Making whole blood for trauma available (again): the American Red Cross experience

Abstract

Since the 1970's, transfusion support in the United States has primarily involved component therapy, which represents the best means to deliver targeted transfusion therapy based on laboratory results and efficiently uses blood products.1, 2 However, during resuscitation following significant blood loss and in life-threatening injuries when timely laboratory-guided component therapy use is not practical, the practice historically has been to first provide crystalloid and RBCs and then transfuse platelets and plasma in the intensive care unit after labs reveal thrombocytopenia and/or coagulopathy.3, 4 In mid to late 2000, the principle of damage control resuscitation, which promotes use of high ratios of RBCs and plasma with very limited use of crystalloid to restore oxygen debt and simultaneously correct/prevent coagulopathy, became widely adopted. Data from many centers also supported the use of platelets as part of damage control resuscitation.5-9 These compelling studies, which were supported by randomized clinical trial data,10 led many centers to develop massive transfusion protocols (MTPs) that facilitated the timely delivery of a balanced complement of blood products to patients at bedside. During the past decade, we have seen a growing interest in the use of whole blood (WB) for resuscitation of patients with traumatic hemorrhagic shock. Data from the military's experience, which is generally favorable or shows no difference in outcomes with both fresh and stored WB, have been limited by their comparison to historical controls and without discrete separation of the WB effect in that most patients received both WB and components.11-13 Nevertheless, the safe and continued use of WB in the military with no significant reported adverse events has led a few civilian trauma centers to begin to introduce its use in hospitals and even in prehospital settings. Moreover, the recently changed AABB Standard 5.15.1 in the 31st edition of the Standards for Blood Banks and Transfusion Services now permit the transfusion of WB if compatible with the recipient, making it easier to use group O WB in trauma settings, where the blood type of the recipient is often unknown.14 Publication of clinical findings from civilian trauma centers who have implemented low-titer group O whole blood (LTOWB) manufactured using a platelet-sparing filter reported that small cohorts of trauma patients receiving one to four units of LTOWB did not have any significant changes in biochemical markers of hemolysis (i.e., lactate dehydrogenase, haptoglobin, and hemolysis) monitored for a few days after transfusion compared to patients receiving component therapy with group A plasma and pooled WB-derived platelets.12, 15-17 In addition, the non–group O recipients of LTOWB also did not have significant differences in hemolysis as compared to recipients who were group O. The 5-day in vivo platelet recovery and survival ratio as compared to autologous platelets of platelet concentrates isolated using the platelet sparing filter was approximately 80%.18 There are only limited published data on in vitro functional studies of platelets in WB manufactured using the platelet-sparing filter.19 A recent study demonstrated that use of a platelet-sparing leukoreduction filter significantly reduced impedence aggregation as compared to nonleukoreduced units but had little effect on viscoelastic parameters and thrombin generation time.19 The clinical relevance of the reduced functionality in platelets using the WB leukoreduction filter is unknown. Interestingly, thromboelastography studies of cold-stored platelets suggest that activity does not diminish until Day 14, and aggregometry to epinephrine and adenosine diphosphate were preserved until Day 21 of storage.11, 20, 21 Cold-stored platelets have been theorized to be more effective at hemostasis in actively bleeding patients over room temperature platelets due to in vitro studies.22 Taken together, these reports reduced concerns for hemolysis and other effects resulting from transfusion of plasma containing anti-A and anti-B when using LTOWB. The titer cutoff used by various centers ranges from less than 50 to 256 as measured by direct agglutination at room temperature in an immediate spin saline tube.13, 15, 23 Both military and civilian centers reported no acute transfusion reactions documented with LTOWB. The growing number of reports from hospitals, the military community, and expert stakeholders supporting the clinical use of LTOWB containing functional platelets provided the rationale to investigate market interest and the operational steps necessary to provide this product to customers seeking its use in both hospital and prehospital settings. The American Red Cross (ARC) began receiving a few scattered inquiries regarding the availability of WB beginning in 2016. To better assess the overall interest in WB for use in damage-control resuscitation and what attributes of the product were most important to physicians, the ARC conducted a brief survey of hospitals with Level I and II trauma centers from July through September 2017. The online survey was sent to over 350 Level I and II trauma centers in the United States using a third-party survey provider to execute and analyze the results. The recipients of the survey included physicians from different backgrounds, but mostly included responses from trauma surgeons, transfusion medicine directors, and other practitioners who were involved