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It will be tragic if medical historian can look back on the WWII period and write of it as a time when so much was learned and so little remembered.—Dr. Henry Beecher (1951) [1]

With the exception of a few cases of whole blood transfusion, including four during the Civil War, crystalloid was the standard of therapy for hemorrhage shock in the nineteenth century and the first two decades of the twentieth century [2,3,4,5]. However, the onset of World War I and the subsequent great influx of severely injured combatants caused Allied surgeons to deem crystalloid “unsatisfactory” for treating massive hemorrhage because of the increased bleeding it caused [6]. That knowledge, along with advances in blood typing and preservation techniques at the beginning of the twentieth century, allowed whole blood to become the standard of care during the final year of World War I [5, 7, 8]. This persisted for the next four decades until dried plasma was developed just prior to WWII, and it became the standard early resuscitation fluid for US military surgeons during the war. It was transfused to maintain a systolic blood pressure of 85 mm Hg along with appropriate skin color and warmth while readying whole blood and attempting to stop the bleeding [1, 9,10,11]. Surgeons learned that warming the patient to physiologic temperature and transfusing whole blood to achieve a lower than normal blood pressure resulted in the “most dramatic improvement” [12, 13].

In the early 1960s, research by leading civilian trauma surgeons seemed to indicate that infusing Ringer’s lactate (LR) before whole blood improved survival for animals in hemorrhagic shock [14,15,16,17,18,19]. These models failed to take into account the chance for rebleeding from achieving a normal blood pressure and were not compared with whole blood resuscitation in scientific studies, but this did not prevent the adoption of crystalloids as a resuscitative fluid for bleeding casualties during the Vietnam War. An influential study published in the mid-1970s seemed to confirm the safety of crystalloid when it said that 1–2 l could be administered while waiting for whole blood to be crossmatched [20].

While increasing volumes of crystalloid were being incorporated into hemorrhagic shock resuscitation, advances in blood fractionation techniques permitted a unit of whole blood to be separated into separate units of red blood cells (RBCs), plasma, and platelets. This allowed for most patients requiring a blood transfusion to be treated with only the component in which they were deficient, thus conserving blood supplies while limiting exposure to potential pathogens and transfusion reactions [21,22,23,24]. At the time, experienced surgeons recommended moderation of crystalloid infusion and asserted that whole blood should be used to replace acute blood loss, but this did not prevent many busy trauma centers in the 1970s from exclusively infusing RBCs and LR in bleeding patients [18, 25,26,27].

The aggressive use of crystalloid and RBC resuscitation only grew in the last two decades of the twentieth century as studies proclaimed that transfusing platelets and plasma was not necessary until laboratory values demonstrated coagulopathy [28,29,30,31]. “Supranormal resuscitation” also became popular at this time because of subsequently refuted studies and HIV transmission was a concern for all blood transfusions [32,33,34,35,36,37,38,39,40,41].

19.1 Damage Control Resuscitation

At the beginning of the twenty-first century, complications resulting from large-volume crystalloid resuscitation, including cardiopulmonary dysfunction, abdominal compartment syndrome, multiple organ dysfunction syndrome, and mortality, were being identified and published [42, 43]. Coagulopathy was also identified in 25–33% of severely injured patients and was associated with increased mortality [44,45,46,47,48,49]. Observations of the clinical utility of whole blood were described from the 1993 Black Hawk Down episode [50]. As a result, the US military surgeons treating patients in Iraq and Afghanistan developed damage control resuscitation (DCR) as a way to mimic the lessons learned by Allied physicians treating thousands of combat casualties during the World Wars. DCR attempted to replicate the success of whole blood by transfusing balanced ratios of plasma and platelets to RBCs to achieve permissive hypotension while maintaining normal temperature and quickly stopping bleeding [51, 52]. This reduced the side effects associated with large-volume crystalloid infusion including dilutional coagulopathy, hypothermia from room temperature infusion, as well as increased inflammation, edema, and organ failure [53,54,55,56,57,58].

19.2 Limit Crystalloid

Large-volume crystalloid infusion worsens the “bloody vicious cycle” of coagulopathy, acidosis, and hypothermia by diluting clotting factors, cooling the patient, and worsening acidosis [27, 53, 54, 59, 60]. It also disrupts cellular mechanisms leading to inflammation and edema. This leads to increased mortality from cardiac, pulmonary, gastrointestinal, and immune system dysfunction as well as morbidity from decreased healing and increased incidences of anastomotic leak, abdominal compartment syndrome, and open abdomen [42, 43, 61,62,63,64,65,66, 56, 57,58,59]. Increased crystalloid resuscitation also results in more blood transfusions and more rapid clot breakdown (hyperfibrinolysis) [67,68,69,70].

19.3 Balanced Resuscitation

After implementing DCR in Iraq and Afghanistan, the military published their initial results with balanced resuscitation in 2007. The first retrospective trial showed improved survival for patients receiving higher ratios of plasma to RBCs [51]. These results were replicated in other military and civilian trials looking at both blunt and penetrating injuries [48, 71,72,73,74,75,76,77,78]. Similar results were found for balanced ratios of platelet transfusion [72, 79,80,81,82,83]. Civilian trauma centers quickly adopted balanced ratio massive resuscitation with 70–85% of level 1 centers now including it in their massive transfusion protocol, up from just a few centers a decade ago [84,85,86].

