REVIEW URRENT C OPINION
What is new in the blood bank for trauma resuscitation Roman Dudaryk a, Aaron S. Hess b, Albert J. Varon a, and John R. Hess c
Purpose of review The aim of the present review was to describe recent changes in blood banking thinking, practice, and products that affect trauma care. Recent findings Prompt balanced hemostatic resuscitation of major hemorrhage from trauma improves outcome and reduces blood use. New blood processes and products can help deliver appropriate doses of procoagulant plasma and platelets quicker and more safely. New processes include holding larger inventories of thawed plasma with risk of wastage and rapid plasma thawers. New products in the blood bank include group A or group A low-titer B thawed plasma and AB or A liquid (never-frozen) plasma for resuscitation, prepooled cultured whole blood–derived platelets in plasma, and prepooled cryoprecipitate in varying pool sizes. Single-donor apheresis or pooled whole blood–derived platelets in additive solution, designed to reduce plasma-related transfusion reactions, are also increasingly available but are not an appropriate blood component for hemorrhage control resuscitation because they reduce the total amount of administered plasma coagulation factors by 10%. Summary Early initiation of balanced massive transfusion protocols leading to hemostatic resuscitation is lifesaving. Changing blood product availability and composition will lead to higher complexity of massive transfusion. It is critical that anesthesiologists understand the composition of the available new blood products to use them correctly. Video abstract http://links.lww.com/COAN/A38 Keywords damage control resuscitation, hemorrhage control resuscitation, platelet additive solutions
INTRODUCTION The approach to resuscitation of the trauma patient with massive uncontrolled bleeding has evolved markedly over the past decade [1]. From the Advanced Trauma Life Support paradigm of first restoring circulating volume and oxygen delivery, then controlling vascular bleeding, and finally fixing coagulation, we have moved to balanced ‘hemorrhage control’ or ‘damage control’ resuscitation across the continuum of prehospital, emergency room, operative, and postoperative care [2]. This new approach appears to save both lives and resources [3 ,4,5]. Along the way, we have become much more sophisticated about the uses and limits of the conventional blood components [6,7]. Just as we are becoming comfortable with the new paradigm of 1 : 1 : 1 resuscitation, blood bankers are changing the components and making new ones available to meet national demands for blood availability and safety [8]. &
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The transfusion medicine community is worried about the availability of the conventional universal donor blood products, group O RhD-negative (O Neg) red blood cells (RBCs) and group AB fresh frozen plasma (FFP), and about alternatives to FFP and conventional platelets in plasma [9,10]. O Neg RBCs are frequently in short supply and are needed
a
Division of Trauma Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida, bDepartment of Anesthesia, University of Wisconsin Hospital and Clinics, Madison, Wisconsin and cDepartment of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, USA Correspondence to John R. Hess, MD, MPH, FACP, FAAAS, Professor of Laboratory Medicine and Hematology, University of Washington School of Medicine; Medical Director, Transfusion Service, Harborview Medical Center, 325 N. Ninth Ave., Seattle, WA 98104, USA. E-mail: [email protected] Curr Opin Anesthesiol 2015, 28:206–209 DOI:10.1097/ACO.0000000000000156 Volume 28 Number 2 April 2015
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KEY POINTS Apheresis plasma, liquid plasma, and group A plasma are all being made to increase the supply of plasma for immediate use in trauma. Prepooled whole blood platelets and prepooled cryoprecipitate will speed the delivery of platelets and cryoprecipitate for trauma patients. ‘Platelets in additive solution’ contain 180 ml less plasma than normal apheresis platelets and are not appropriate for hemostatic resuscitation if alternatives are available.
for O Neg patients, infants, and remote care situations without laboratory support. Using O Neg units in trauma only for women of childbearing potential or RhD-alloimmunized individuals helps preserve this precious national resource. Six percent of the population is O Neg and, by heavily recruiting such donors, 10 or 11% of the RBCs in the system are O Neg. AB donors are more rare – only 4% of individuals – and the decision not to use women as plasma donors to prevent transfusionrelated acute lung injury reduces the availability of AB FFP by half. Whole blood–derived AB FFP is almost always in short supply, and as a result there are a series of new plasma products. These are discussed below. Anesthesiologists need to be aware that a new low-plasma platelet product, platelets in platelet additive solution, can reduce the delivery of coagulation factors in damage control resuscitation [11].