in massive transfusion for trauma at their institutions. It was important to have participation from both end users of blood products and transfusion medicine specialists because anecdotal information suggested that there may be a difference of opinion on the use of WB for trauma between these groups. The goal of the survey was not only to assess interest in WB for trauma but also to determine which potential attributes of the product including ABO group, Rh group, leukoreduction, low titer, and pathogen reduction were most important to end users and transfusion medicine specialists. A secondary goal of the survey was to determine how many WB units hospital practitioners anticipated they may use to replace the group O RBC units in their overall RBC inventory typically used for trauma. There were 98 total responses from the group of trauma centers surveyed. The relatively low response rate (approx. 30%) represents a major limitation of the analysis of the survey results as a gauge to extrapolate views held by hospital users. The respondents included 52 (53%) physicians in the transfusion medicine department (TM group), 30 (31%) on the trauma surgical team (TS group), and 16 (16%) who worked in “other” departments (Other group). The backgrounds of physicians in the Other group included critical/intensive care, trauma/emergency department (nonsurgical), anesthesiology, operational military medicine, pediatric intensive care, prehospital specialist, and research scientist. Due to the low number of expected respondents and the complexity of the questions in the survey, adequate statistical analysis could not be performed, but the information does provide some qualitative insight into the opinions of practitioners at the Level I and II trauma centers. Our respondents largely (approx. 80%) reported using component therapy without laboratory guidance for managing massive transfusions (Fig. 1). Interestingly, 10% of the respondents from hospitals containing fewer than 550 beds confirmed using WB as part of their resuscitation packet. When asked about their preference for either WB or a “massive transfusion pack” containing standard components in a prescribed ratio of RBCs, plasma, and platelets, more than half of all respondents indicated they preferred WB (58%). Of interest, this preference was different among the different categories of users. A large majority of physicians outside of the Transfusion Service (93%) and Other groups (75%) preferred using WB while only 33% of the TM group shared this preference (Fig. 2A). Respondents were permitted to provide open comments regarding their response to this question, and there were clear differences between the groups that preferred WB and massive transfusion packs. The respondents who preferred WB most commonly stated that WB provides more effective oxygen-carrying capacity, coagulation factors, and volume in the same package while ensuring the correct component ratio, thus allowing hemostasis and hemodynamic stability to be achieved faster (Fig. 2B). Others felt that easy administration and improved efficiency (i.e., no need for multiple components, no thawing of plasma) were important. Additionally, respondents believed that qualitative factors like limiting donor exposures and using a product closer in physiology to the patient's own blood with fewer additives were better for the patient. Respondents who favored continuing their current massive transfusion protocol practice stated that there was a lack of evidence or research evaluating patient outcomes to support the use of WB. Other concerns included the potential for mistransfusion, lack of confidence in cold-stored platelets, and inventory management issues (e.g., dual inventory, expiration of WB, availability of WB). These respondents also reported that fixed-ratio component therapy in an MTP allowed for optimal flexibility and that ratios could be altered to meet the needs of the patients. Some respondents also indicated that WB must be ABO identical according to the AABB Standards for Blood Banks and Transfusion Services, 30th edition. It is possible that the difficult prospect of having to obtain a variance to the Standards, as has been reported by others, may also have been an influencing factor related to this response.24 Respondents were given the opportunity to rank various possible attributes of a WB product for use in trauma resuscitation in order of preference or importance to them (Table 1). The most important attribute according to all groups was that the WB should be group O (54% of all respondents). Overall, 35% preferred O negative and 19% preferred O positive, but among the TM group, there was a stronger preference for O positive (27%) compared to the overall response and to the TS and Other groups (13% and 6%, respectively). This difference may be due to the overall comfort level of practitioners in using Rh-positive blood in potentially Rh-negative recipients based on training and clinical practice experience. The only other ABO/Rh combinations assessed on the survey were A positive and A negative, but very few of the total respondents indicated a preference for those blood groups (5% for A positive and 2% for A negative, respectively). The next most preferred attributes among the total respondents were low-titered (22%), leukoreduced (20%), and leukoreduced WB using a platelet-sparing filter (15%). Interestingly, there was a slightly stronger preference for leukoreduced WB compared to low-titered WB among the TM group (29% vs. 23%). Only 3% of the total respondents