The concept of “damage control resuscitation” promotes the use of balanced blood product resuscitation with a high ratio of plasma and platelets to red blood cells.1 In practice, this requires rapidly transfusing multiple blood products, each stored in multiple bags of differing volumes and with various methods of preparation, shelf life, and availability.2,3 Initially, data comparing whole blood (WB) versus component therapy4 were lacking, but the use of WB in modern military medicine has demonstrated both safety as well as a potential survival benefit to using WB over component therapy.5–10 These favorable outcomes in type-specific, warm WB transfusions prompted renewed interest in reexploring the historic practice of cold-stored type-O WB (CWB) to expand the availability of WB for rapid resuscitation of patients with hemorrhagic shock in both military and civilian settings.11–14
Recent civilian studies evaluating both type-specific and type-O CWB have demonstrated both safety and potential benefit for patients in hemorrhagic shock.15–19 However, the civilian experience with CWB remains limited to single-center reports, and questions remain on the safety of this approach, especially regarding the risk of hemolysis, and the efficacy over the current damage control resuscitation approach using blood component therapy (BCT). While these studies present a trend in less overall blood product use, the data are inconsistent because other authors have reported no difference.20 Furthermore, these studies are aimed at evaluating total blood product use over a 24-hour period and not focused on the acute resuscitative period. Similar to overall product use, survival in several studies was also measured at intervals beyond the initial resuscitation.8,10,20 There is no definitive answer in the literature for improvement in mortality at the 24-hour or 30-day periods for recipients of WB, as conflict exists between studies. None of these published studies report on the initial impact of use of WB during the initial resuscitation in terms of mortality.
While hemolytic reactions, overall mortality and 24-hour total product use have all been reported, as well as ongoing studies looking at detailed laboratory evaluation of CWB patients, no study to date highlights solely the initial impact of CWB during the initial resuscitation. We hypothesize that the initial resuscitation with CWB for patients in hemorrhagic shock will result in an increased likelihood of survival versus patients who are transfused with BCT. Furthermore, we hypothesize that patients in the CWB group need fewer ongoing blood transfusions during the initial 4-hour resuscitation and use less blood products overall during the first 24 hours of hospitalization.
Our group performed a dual-center, retrospective case-match study of patients who received CWB between September 2016 and October 2018. Both participating centers are verified Level I trauma centers located in urban areas. The study was approved by the institution's respective institutional review boards.
The CWB was obtained from local Food and Drug Administration-approved suppliers and were from male, group O donors, tested to have an antibody titer less than 200 by immediate spin using A1 and B cells, and prestorage leukoreduced with a platelet sparing filter (Terumo IMUFLEX). A titer less than 200 was chosen to obtain AABB variance approval for use of WB for trauma resuscitation at Cooper University Hospital. Furthermore, a titer less than 200 was used by the blood supplier for this study (American Red Cross) to ensure both a low risk of hemolysis and adequate blood product supply.
WB units were kept for up to 15 days between 1°C and 6°C (stored in citrate-phosphate-dextrose), at which point they were packed down for use as a red cell product or discarded if not utilized.
Criteria to receive CWB were standardized across both institutions and included male patients 16 years or older, female patients older than 50 years, any in-hospital systolic blood pressure less than 90 mm Hg, and an identifiable source of hemorrhage. An identifiable source of hemorrhage was defined as a positive focused assessment with sonography in trauma (FAST), hemothorax demonstrated on chest X-ray or following thoracostomy tube insertion, extremity tourniquet in place, or other external signs of bleeding. Patients who underwent prehospital cardiopulmonary resuscitation or cardiopulmonary resuscitation in the trauma bay prior to blood transfusion were excluded, and patients with a known or suspected severe traumatic brain injury (TBI) were excluded from CWB transfusion. Per the hospitals guidelines at the time of the study, younger female patients were excluded from receiving CWB and therefore not included in the study. Each institution had 2 units to 4 units of CWB immediately available. The decision to transfuse CWB was left to the clinical discretion of the attending trauma surgeon based on whether the patient met the aforementioned clinical criteria. Furthermore, the decision to continue the transfusion of CWB beyond the first unit was left to the discretion of the surgeon. Eligible patients had their demographic, clinical, and treatment information collected through a standard form. Outcome and additional clinical information were retrospectively collected via a chart abstraction of the electronic medication record. In addition, a blood bank quality assurance review on each case looked for evidence of incompatibility or hemolysis in a posttransfusion specimen through evaluation of chemistry potassium and hemolytic indices.