ALTERNATIVES TO WHOLE BLOODDERIVED FRESH FROZEN PLASMA FFP is plasma that is frozen within 8 h of collection. When made from whole blood, it is approximately 80% plasma and 20% anticoagulant with an International Normalization Ratio of approximately 1.1. Thawed, it can be kept for up to 24 h. Most blood collected in the USA, however, comes from mobile blood drives and the plasma is not frozen until 8 h after collection. Such plasma is called FP24, indicating that it was frozen within 24 h of collection, and it is in most respects identical to FFP. Relabeled as thawed plasma, both FFP and FP24 can be kept thawed for up to 5 days, which makes allowance for storage in the emergency room [12 ]. Most transfusion services view all of these products as equivalent when given in compatible blood types. Plasma can also be collected by apheresis, returning the platelets and RBCs to the donor at the time of collection. Because there are no associated iron losses, &
the limit on donation of six times a year does not apply and the US Food and Drug Administration allows apheresis plasma donors to donate up to 600 ml per donation up to twice a week and 24 times in a year, similar to apheresis platelet donors. This plasma is then broken down into 200 ml units. The plasma is more concentrated in apheresis plasma because the anticoagulant solution uses twice the concentration of citrate in half the volume resulting in units that are approximately 90% plasma. Unfortunately, AB apheresis plasma is uncommon because AB donors are uncommon, apheresis procedures are relatively time-consuming and expensive, and the donors tend to be used as platelet donors rather than plasma donors [13].
LIQUID PLASMA Liquid plasma (LQP) also known as ‘never-frozen plasma’ is a blood product left over from the 1960s and 1970s, when whole blood in citrate phosphate and dextrose could be stored for only 21 days. At the end of those 21 days, the plasma could be separated and kept for another 5 days. As a result of those never-rescinded regulations, it is legal to keep neverfrozen plasma for a total of 26 days because most blood is collected into citrate phosphate and dextrose. Ten years ago, only one hospital in the USA was doing this, but use is now spreading under the pressure of maintaining liquid inventories for immediate use. With this extended shelf life, LQP can also be used in prehospital settings. Initial concerns about its safety and effectiveness have been addressed [14]. A recent study [15] compared the hemostatic potential of LQP with thawed FFP in vitro, demonstrating superiority of LQP in terms of thrombin generation and the dynamics of clot formation and strength on thromboelastogram. Retrospective analysis of a large transfusion database from Sweden comparing use of FFP with that of LQP [16] demonstrated a lower mortality at 14 days after transfusion in the LQP group, providing more evidence that LQP is as well tolerated as FFP. Several trauma centers have already included LQP in their massive transfusion protocol (MTP), and in the near future we are likely to see increased utilization of this product as more suppliers make it available.
