Thomas Mathis MS-3, AEMT, USAR MC
Abdul-Rahman Saleh MS-3, MLS
Kevin Le MS-3, EMT-B
Campbell University School of Osteopathic Medicine
Introduction
Blood products are an essential component of trauma resuscitation. In the experience of both the Afghan and Iraq Wars as well as that of operating rooms and emergency departments throughout the country, timely administration of blood products has proven to decrease morbidity and mortality in prehospital trauma victims suffering from hemorrhagic shock.1-2 The benefit is so significant that civilian helicopter-based EMS programs routinely provide prehospital transfusion to hemodynamically unstable trauma patients.3 The benefit of concurrent hemorrhage control and blood product administration cannot be understated. However, the practices surrounding prehospital blood products is still in its infancy, with different agencies and organizations coming to vastly different conclusions as to its feasibility and application. Through an organized review of the current literature, we provide a summary of the contemporary trends related to prehospital transfusion practices and a window into the future advances of both transfusion products and the trauma systems which incorporate them.
The Past
Prehospital transfusion was first reported as early as the Franco-Prussian war of 1870 for high-risk combat casualties, yet its modern use was only recently cemented with US military combat casualties in the Afghan and Iraq Wars.4 The evolution of prehospital transfusion can be tracked by the intervening conflicts that the United States has experienced. World War I and the interwar years saw advances in blood typing and agglutination, but it wasn’t until World War II, when plasma products were perfected, that medics and military physicians began regularly administering plasma transfusions to battlefield trauma patients. The Korean War saw the role of blood product transfusion diminish and the advent of balanced salt solution resuscitation as a method for preventing post-traumatic renal failure.2,5 The influence of this transition still lingers today, and it was not until the 1980’s that new emphasis was placed on hemostasis over perfusion in a strategy that is commonly referred to as damage control resuscitation (DCR).5 However, the use of crystalloids remains ubiquitous.
While the use of intravenous salt solutions might temporarily increase the intravascular volume and blood pressure, there is no increase in the oxygen carrying capacity of the hemocardiovascular system.6 Crystalloid infusion in traumatic shock causes dilutional coagulopathy, anemia, endothelial damage, and tissue edema, leading to increased morbidity and mortality. In 1994, Bickel et al. published a groundbreaking article in the New England Journal of Medicine which showed delayed fluid resuscitation improved survival among patients with penetrating torso trauma and reduced length of hospital stay.7 More recently, a 2014 meta-analysis found that mortality increased in patients with traumatic shock who received liberal fluid resuscitation versus a restrictive fluid strategy.8 In 2015, a retrospective analysis of 941 prehospital trauma patients found that those receiving more than one liter of crystalloid fluid had a significantly increased likelihood of requiring transfusion in the emergency department.9
Intensive study of its negative effects has instigated a steady decline in the role crystalloids play in trauma resuscitation. Blood product transfusion has emerged as the gold standard for volume replacement in DCR even in the prehospital setting, with the US Military’s Committee on Tactical Combat Casualty Care (CoTCCC) recommending whole blood (WB) as the fluid of choice in 2014. However, in subsequent years after that recommendation, the CoTCCC found that 7% of all military prehospital trauma casualties continued to receive crystalloid infusion compared with 2% receiving packed red blood cells (pRBCs) and 0.5% receiving WB.2 Additionally, many studies pertaining to the influence of prehospital blood products cite frequent crystalloid crossover of treatment groups as a persistent limiting factor. As such, there continues to be a precipitous gap between the clinical ideal and the practical application of prehospital blood transfusion. However, there is a growing movement within the military and civilian community to close this disparity today.
The Present
In recent years, the trauma community has shown early transfusion of blood products to be both safe and beneficial. Plasma, packed red blood cells (pRBCs), and platelets have all been intensively scrutinized. In 2018, a study of helicopter-based prehospital plasma administration, commonly referred to as the PAMPeR trial, demonstrated extensive reduction in 30-day mortality for trauma victims comprising a wide array of morbidities, including prolonged transport time, blunt force etiology, traumatic brain injury, and on-scene transfusion initiation.10 Coincidentally, a competing 2018 study, known as the COMBAT trial, found that there was no increase in transfusion related adverse events associated with plasma administration during urban ground-based EMS transportation, but there was no significant survival benefit at 28-days.11 However, multiple post hoc combined analyses of both trials found increased 24-hour and 28-day survival when study groups were controlled for age, injury severity and trial cohorts.12 Plasma was shown not only to replace clotting factors themselves but also to stabilize the endothelium and innate immune system, decreasing vascular leakage and edema.