19.4 Survival Bias

A limitation to retrospective studies was highlighted in 2009 by a trial that examined the increased time required to thaw fresh frozen plasma (FFP) (93 min) for transfusion compared with RBCs (18 min) [87]. As a result, patients who survived ultimately received balance ratios of plasma, while those who died within the first few hours received RBCs but not other components which require longer to prepare. Prethawed plasma and never-frozen plasma are now available in more than 85% of surveyed trauma centers, to overcome the time required to thaw FFP [86, 88,89,90,91,92,93].

The PROPPR trial was a prospective, randomized, multicenter trial designed to evaluate the difference in outcomes between the two most common resuscitation ratios (1:1:1 and 1:1:2 (plasma/platelet/RBC)) [94]. While it did not show an improvement in 24 h or 30-day mortality, it did show the benefits of early balanced plasma and platelet resuscitation with decreased mortality at 3 h, decreased hemorrhagic death at 24 h, and increased median time to hemorrhage death [94,95,96,97]. PROPPR also showed no increase in complications for those treated with a 1:1:1 ratio, indicating that it is safe to transfuse higher ratios of plasma and platelets [94].

19.5 Whole Blood

While balance resuscitation was rapidly adopted in civilian trauma centers, the US military continued a long tradition of whole blood transfusions. Military physicians have safely transfused more than a million units of whole blood during wars over the past century, including more than 10,300 units of fresh whole blood to treat massively injured combatants in Iraq and Afghanistan [7, 8, 41, 98, 99]. Much of the transfused whole blood during these conflicts was provided by a walking blood bank of prescreened soldiers in rural settings. Retrospective reviews from these wars show improved 24-h and 30-day survival for massively transfused patients who received warm, fresh whole blood compared with those who received balanced ratios of blood components [100, 101]. This superiority is a result of the improved oxygen-carrying capacity, coagulation factors, platelet activity, flow characteristics, decreased dilution by storage solutions, and the superior hemostatic potential of whole blood compared to reconstituted component therapy [41, 98, 102].

19.6 Permissive Hypotension

In addition to replacing blood loss with whole blood or a balanced approximation, another component of damage control resuscitation is permissive hypotension. Originally described by World War I and II physicians, permissive hypotension contends that maintaining a lower than normal blood pressure decreases blood loss [9, 13]. The theory was confirmed by multiple animal models of uncontrolled hemorrhage [50, 103,104,105,106,107] and randomized trials in penetrating and blunt trauma patients [108,109,110].

19.7 Hypothermia

Hypothermia is common in severely injured trauma patients because of environmental exposure and infusion of room temperature fluids. It causes increased bleeding and mortality because of a reduction in coagulation enzyme activity and clot formation [27, 111,112,113,114,115]. Warming fluids and other rewarming techniques should be used to reverse these processes [57].

19.8 Stopping Hemorrhage

Rapid hemorrhage control is an important component of DCR because exsanguination is the leading cause of potentially survivable trauma deaths [116]. Tourniquets are effective for controlling extremity hemorrhage, and they have a low incidence of complications [117, 118]. Hemostatic dressings are effective for controlling compressible bleeding, but two-thirds of hemorrhagic deaths result from non-compressible torso trauma, so resuscitative endovascular balloon occlusion of the aorta (REBOA) has made a resurgence for quickly halting abdominal and pelvic hemorrhage with less morbidity than a resuscitative thoracotomy [116, 119,120,121,122]. Centers should implement a comprehensive hemorrhage control bundle, to begin prehospital and extend through the operating room [96].

19.9 Viscoelastic Hemostatic Assays

When bleeding slows, viscoelastic hemostatic assays (VHA), such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), can be used to guide resuscitation more precisely than fixed component ratios by evaluating clot formation, stability, and degradation as well as diagnose hypo- and hypercoagulable states [58, 123,124,125,126]. Rapid TEG is capable of predicting the need for component transfusions within 5 min, and a recent randomized control trial showed improved mortality and decreased blood component transfusions when comparing it with conventional coagulation tests [127, 128].

VHA also provide information on fibrinolysis, which is a spectrum of clot degradation ranging from hyperfibrinolysis with unmitigated hemorrhage to fibrinolysis shutdown causing excessive thrombus and subsequent organ dysfunction [129]. Fibrinolysis is diagnosed based on TEG LY30, and both extremes cause increased mortality [68, 129]. Administering tranexamic acid (TXA) within 3 h of injury reverses this laboratory abnormality, but it remains to be seen if this treatment for hyperfibrinolysis (LY30 > 3%) improves patient outcomes [130,131,132].

Conclusion

Cutting edge therapy for hemorrhage shock is nearly identical to the methods established while resuscitating thousands of critically wounded soldiers during WWI and WWII. The biggest difference is the currently accepted practice of balanced blood component therapy rather than whole blood, which was successfully used for half a century before being supplanted by crystalloid and RBCs, despite no comparison studies in uncontrolled hemorrhage. Because fractionated blood components are inferior to whole blood in oxygen-carrying capacity and coagulation, the best replacement for blood loss is almost assuredly whole blood. As a result, whole blood needs to be seriously evaluated as the therapy of choice for massively bleeding patients.