TYPE A PLASMA Early administration of FFP during hemostatic resuscitation requires around-the-clock availability of thawed units. After thawing, those units must be used within 5 days or discarded. To prevent waste, if not used within 3–4 days, AB FFP units are frequently allocated to general use and dispensed as
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universal donor thawed plasma. In low-volume trauma centers, this practice leads to increased use and wastage of AB FFP, to a degree that suppliers are not able to meet the increased demand for this valuable commodity. Recently, use of type A thawed plasma has been proposed as an alternative to type AB in initial stages of MTP before type-specific FFP is available [17]. Type A plasma is widely available: 40% of the American population shares this blood group. On the basis of population frequencies of 45% type O and 40% type A, type A plasma can be safely transfused in approximately 85% of patients admitted to a trauma center. If used in the remaining 15% of patients (type B and type AB), the theoretical risk of hemolytic transfusion reaction is limited by the generally low levels of anti-B antibodies in most North American donors. If only units with a low titer of anti-B antibody are selected, the risk can be further mitigated. Groups at Dartmouth-Hitchcock Medical Center and the University of Massachusetts, Worchester, have each published experience using this scheme [18 ,19]. In both series, only a few units were allowed to be administered, with additional FFP being type compatible. Data from three of the sites in the Pragmatic Randomized Optimal Plasma and Platelet Ratios (PROPPR) trial are in press with some group B and AB patients receiving up to nine group A units, but the total numbers of patients in all of the series combined is small because numbers of B and AB patients are small [20 ]. It is worth mentioning that development and implementation of such an approach still carries an increased risk of transfusion reaction that has to be accepted by the hospital transfusion committee and treating physicians. &
European guideline on the management of bleeding following trauma [22] recommends maintaining the fibrinogen concentration above 1.5–2.0 g/l (150– 200 g/dl). This can be achieved by either fibrinogen concentrate, which is not approved for this use in the USA, or cryoprecipitate. Although cryoprecipitate is included in the vast majority of MTPs, the recently published Prospective Observational Multicenter Major Transfusion (PROMMTT) study [23 ] indicated that the majority of patients did not receive cryoprecipitate or received it very late. One of the obvious explanations for this delay is the labor-intensive and time-consuming process of pooling multiple small units of cryoprecipitate into pools that usually contain 5–6 U of single-donor cryoprecipitate. The process can take a technologist much of an hour at a time when the transfusion service is very busy [24]. Such a delay can be avoided by prepooling the cryoprecipitate component immediately after separation from plasma but prior to freezing. This product has been available from a few blood centers for more than a decade, but increasing demand is leading to increasing availability. Pooled cryoprecipitate can be rapidly thawed as a pool contains only 60–120 ml and will allow timely correction of a low fibrinogen content in bleeding trauma patients. As a unit of cryoprecipitate typically contains 200– 350 mg of fibrinogen, a pool will contain 1–2 g. A trauma dose for an adult will generally be of the order of two pools and may need to be repeated. &&
&&
RAPID THAWING DEVICES FFP is stored frozen at 308C, and thawing requires approximately 25 min of immersion with agitation in a 378C water bath. There is one company in North America that sells a microwave licensed for thawing FFP without damaging the plasma with local overheating, and the device can thaw 1 U in 6 min and 2 U in 10–12 min [21]. A pair of such units can markedly speed the release and improve the pace of plasma release in massive transfusion situations. Anesthesiologists serving on transfusion committees can help transfusion services justify the cost of these devices to hospital administrators. There is a need for such better and cheaper devices as well.
PREPOOLED CRYOPRECIPITATE Decreased fibrinogen concentration has been linked to trauma-induced coagulopathy. An updated 208
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NEW PLATELET PRODUCTS Platelets are critical in injury care and an important part of MTPs [25]. Platelets, however, carry the highest risk of bacterial contamination among all blood products, at approximately 1 in 2000 U collected, so a pool of five is estimated to have a risk of contamination approximately 1 in 400 [26]. It is not uncommon for a trauma patient to receive four or five sets of pooled platelets, which can increase the risk of platelet-related sepsis to below 1 in 100. Such patients frequently have complex injuries and multiple sources of potential infection, which make the diagnostic connection to platelet transfusion difficult. Platelet pools made from whole blood with sterile connection technology have no increased risk of poolingassociated contamination. Routine surveillance cultures taken at 24 h after pooling detect approximately 70% of contaminated pools, which significantly reduces the chance of bacterial contamination from transfusion of multiple pooled units to a single patient – bringing it closer to the 1 : 5000 risk associated with conventional apheresis platelets. Platelets in additive solution are another new product that is available in blood banks of some Volume 28 Number 2 April 2015
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New blood products for trauma resuscitation Dudaryk et al.