indicated that nonleukoreduced WB was preferred. Pathogen-reduced WB (when licensed and available) had a 12% preference among total respondents, but was tied for the second most preferred attribute within the TS group along with low-titered WB (23% for both). The survey respondents were also asked to indicate what isohemagglutinin titer they would consider to be the highest titer acceptable as a low-titer cutoff for WB. The options provided included 100, 150, 200, and 256. The survey also allowed for suggesting another titer under “other” or to indicate this question was not applicable. Surprisingly, 22% of respondents indicated that the titer cutoff was not applicable, but it is unclear if this option was selected because they did not plan to use WB, did not think titer was important, or some other reason. Of the actual titer options proposed, the total respondents indicated the acceptable highest titers in order of preference were 256 (20%), 100 (18%), “other” (17%), 200 (13%), and 150 (8%). Among the 17% of total respondents who indicated “other,” the other suggested titers were 50 and 128. The most selected titer in the TM group was 100 (25%) followed by 200 (12%), excluding the response of “not applicable” (29%). For the TS group, the majority favored 256 (37%), while in the Other group, major preference was equally split between 256 and 200 (31% for both). While there does not appear to be a titer cutoff favored by a large majority of respondents, preferences for titer cutoffs may be influenced by overall preference for using either WB or massive transfusion packs in trauma. Of the total survey respondents who indicated a preference for WB in trauma, 44% indicated a titer of 256 or 200 was acceptable. For those who indicated a preference for massive transfusion packs, most indicated a preference for either 100 (22%), the lowest titer suggested, or that titer was not applicable. It is possible that among those respondents who favor WB, higher titer cutoffs are acceptable because they are more comfortable with these titers based on the published experience of existing WB users.25 Respondents to the survey were also asked to consider specific bleeding situations and patient types where they would consider using WB for hemorrhage control. Some of these included other situations where significant bleeding could occur outside of trauma and different locations for prehospital administration of blood. The top five situations for the use of WB from the total respondents were any patient experiencing massive bleeding (48%), in the air ambulance (46%), in the ground ambulance (32%), for surgical patients (31%), and within the first hour of massive hemorrhage (27%). For both the TS group and respondents who prefer WB, the same five situations are the most mentioned, but use in surgical patients is the third most common choice for both. The Other group also has a similar order of preference to the total overall group, but the fifth most common indication is for acute blood loss of any kind. The top five situations for the TM group is different from the others and includes only certain patients experiencing massive bleeding, in the air ambulance, any patient experiencing massive bleeding, within the first hour of massive bleeding, and within the first 24 hours of massive bleeding. The survey also included questions to assess the percentage of the group O inventory that they would transition to WB, should that be available. The TM responders estimated that they would transition 5% to 10% of their group O inventory to WB. Our survey did not query the maximum number of units the respondents felt confident administering before switching to component therapy. The LTOWB offered by the ARC will be O positive and O positive in citrate phosphate dextrose solution. The product will be manufactured using a platelet-sparing leukoreduction system (Imuflex WB-SP, Terumo BCT). The units will be labeled to reflect that it contains anti-A and anti-B titers less than 200. Each unit can be stored between 1 and 6˚C for up to 21 days without agitation. LTOWB will be manufactured from male or never-pregnant donors to reduce the risk of TRALI. After determining our WB product offering and recognizing that since our initial survey, several civilian reports have been published with better safety data of LTOWB, and the new AABB Standards allowed for the use of low-titered WB without a variance,11,14-16 we were interested in determining the relatively low among TM physicians had the TM physicians from hospitals with Level I trauma by the Of the 30 respondents, 23 TM respondents favored WB for resuscitation of traumatic primarily as part of an Only one stated that they WB for other as The TM physicians from the hospitals that did not to use WB of massive to obtain products with and as the potential This is a from about of 52 TM physicians who favored WB on the Interestingly, of the respondents from pediatric trauma the TM physicians of stated that they would not use WB for pediatric resuscitation, lack of published There are no studies of transfusion resuscitation in pediatric and very limited data the safety of LTOWB in in the of hemorrhagic The survey responses we received suggested that most TM physicians were not to extrapolate from the with to use of WB in trauma for this However, because data supporting balanced component use in are also it to be seen like to more with WB, are included in the of to LTOWB into pediatric A limitation to of our survey results in the that in our first survey, we both Level I and