In addition to plasma, pRBCs are one of the most commonly employed blood products in the field today. Eighty-four percent of French mobile emergency and resuscitation teams are able to transfuse pRBCs in the prehospital setting. However, only 25.3% of US helicopter EMS programs independently carry uncrossmatched blood as of 2016. Experience with pRBCs varies from less than seven years to greater than 35 years amongst developed countries.13 Despite the disparate experience and accessibility of pRBCs, it is safe and efficacious. In a systematic review of prehospital pRBC transfusion, eleven separate civilian EMS studies reported no transfusion reactions, but patients were more likely to be hypocalcemic and hypothermic upon arrival. While a mortality benefit of pRBC administration was not consistently found in the same review, six civilian studies and all military studies did show increased survival at various time intervals, although not a single study analyzed was a randomized control trial.14
The last of the commonly utilized, prehospital blood products are platelets. The transfusion of platelets achieves early hemostasis in a massive hemorrhage following a substantial traumatic injury. In the US, the majority of platelets are stored at room temperature in bulky storage agitators with constant agitation to prevent clotting. To fully utilize the benefits of platelets in a timely manner with practicality, cold stored platelets (CSP) were developed, which intrinsically has one unit of plasma for suspension. The major limitation associated with CSP is shelf life since it expires in three days. CSPs are now being carried on helicopters and administered to trauma victims in the prehospital setting, typified by trauma center guidelines developed by the Mayo Clinic. In the prehospital transfusion setting, the CSP unit is given after the administration of a pRBC unit. The administration of the CSP unit in conjunction with pRBCs results in a 1:1:1 ratio of platelets, plasma, and pRBCs.15-16
The PROPPR trial, a 2015 hospital-based randomized control trial studying the application of a 1:1:1 platelet, plasma, and pRBC transfusion ratio found that recipients had similar survival rates and decreased propensity for exsanguination at 24 hours compared to a 1:1:2 ratio.17 This indirectly validates current transfusion practices in the prehospital setting. As of 2017, the Mayo Clinic transfuses trauma patients on critical care transports with a 1:1:1 ratio, starting with one unit each of cold stored platelets and pRBCs, and then subsequently transfusing one unit of cold stored whole blood (WB). In both the dual unit and WB stages, the combination of components achieves a 1:1:1 ratio of platelets, plasma, and pRBCs. Norwegian helicopter EMS, instituting a national transfusion initiative in 2013, prefers a “plasma first” methodology of freeze-dried plasma, pRBCs, and leukocyte reduced WB. In both the practices of the Mayo Clinic and Norwegian HEMS, the most significant barriers to adoption and practice have been storage capabilities and product wastage.15 Additional innovation is needed to increase blood product adoption and improve the functionality of prehospital transfusion.
The Future
The Mayo Clinic’s WB strategy alludes to the ease with which plasma, platelets, and pRBCs can be administered in a 1:1:1 ratio through a single transfusion product. The utilization of whole blood provides a balanced resuscitation method with the ease of one bag and one storage setting. Whole blood also offers the advantages of lower transfusion volume, ease of administration, and exposure of the patient to only a single donor.18
The practicality and benefit of a low titer type O whole blood (LTOWB) transfusion protocol has been trialed throughout the country with positive results. Since 2018, the Southwest Texas Regional Advisory Council trauma service has performed LTOWB prehospital transfusions in both urban and rural environments by air and ground transport. In retrospective analysis, prehospital transfusions showed decreased incidence of massive transfusion events compared to no prehospital transfusion. Additionally, patients receiving prehospital LTOWB required less initial volume replacement. ED mortality was reduced and length of stay mortality trended toward improvement.19 In a prospective, cluster randomized pilot study known as the PPOWER trial, the University of Pittsburgh Medical Center demonstrated that prehospital transfusion with LTOWB significantly lowered red cell component requirements at 6 hours and 24 hours. Additionally, prehospital LTOWB lowered K time and maximal amplitude thromboelastography indices compared to pRBC prehospital transfusion. This study validated the feasibility of a large, multicenter prospective trial of LTOWB in the future.20
While storage of cold stored blood products serves as one of the major challenges associated with prehospital transfusions, the Norwegian emergency medical service has demonstrated the practicality of freeze-dried plasma (FDP). FDP stored at room temperature is dissolved in 200-300 ml of sterile water and is ready to be injected in three to six minutes. FDP has been assessed safe to use with over 500,000 units of FDP transfused without any reported side effects.15 FDP also provides the same neuroprotection as compared to fresh plasma in animal surgical models of TBI.21 The Israeli Defense Force (IDF) Medical Corps instituted a strategic plan in 2012 that designated FDP as the resuscitation fluid of choice in the prehospital setting. The IDF found in a retrospective analysis of casualties from 2013 to 2016 that FDP improved INR and fibrinogen levels, but failed to show meaningful benefit in hemoglobin or platelet levels.21 Similarly, a study of IDF storage practices found that under field conditions there was negligible degradation of FDP clotting factors at twelve months.22 Representing its potential for civilian EMS, a single center, retrospective analysis of FDP use in Southeast England helicopter evacuations demonstrated quicker transfusion initiation times and lower pRBC volumes needed in treatment of critical trauma patients.23 Globally, FDP is considered safe and effective with many advanced organizations adopting its use, but multicenter, randomized control trials are still needed to validate these claims.
Conclusion
Blood product transfusion, coupled with prompt control of compressible hemorrhage, is the greatest intervention currently available to prehospital providers to decrease morbidity and mortality in trauma patients. However, the transfusion of blood products in the prehospital setting in a timely manner includes multiple practical challenges particularly with limited resources and personnel. Yet, the establishment of prehospital transfusion criteria is crucial and lifesaving. Various observational studies highlight improvement in care and mortality with the utilization of prehospital, blood product transfusion, but few randomized control trials have been able to illustrate the benefits definitively. Whole blood and freeze-dried plasma offer perhaps the greatest promise in providing this resuscitation modality to the greatest number and diversity of EMS organizations. Concerted efforts should be made not only to prove these products’ validity through prospective study, but also to innovate new methods for incorporating them into the standard logistics of prehospital services.
References
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