centers. In this product, 65% of the normal 300 ml of plasma in apheresis platelet units is replaced by a saline nutrient solution [27]. The lost plasma will reduce the total plasma in 6 U of RBC, 6 U of FFP, and this unit of apheresis platelets by just over 10% and have the effect of reducing the concentration of administered plasma coagulation factors from 65 to 58% of normal. This is half of the difference in administered plasma concentrations, 65 vs. 52%, in the 1 : 1 : 1 and 1 : 1 : 2 plasma : platelet : RBC unit ratio arms of the PROPPR trial [28 ]. In trauma patients, this product should be avoided if alternative preparations of platelets are available. &
CONCLUSION Hemostatic resuscitation with early, high-ratio (1 : 1) administration of RBCs to FFP is becoming the standard of care of bleeding trauma patients requiring massive transfusion. Medical societies in both the USA and Europe have recognized the vital importance of this approach to the care of the critically injured. Increasing demand and limited supply of AB plasma motivates the transfusion and trauma communities to search for other products and processes to make plasma for resuscitation available quickly. Type A-low-B titer plasma and LQP are becoming new alternative products for early FFP administration. Prepooled cryoprecipitate and whole blood platelet pools will further improve efficiency and quality of MTPs. Well observed series of cases are urgently needed to compare these new blood products with current standards of care. Acknowledgements J.R.H. was supported in part by the US National Heart Lung and Blood Institute through the PROPPR trial U01HL077863. Financial support and sponsorship None. Conflicts of interest J.R.H. is the inventor of the AS-7 RBC additive solution. He receives patent royalties from the US Army and the University of Maryland and has received consulting fees from Haemonetics Corporation, licensee of the patents.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Dudaryk R, Pretto EA Jr. Resuscitation in a multiple casualty event. Anesthesiol Clin 2013; 31:85–106.
2. Langan NR, Eckert M, Martin MJ. Changing patterns of in-hospital deaths following implementation of damage control resuscitation practices in US forward military treatment facilities. JAMA Surg 2014; 149:904–912. 3. Karam O, Tucci M, Combescure C, et al. Plasma transfusion strategies for & critically ill patients. Cochrane Database Syst Rev 2013; 12:CD010654. This review of 600 articles found no large randomized trials of plasma transfusion strategies. We all await the results of the PROPPR trial. 4. Duchesne JC, Kimonis K, Marr AB, et al. Damage control resuscitation in combination with damage control laparotomy: a survival advantage. J Trauma 2010; 69:46–52. 5. Bradley M, Galvagno S, Dhanda A, et al. Damage control resuscitation protocol and the management of open abdomens in trauma patients. Am Surg 2014; 80:768–775. 6. Tobin JM, Grabinsky A, McCunn M, et al. A checklist for trauma and emergency anesthesia. Anesth Analg 2013; 117:1178–1184. 7. Tobin JM, Varon AJ. Update in trauma anesthesiology: perioperative resuscitation management. Anesth Analg 2012; 115:1326–1333. 8. Hess JR. Conventional blood banking and blood component storage regulation: opportunities for improvement. Blood Transfus 2010; 8:S9–S15. 9. Goodnough LT, Spain DA, Maggio P. Logistics of transfusion support for patients with massive hemorrhage. Curr Opin Anaesthesiol 2013; 26:208–214. 10. Quillen K. In search of plentiful universal donor plasma: what might Landsteiner say? Transfusion 2013; 53:1863–1864. 11. Cohn CS, Stubbs J, Schwartz J, et al. A comparison of adverse reaction rates for PASC versus plasma platelet units. Transfusion 2014; 54:1927–1934. 12. Radwan ZA, Bai Y, Matijevic N, et al. An emergency department thawed plasma & protocol for severely injured patients. JAMA Surg 2013; 148:170–175. Another excellent example of a large retrospective study demonstrating a survival advantage with early plasma administration reducing RBC use and saving lives. 13. Strauss RG. Safety of donating multiple products in a single apheresis collection: are we expecting too much? J Clin Apher 2003; 18:135–140. 14. Cao Y, Dua A, Matijevic N, et al. Never-frozen liquid plasma blocks endothelial permeability as effectively as thawed fresh frozen plasma. J Trauma Acute Care Surg 2014; 77:28–33. 15. Matijevic N, Wang YW, Cotton BA, et al. Better hemostatic profiles of neverfrozen liquid plasma compared with thawed fresh frozen plasma. J Trauma Acute Care Surg 2013; 74:84–90. 16. Norda R, Andersson TM, Edgren G, et al. The impact of plasma preparations and their storage time on short-term posttransfusion mortality: a populationbased study using the Scandinavian Donation and Transfusion database. J Trauma Acute Care Surg 2012; 72:954–960. 