Level II hospitals and did not it to ARC our second survey to TM physicians of only Level I trauma centers by the ARC and we had a relatively high response with our first survey, we did not information on maximum number of WB units that respondents felt were before to component therapy. While there to be interest in using LTOWB in physicians and a growing interest among TM physicians as assessed by the survey, the for the product is only in the A few hospitals by the ARC have protocols using LTOWB in their and of them have differences in the number of units and delivery The number of hospitals beginning to use LTOWB is but the current in the number of units when compared to standard RBC components is However, there are many more parameters for LTOWB for use in hospitals when compared to standard components, even small of units more and to deliver on a The most to delivery of LTOWB units for existing hospital given the small overall unit is to a The order includes a specific number of units on a that replace units that may have been used in an MTP or those that are for LTOWB a of units at the blood may be but for now a would and in of the LTOWB These units could be into RBC components before but these products have a and are more difficult to to Of the TM respondents of our second survey of Level I trauma stated that they would use the WB for trauma until its and the were Only one of the respondents was to use it for to and are when to and LTOWB. Of the specific attributes for LTOWB, group and acute donors are the that must be first before a unit is even that these units are to and the number of units is the used to LTOWB must be to be to blood or where these donors are to for as a first of donors could be one to but this is less and more than on with donors ABO is the are sent to the targeted blood the must the donors to that they have not in the hours platelet and the WB must be from donors who are who have been or who have been and have been and to be for to risk of The ARC does not for in WB only male or never-pregnant donors are for LTOWB the for and of these units is very a donor who does not meet these may be in an LTOWB and be used as LTOWB. To for this a few units may need to be the number to the order to the order can be This practice also for potential unit in of due to to the positive or not the low-titer demonstrated by our survey there is no specific anti-A and anti-B isohemagglutinin titer that all potential users Our of LTOWB have preferred to use 200 as the low-titer Some other and centers have used either or the same low-titer In published studies to there have been no reports of hemolysis from LTOWB transfusion of the low-titer 23 The choice of a titer cutoff also has an on the of donors or units that may be for use as LTOWB. to a donor of low-titer group O donors have that titer can with units must be at When using for low-titer more units are to not as LTOWB. units must be to for this loss as The ARC experience with using a 200 low-titer cutoff for LTOWB has that to of the units for use as LTOWB have been the low-titer some could that of WB is not given the concerns during damage control resuscitation in a of the units a of of the low-titer cutoff does for donors or units with potentially high titers that could hemolysis in even small Additionally, by of WB for use in hemorrhage as common the use of LTOWB for other massive hemorrhage is more The of leukoreduced WB in the Terumo not only at the of but also at the to the for the licensed by the and the WB unit must be leukoreduced at room temperature within hours of This within which to the WB unit must be and to into the and as these are to as products because of the for of In to may other products that for including WB manufactured into WB-derived platelets, fresh plasma, and fresh for other uses trauma. These products must also be within hours of in the of manufactured from a product in for any of these products of and limitation for products is the of the blood from the For large only a that is to the is typically used when product This the donor for these products and in some direct for donors who may be for multiple product of which products are more or must be in to an adequate of all types of In most LTOWB to the top of the compared to the other products because of its and the lack of a product (e.g., platelets for WB-derived platelets or plasma within 24 hours for fresh for LTOWB is timely delivery of the product to the hospital to for the maximum number of days of use with and of other products that may also have limited LTOWB could be and in as little as days and labeled for However, other blood products either with a or that are as fresh and will be used in their may in the order to To these the ARC typically LTOWB units to days after LTOWB units for are closer to days after There are for LTOWB units outside of and in those given all the those units may be by days after for LTOWB to potential with another important RBC units for and units for patients. LTOWB a more or the number of units those units from an donor who are actively for both pediatric needs and used as a for units more to be negative for certain RBC to which patients commonly develop This is one that the ARC is as for these uses for blood is in a blood where overall are on the the and the ARC is about making LTOWB to their hospitals and patients. While data on its clinical is not it is clear that the use of WB the of resuscitation by the transfusion of one of up to with the of platelets, to provide a balanced complement of blood The have no of