁴⁷

As a result of these and other promising findings, centers providing transfusion of LTOWB have expanded across the globe, with the most recent Joint Trauma System consensus recommending LTOWB as the resuscitative fluid of choice for hemorrhagic shock in combat.^51,52 Nonetheless, outcomes data remain limited by small sample sizes, retrospective designs, and heterogeneity in WBT types and practices.⁵³ Among the latter, military experiences have demonstrated mortality benefits in the setting of fresh WBT, a product unavailable to the civilian sector in lieu of cold-stored whole blood.⁵³ Furthermore, as illustrated by the PAMPer and Control Of Major Bleeding After Trauma trials with regard to plasma, the practical considerations of setting, timing, and dose of optimal pre-hospital WBT, bear further delineation.^42,54 Lastly, the financial motivations and economic impact of blood fractionation that drove the conversion of WBT to BCT remain in place, disincentivizing a widespread return to WBT. Though great strides have been made to return WBT as the centerpiece for resuscitation in hemorrhagic shock, a true benefit profile and indication for resuscitation to include WBT vs BCT alone have yet to be demonstrated. Moving into the era of personalized medicine, future trials are needed to identify both the logistical considerations of WBT and also the appropriate optimization of the various components within whole blood.⁵⁵

Future directions

The frontier of blood product transfusion is less likely to be won on the macroscopic battlefields of wartime conflict, but instead in the microscopic resuscitation of the endothelium. Recent prospective observational data have shown that sympatho-adrenal activation is associated with damage to the endothelial glycocalyx, the proteoglycan and glycoprotein luminal lining of the vascular endo-thelium, and is independently predictive of mortality in trauma patients.⁵⁶ Syndecan-1 is the major transmembrane, cell surface proteoglycan on endothelial cells, the ectodomain of which is shed in the setting of hemorrhagic or septic shock.⁵⁷ Preclinical studies have shown that animals subjected to hemorrhagic shock and resuscitated with plasma, demonstrate partial restoration of the glycocalyx, as indicated by syndecan-1 expression, and decreased vascular permeability vs crystalloid controls.^58,59 While these results suggest a promising direction for research, the concept is not entirely new. Repair of the endothelium during hemorrhagic shock was first proposed in the 1970s and 80s using fibronectin, a component of the endothelial glycocalyx, or its plasma circulating form, cold-insoluble globulin.⁶⁰ Further preclinical and clinical studies and trials are needed to comprehensively define the role of the endothelium in shock resolution and its response to various blood product transfusions.

Conclusions

The 355-year story of blood has afforded a narrative of success, failure, adaptation, and perseverance. It is a singular example of the iterative course science has navigated through the generational efforts of discovery. The evolution of transfusion practice has returned our most recent attention to the benefits of whole blood and blood plasma, first proposed by early 20^th century innovators more than 100 years ago. Many trauma centers are now using whole blood transfusion as a front-line treatment, in combination with blood component therapy, for hemorrhagic shock with improved outcomes.⁶¹ Taken together with the developing endothelial data, further research is needed to determine whether the superiority of outcomes is tied to the transfusion of whole blood, as our predecessors suspected.

Abbreviations and Acronyms

BCT

blood component therapy

WBT

whole blood transfusion

ECF

extracellular fluid

LTOWB

low titer group O whole blood