17. Isaak EJ, Tchorz KM, Lang N, et al. Challenging dogma: group A donors as ‘universal plasma’ donors in massive transfusion protocols. Immunohematology 2011; 27:61–65. 18. Mehr CR, Gupta R, von Recklinghausen FM, et al. Balancing risk and benefit: & maintenance of a thawed group A plasma inventory for trauma patients requiring massive transfusion. J Trauma Acute Care Surg 2013; 74:1425–1431. Description of the Dartmouth–Hitchcock experience with using low-titer-B group A plasma as the primary resuscitation fluid in an isolated mid-volume trauma center. 19. Chhibber V, Greene M, Vauthrin M, et al. Is group A thawed plasma suitable as the first option for emergency release transfusion? Transfusion 2014; 54:1751–1755. 20. Novak DJ, Bai Y, Cooke RK, et al., on behalf of the PROPPR Study Group. && Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: the experience of the PROPPR trial centers. Transfusion 2015; 65 (in press). Description of how each of the 12 PROPPR study sites found locally workable ways to make thawed plasma immediately available for trauma patients. 21. Hirsch J 1, Bach R, Menzebach A, et al. Temperature course and distribution during plasma heating with a microwave device. Anaesthesia 2003; 58:444– 447. 22. Spahn DR, Cerny V, Coats TJ, et al., Task Force for Advanced Bleeding Care in Trauma. Management of bleeding following major trauma: a European guideline. Crit Care 2007; 11:R17. 23. Holcomb JB, Fox EE, Zhang X, et al. Cryoprecipitate use in the Prospective && Observational Multicenter Major Trauma Transfusion study (PROMMTT). J Trauma Acute Care Surg 2013; 75 (1 suppl 1):S31–S39. Even big centers use little cryoprecipitate and use it late. 24. Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev 2009; 23:177–188. 25. Stansbury LG, Hess AS, Thompson K, et al. The clinical significance of platelet counts in the first 24 hours after severe injury. Transfusion 2013; 53:783–789. 26. Brecher ME, Blajchman MA, Yomtovian R, et al. Addressing the risk of bacterial contamination of platelets within the United States: a history to help illuminate the future. Transfusion 2013; 53:221–231. 27. Capocelli KE, Dumont LJ. Novel platelet storage conditions: additive solutions, gas, and cold. Curr Opin Hematol 2014; 21:491–496. 28. Baraniuk S, Tilley BC, Del Junco DJ, et al., PROPPR Study Group. Pragmatic & Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial: design, rationale and implementation. Injury 2014; 45:1287–1295. The PROPPR study design manuscript; results are expected approximately at the end of 2014.
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What is new in the blood bank for trauma resuscitation Roman Dudaryk a, Aaron S. Hess b, Albert J. Varon a, and John R. Hess c
Purpose of review The aim of the present review was to describe recent changes in blood banking thinking, practice, and products that affect trauma care. Recent findings Prompt balanced hemostatic resuscitation of major hemorrhage from trauma improves outcome and reduces blood use. New blood processes and products can help deliver appropriate doses of procoagulant plasma and platelets quicker and more safely. New processes include holding larger inventories of thawed plasma with risk of wastage and rapid plasma thawers. New products in the blood bank include group A or group A low-titer B thawed plasma and AB or A liquid (never-frozen) plasma for resuscitation, prepooled cultured whole blood–derived platelets in plasma, and prepooled cryoprecipitate in varying pool sizes. Single-donor apheresis or pooled whole blood–derived platelets in additive solution, designed to reduce plasma-related transfusion reactions, are also increasingly available but are not an appropriate blood component for hemorrhage control resuscitation because they reduce the total amount of administered plasma coagulation factors by 10%. Summary Early initiation of balanced massive transfusion protocols leading to hemostatic resuscitation is lifesaving. Changing blood product availability and composition will lead to higher complexity of massive transfusion. It is critical that anesthesiologists understand the composition of the available new blood products to use them correctly. Video abstract http://links.lww.com/COAN/A38 Keywords damage control resuscitation, hemorrhage control resuscitation, platelet additive solutions