All patients who received CWB and were retrospectively deemed appropriate candidates based on the inclusion and exclusion criteria. They were subsequently matched via a 1:2 propensity match against any trauma patient who received 1 unite or greater of packed red cells (PRBCs). Patients were matched on arrival heart rate, arrival systolic blood pressure, and mechanism of injury (MOI). Fisher's exact test and Wilcoxon rank sums test were used to test for group differences between categorical and continuous variables respectively including demographic characteristics, blood product utilization, length of stay, and mortality. Statistical significance was defined as p ≤ 0.05. SAS v9.4 (SAS Institute, Cary, NC) was used for all analyses. Our primary endpoint was trauma bay mortality. Secondary endpoints included 30-day mortality, 4-hour and 24-hour posttransfusion laboratory values, and overall blood product utilization.
During the study period 11,128 patients were evaluated in the trauma bay of both participating institutions with 5% (n = 562) requiring blood transfusions during their initial resuscitation. A total of 107 patients received CWB during the study period with 16 patients being excluded due to the inability to adequately match these patients to the control patients. The remaining 91 patients were matched to 182 BCT patients for final analysis (Fig. 1). Injury Severity Score (ISS), MOI, GCS, vital signs, and initial laboratory values were not different between groups (all p > 0.05) (Table 1 and Table 2).
Of the eligible patients who received CWB, 55% (n = 50) received one unit, 41% (n = 37) received two units, and the remaining received greater than two units (n = 4). Patients were converted to standard component therapy following the initial CWB transfusion as per surgeon discretion based on the limited availability of CWB. There was no difference in the number of patients who went directly from the trauma bay to the OR in either group (BCT, 106/181 (59%) vs. CWB, 60/91 (66%); p = 0.292) or from the trauma bay to Interventional Radiology (BCT, 5/181 (3%) vs. 2/91 (2%); p = 1.0). Patients who were transfused initially with CWB were more likely to survive their trauma bay resuscitation demonstrated by an 8.8% mortality in the BCT compared with a 2.2% mortality in the CWB group (p = 0.039). There was no difference in the 24-hour or the 30-day mortality between the groups (p > 0.05) (Fig. 2). The most common cause of death among all patients was acute hemorrhage, affecting 70% and 75% of all death in their respective groups. Other causes of death were due to TBI, multisystem organ failure, or sepsis. There was no evidence of hemolytic or other transfusion reactions in either group, and no deaths were directly attributable to blood product administration. There was one case of transfusion-associated circulatory overload (TACO) in the CWB group. A young male patient who suffered multiple torso gunshot wounds resulting in a tension hemothorax and a spinal cord injury was massively resuscitated with blood products (CWB followed by PRBC, fresh frozen plasma (FFP), and cell-saver) as well as crystalloid (>7 L) during his initial resuscitation and operating room course, resulting in progressive hypoxemia and eventual veno-venous extracorporeal membrane oxygenation. The patient recovered and was discharged from the hospital.
The CWB patients had higher mean hemoglobin (BCT, 10 ± 2 g/dL vs. CWB, 11 ± 2 g/dL; p = 0.004) and mean hematocrit (BCT, 29.2 ± 6.1% vs. CWB, 32.1 ± 5.9%; p = 0.006) at 24 hours, while there was no difference in the overall platelet count between the groups (Table 2). No differences were observed in the number of units of resuscitative adjuncts given, such as prothrombin complex concentrate or fibrinogen, between groups (all p > 0.05). Overall, we identified no differences in the total amount of blood products transfused between the two groups either at the 4-hour period or the 24-hour period. While there was wide variation in total amount of product transfused in both groups (Table 3), none of these values reached statistical significance.