INTRODUCTION The approach to resuscitation of the trauma patient with massive uncontrolled bleeding has evolved markedly over the past decade [1]. From the Advanced Trauma Life Support paradigm of first restoring circulating volume and oxygen delivery, then controlling vascular bleeding, and finally fixing coagulation, we have moved to balanced ‘hemorrhage control’ or ‘damage control’ resuscitation across the continuum of prehospital, emergency room, operative, and postoperative care [2]. This new approach appears to save both lives and resources [3 ,4,5]. Along the way, we have become much more sophisticated about the uses and limits of the conventional blood components [6,7]. Just as we are becoming comfortable with the new paradigm of 1 : 1 : 1 resuscitation, blood bankers are changing the components and making new ones available to meet national demands for blood availability and safety [8]. &
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The transfusion medicine community is worried about the availability of the conventional universal donor blood products, group O RhD-negative (O Neg) red blood cells (RBCs) and group AB fresh frozen plasma (FFP), and about alternatives to FFP and conventional platelets in plasma [9,10]. O Neg RBCs are frequently in short supply and are needed
a
Division of Trauma Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida, bDepartment of Anesthesia, University of Wisconsin Hospital and Clinics, Madison, Wisconsin and cDepartment of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, USA Correspondence to John R. Hess, MD, MPH, FACP, FAAAS, Professor of Laboratory Medicine and Hematology, University of Washington School of Medicine; Medical Director, Transfusion Service, Harborview Medical Center, 325 N. Ninth Ave., Seattle, WA 98104, USA. E-mail: [email protected] Curr Opin Anesthesiol 2015, 28:206–209 DOI:10.1097/ACO.0000000000000156 Volume 28 Number 2 April 2015
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New blood products for trauma resuscitation Dudaryk et al.
KEY POINTS Apheresis plasma, liquid plasma, and group A plasma are all being made to increase the supply of plasma for immediate use in trauma. Prepooled whole blood platelets and prepooled cryoprecipitate will speed the delivery of platelets and cryoprecipitate for trauma patients. ‘Platelets in additive solution’ contain 180 ml less plasma than normal apheresis platelets and are not appropriate for hemostatic resuscitation if alternatives are available.
for O Neg patients, infants, and remote care situations without laboratory support. Using O Neg units in trauma only for women of childbearing potential or RhD-alloimmunized individuals helps preserve this precious national resource. Six percent of the population is O Neg and, by heavily recruiting such donors, 10 or 11% of the RBCs in the system are O Neg. AB donors are more rare – only 4% of individuals – and the decision not to use women as plasma donors to prevent transfusionrelated acute lung injury reduces the availability of AB FFP by half. Whole blood–derived AB FFP is almost always in short supply, and as a result there are a series of new plasma products. These are discussed below. Anesthesiologists need to be aware that a new low-plasma platelet product, platelets in platelet additive solution, can reduce the delivery of coagulation factors in damage control resuscitation [11].
ALTERNATIVES TO WHOLE BLOODDERIVED FRESH FROZEN PLASMA FFP is plasma that is frozen within 8 h of collection. When made from whole blood, it is approximately 80% plasma and 20% anticoagulant with an International Normalization Ratio of approximately 1.1. Thawed, it can be kept for up to 24 h. Most blood collected in the USA, however, comes from mobile blood drives and the plasma is not frozen until 8 h after collection. Such plasma is called FP24, indicating that it was frozen within 24 h of collection, and it is in most respects identical to FFP. Relabeled as thawed plasma, both FFP and FP24 can be kept thawed for up to 5 days, which makes allowance for storage in the emergency room [12 ]. Most transfusion services view all of these products as equivalent when given in compatible blood types. Plasma can also be collected by apheresis, returning the platelets and RBCs to the donor at the time of collection. Because there are no associated iron losses, &
the limit on donation of six times a year does not apply and the US Food and Drug Administration allows apheresis plasma donors to donate up to 600 ml per donation up to twice a week and 24 times in a year, similar to apheresis platelet donors. This plasma is then broken down into 200 ml units. The plasma is more concentrated in apheresis plasma because the anticoagulant solution uses twice the concentration of citrate in half the volume resulting in units that are approximately 90% plasma. Unfortunately, AB apheresis plasma is uncommon because AB donors are uncommon, apheresis procedures are relatively time-consuming and expensive, and the donors tend to be used as platelet donors rather than plasma donors [13].
LIQUID PLASMA Liquid plasma (LQP) also known as ‘never-frozen plasma’ is a blood product left over from the 1960s and 1970s, when whole blood in citrate phosphate and dextrose could be stored for only 21 days. At the end of those 21 days, the plasma could be separated and kept for another 5 days. As a result of those never-rescinded regulations, it is legal to keep neverfrozen plasma for a total of 26 days because most blood is collected into citrate phosphate and dextrose. Ten years ago, only one hospital in the USA was doing this, but use is now spreading under the pressure of maintaining liquid inventories for immediate use. With this extended shelf life, LQP can also be used in prehospital settings. Initial concerns about its safety and effectiveness have been addressed [14]. A recent study [15] compared the hemostatic potential of LQP with thawed FFP in vitro, demonstrating superiority of LQP in terms of thrombin generation and the dynamics of clot formation and strength on thromboelastogram. Retrospective analysis of a large transfusion database from Sweden comparing use of FFP with that of LQP [16] demonstrated a lower mortality at 14 days after transfusion in the LQP group, providing more evidence that LQP is as well tolerated as FFP. Several trauma centers have already included LQP in their massive transfusion protocol (MTP), and in the near future we are likely to see increased utilization of this product as more suppliers make it available.
TYPE A PLASMA Early administration of FFP during hemostatic resuscitation requires around-the-clock availability of thawed units. After thawing, those units must be used within 5 days or discarded. To prevent waste, if not used within 3–4 days, AB FFP units are frequently allocated to general use and dispensed as
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universal donor thawed plasma. In low-volume trauma centers, this practice leads to increased use and wastage of AB FFP, to a degree that suppliers are not able to meet the increased demand for this valuable commodity. Recently, use of type A thawed plasma has been proposed as an alternative to type AB in initial stages of MTP before type-specific FFP is available [17]. Type A plasma is widely available: 40% of the American population shares this blood group. On the basis of population frequencies of 45% type O and 40% type A, type A plasma can be safely transfused in approximately 85% of patients admitted to a trauma center. If used in the remaining 15% of patients (type B and type AB), the theoretical risk of hemolytic transfusion reaction is limited by the generally low levels of anti-B antibodies in most North American donors. If only units with a low titer of anti-B antibody are selected, the risk can be further mitigated. Groups at Dartmouth-Hitchcock Medical Center and the University of Massachusetts, Worchester, have each published experience using this scheme [18 ,19]. In both series, only a few units were allowed to be administered, with additional FFP being type compatible. Data from three of the sites in the Pragmatic Randomized Optimal Plasma and Platelet Ratios (PROPPR) trial are in press with some group B and AB patients receiving up to nine group A units, but the total numbers of patients in all of the series combined is small because numbers of B and AB patients are small [20 ]. It is worth mentioning that development and implementation of such an approach still carries an increased risk of transfusion reaction that has to be accepted by the hospital transfusion committee and treating physicians. &
European guideline on the management of bleeding following trauma [22] recommends maintaining the fibrinogen concentration above 1.5–2.0 g/l (150– 200 g/dl). This can be achieved by either fibrinogen concentrate, which is not approved for this use in the USA, or cryoprecipitate. Although cryoprecipitate is included in the vast majority of MTPs, the recently published Prospective Observational Multicenter Major Transfusion (PROMMTT) study [23 ] indicated that the majority of patients did not receive cryoprecipitate or received it very late. One of the obvious explanations for this delay is the labor-intensive and time-consuming process of pooling multiple small units of cryoprecipitate into pools that usually contain 5–6 U of single-donor cryoprecipitate. The process can take a technologist much of an hour at a time when the transfusion service is very busy [24]. Such a delay can be avoided by prepooling the cryoprecipitate component immediately after separation from plasma but prior to freezing. This product has been available from a few blood centers for more than a decade, but increasing demand is leading to increasing availability. Pooled cryoprecipitate can be rapidly thawed as a pool contains only 60–120 ml and will allow timely correction of a low fibrinogen content in bleeding trauma patients. As a unit of cryoprecipitate typically contains 200– 350 mg of fibrinogen, a pool will contain 1–2 g. A trauma dose for an adult will generally be of the order of two pools and may need to be repeated. &&
&&
RAPID THAWING DEVICES FFP is stored frozen at 308C, and thawing requires approximately 25 min of immersion with agitation in a 378C water bath. There is one company in North America that sells a microwave licensed for thawing FFP without damaging the plasma with local overheating, and the device can thaw 1 U in 6 min and 2 U in 10–12 min [21]. A pair of such units can markedly speed the release and improve the pace of plasma release in massive transfusion situations. Anesthesiologists serving on transfusion committees can help transfusion services justify the cost of these devices to hospital administrators. There is a need for such better and cheaper devices as well.