Subset analysis of patients who received massive transfusion (MT), defined as receiving greater than 4 units of PRBCs within the first hours from arrival or greater than 10 units of PRBCs within the first 24 hours, was performed. A total of 123 (45%) patients in the study received a MT (MT-BCT, n = 81; MT-CWB, n = 42). Of these 123 patients, 77 (63%) had a penetrating MOI. The MT patients were more likely to have a positive FAST (51%) when compared with non-MT patients (27%) (p = 0.001). The MT patients had a higher ABC score than non-MT patients (1.94 ± 0.9 vs. 1.24 ± 1.0; p < 0.001), received more PRBC, plasma, and platelet transfusions at both the 4-hour and 24-hour time frames (all p < 0.001), and had a higher 30-day mortality (40% vs. 15%;p < 0.001).
Further analysis of the MT group was completed with attention to comparing the MT BCT (MT-BCT) and MT CWB (MT-CWB) groups. There was no difference in baseline vitals or demographics between the MT-BCT and MT-CWB groups (Table 1). Patients in the MT-CWB group had a lower platelet count and longer PTT on arrival, but no difference at the 4-hour and 24-hour periods. Hemoglobin (Hgb) and hematocrit (Hct) at the 24-hour period were higher in the MT-CWB group compared with the MT-BCT group (Table 4). There was no difference in the 30-day mortality between the MT-BCT and MT-CWB groups (41% vs. 38%;p = 0.839).
To our knowledge, this is the first multicenter study on initial WB resuscitation in civilian trauma patients presenting with hemorrhagic shock. Our data demonstrate that type-O low antibody titer CWB is associated with improved trauma bay survival in these patients. The CWB resuscitation also resulted in a higher mean hemoglobin at 24 hours suggesting a hemostatic benefit. Finally, CWB appears to be safe with no evidence of hemolysis and only one transfusion-associated complication.
Whole blood has been a standard means of resuscitation for injured soldiers in hemorrhagic shock for over 100 years, extending back to combat in World War I.6,21 The use of WB in military settings continued through the middle of last century with a large number of transfusions occurring in World War II and extending into the conflicts in Korea and Vietnam.3 During this time, there did not appear to be any documented fatalities from this method of transfusion, but data may have not been properly collected due to the use of the WB in austere environments, as well as other priorities of the military medical team. The reason for the use of WB in these settings was one largely based on convenience and availability. Authors have described the method of the “walking blood bank”22,23 whereby uninjured soldiers are readily available to donate their blood emergently to an injured colleague. The process of fractionating blood products to extend shelf life and allow for component-specific transfusion based on component deficiencies lead to a decreased availability and use of WB. While BCT has become the standard method of storing, distributing, and transfusion blood products following the Vietnam War, resurgence of the use of WB reemerged during the recent military conflicts in the Middle East.24
None of the recipients of WB in our study had any demonstrated transfusion reaction or negative sequelae attributed to the transfusion of CWB alone. Previous authors have also failed to identify transfusion reactions nor hemolysis with the administration of multiple units of WB, consistent with our own findings.14,16,17,25 One patient in the CWB group did develop TACO which is a known complication from massive resuscitation.26,27 To mitigate the risk of TACO, it is important to note the volume differences between CWB (approximately 500 mL) and PRBC (approximately 250–350 mL) when starting a WB program and to encourage frequent reassessment of bleeding rates and resuscitation rates during WB resuscitation.