PREPOOLED CRYOPRECIPITATE Decreased fibrinogen concentration has been linked to trauma-induced coagulopathy. An updated 208
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NEW PLATELET PRODUCTS Platelets are critical in injury care and an important part of MTPs [25]. Platelets, however, carry the highest risk of bacterial contamination among all blood products, at approximately 1 in 2000 U collected, so a pool of five is estimated to have a risk of contamination approximately 1 in 400 [26]. It is not uncommon for a trauma patient to receive four or five sets of pooled platelets, which can increase the risk of platelet-related sepsis to below 1 in 100. Such patients frequently have complex injuries and multiple sources of potential infection, which make the diagnostic connection to platelet transfusion difficult. Platelet pools made from whole blood with sterile connection technology have no increased risk of poolingassociated contamination. Routine surveillance cultures taken at 24 h after pooling detect approximately 70% of contaminated pools, which significantly reduces the chance of bacterial contamination from transfusion of multiple pooled units to a single patient – bringing it closer to the 1 : 5000 risk associated with conventional apheresis platelets. Platelets in additive solution are another new product that is available in blood banks of some Volume 28 Number 2 April 2015
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New blood products for trauma resuscitation Dudaryk et al.
centers. In this product, 65% of the normal 300 ml of plasma in apheresis platelet units is replaced by a saline nutrient solution [27]. The lost plasma will reduce the total plasma in 6 U of RBC, 6 U of FFP, and this unit of apheresis platelets by just over 10% and have the effect of reducing the concentration of administered plasma coagulation factors from 65 to 58% of normal. This is half of the difference in administered plasma concentrations, 65 vs. 52%, in the 1 : 1 : 1 and 1 : 1 : 2 plasma : platelet : RBC unit ratio arms of the PROPPR trial [28 ]. In trauma patients, this product should be avoided if alternative preparations of platelets are available. &
CONCLUSION Hemostatic resuscitation with early, high-ratio (1 : 1) administration of RBCs to FFP is becoming the standard of care of bleeding trauma patients requiring massive transfusion. Medical societies in both the USA and Europe have recognized the vital importance of this approach to the care of the critically injured. Increasing demand and limited supply of AB plasma motivates the transfusion and trauma communities to search for other products and processes to make plasma for resuscitation available quickly. Type A-low-B titer plasma and LQP are becoming new alternative products for early FFP administration. Prepooled cryoprecipitate and whole blood platelet pools will further improve efficiency and quality of MTPs. Well observed series of cases are urgently needed to compare these new blood products with current standards of care. Acknowledgements J.R.H. was supported in part by the US National Heart Lung and Blood Institute through the PROPPR trial U01HL077863. Financial support and sponsorship None. Conflicts of interest J.R.H. is the inventor of the AS-7 RBC additive solution. He receives patent royalties from the US Army and the University of Maryland and has received consulting fees from Haemonetics Corporation, licensee of the patents.
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