No difference in 30-day mortality was identified between the groups and is consistent with other published work. Some previous civilian data have even suggested a trend toward improved survival with the use of WB,11 although this was not seen in our study. Military data have had more success in identifying long-term improvement in mortality beyond the initial 24-hour period for several possible reasons, including the use of larger relative volumes of WB to components and the availability of warm, fresh WB without any significant storage lesion.8,10 The strength of our work is that we were able to show an initial survival benefit in the CWB group compared with the BCT group, despite both groups arriving to the trauma bay with similar hemodynamic parameters and initial laboratory values. Our data demonstrate that patients who receive CWB as their initial blood product were more likely to survive their trauma bay resuscitation, and this survival benefit matched the CWB transfusion timing.
In the subset of MT patients, the lack of difference in mortality among these two groups may be due to the benefits of CWB being masked in patients who are transfused such large amounts of component blood products. Differences in long-term survival may be more apparent in patients who have ongoing CWB transfusion as opposed to limited use as the initial blood product given.
Our study is not without its limitations. While our matched populations were similar in terms of MOI, arrival GCS, and shock index, we saw a large variability in the number of units of fractionated blood products given in both groups. This variability was evident both within the groups and across the WB and BCT groups. In addition, based on our power analysis, a much larger study would be required to detect a smaller but still clinically significant mortality benefit at the 24-hour and 30-day periods. Ongoing clinical studies including Shock, WB, and Assessment of TBI (ClinicalTrials.gov Identifier: NCT03402035) should further elucidate a survival benefit to type-O low antibody titer CWB.
We demonstrate that patients who were resuscitated with WB rather than standard BCT during their initial trauma resuscitation were less likely to die in the trauma bay. Study patients also had higher mean hemoglobin and hematocrit values at 24 hours following their initial resuscitation. Further, there was no difference in platelet count despite literature raising concern over the use of platelet sparing filters in the processing of WB. Our study adds to the growing body of literature that, complemented by military WB data, should shift the standard of care to CWB as the first-line transfusion product for patients in hemorrhagic shock.
J.P.H. participated in the study design, literature review, data analysis, article writing, critical review. J.W.C. participated in the study design, literature review, data analysis, article writing, critical review. C.Z. participated in the study design, literature review, data collection, data analysis, article writing, critical review. J.S.R. participated in the literature review, data collection. S.A.M. participated in the data collection, data analysis, critical review. A.J.Y. participated in the data collection, data analysis, critical review. M.S. participated in the data collection, data analysis, critical review. J.F.G. participated in the data collection, data analysis, critical review. F.F. participated in the data collection, data analysis, critical review. A.M. participated in the data collection, data analysis, critical review. J.F.G. participated in the data analysis, critical review. M.J.S. participated in the study design, data analysis, article writing, critical review. J.P. participated in the study design, critical review.
Dr. Joshua Hazelton is the Chief Medical Officer for Z-Medica. This relationship is not in conflict with the subject matter of this article.
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The authors have performed a retrospective analysis of 91 patients who received liquid cold stored whole blood (CWB) at 2 institutions. These patients are matched 1:2 to a similar group of patients who received blood component therapy (BCT). The authors’ main conclusion was that trauma bay mortality was less in patients who received CWB versus BCT (8.8% vs 2.2%). The study is interesting and adds to the early growing body of literature concerning CWB. However, like any good study, it raises more questions than it provides answers.
It is not clear why some of these similarly matched patients received CWB and some received BCT. Could the choice of blood therapy be associated with a bias? The authors do not report what the trauma bay time was and it is possible that whole blood patients left the trauma bay earlier and death was just being displaced to a different area. The authors do provide survival curves and there does appear to be an association of CWB with later death in all patients but not in the subset of patients who received a massive transfusion. Similarly, there was no overall survival benefit seen in massive transfusion patients. Additional points of interest include the CWB group only received a median of 1 unit and there was no difference in component therapy delivered between the groups. Furthermore, there was no difference in 24 hour or 30-day survival. Ultimately, one must question if there was any true benefit of administering CWB at all in this study. Hopefully, studies reporting on larger volume transfusions with CWB will lead to the answers this study raises.
–Martin A. Schreiber, MD FACS FCCM Oregon