A review and analysis of outcomes in randomized clinical trials of plasma transfusion in patients with bleeding or for the prevention of bleeding: The BEST collaborative study.

BACKGROUND: Previous systematic reviews have revealed an inconsistency of outcome definitions as a major barrier in providing evidence-based guidance for the use of plasma transfusion to prevent or treat bleeding. We reviewed and analyzed outcomes in randomized controlled trials (RCTs) to provide a methodology for describing and classifying outcomes. STUDY DESIGN AND METHODS: RCTs involving transfusion of plasma published after 2000 were identified from a prior review (Yang 2012) and combined with an updated systematic literature search of multiple databases (July 1, 2011 to January 17, 2023). Inclusion of publications, data extraction, and risk of bias assessments were performed in duplicate. (PROSPERO registration number is: CRD42020158581). RESULTS: In total, 5579 citations were identified in the new systematic search and 22 were included. Six additional trials were identified from the previous review, resulting in a total of 28 trials: 23 therapeutic and five prophylactic studies. An increasing number of studies in the setting of major bleeding such as in cardiovascular surgery and trauma were identified. Eighty-seven outcomes were reported with a mean of 11 (min-max. 4-32) per study. There was substantial variation in outcomes used with a preponderance of surrogate measures for clinical effect such as laboratory parameters and blood usage. CONCLUSION: There is an expanding literature on plasma transfusion to inform guidelines. However, considerable heterogeneity of reported outcomes constrains comparisons. A core outcome set should be developed for plasma transfusion studies. Standardization of outcomes will motivate better study design, facilitate comparison, and improve clinical relevance for future trials of plasma transfusion.

The safety of ABO minor incompatible platelets transfusions using a rapid infuser.

BACKGROUND: Administering platelets through a rapid infuser is proven to be safe. However, the clinical significance of infusing ABO-incompatible platelets with red blood cells (RBCs) in a rapid infuser remains unclear. There is a theoretical risk that isoagglutinin in the plasma of a platelet unit can interact with RBCs and induce hemolysis. MATERIALS AND METHODS: Seven in vitro studies were performed including five cases (type A RBCs and type O platelets) and two controls (type A RBCs and platelets). Anti-A titers were measured in platelet units. An RBC unit and a platelet unit were mixed in the rapid infuser reservoir and incubated for 30 min. The primary outcome was the presence of hemolysis based on the following parameters: free hemoglobin concentration, hemolysis check, direct antiglobulin test (DAT), and direct agglutination. RESULTS: The post-mix DAT was positive for IgG in all test samples (5/5), and weakly positive for complement in 3/5. The changes in free Hb in test cases between measured and calculated post-mix spanned -2.2 to +3.4 mg/dL. Post-mix hemolysis check was negative in 3/5 and slightly positive in 2/5 cases, with no significant differences compared to the control case. Anti-A titers ranged from 16 to 512 and were not associated with hemolysis. All samples were negative for direct agglutination. CONCLUSION: Our study suggested that mixing ABO-incompatible platelets with RBCs in a rapid infuser does not induce in vitro hemolysis. These findings support the use of rapid infusers regardless of platelet compatibility in support of hemostatic resuscitation.

Hypocalcaemia upon arrival (HUA) in trauma patients who did and did not receive prehospital blood products: a systematic review and meta-analysis.

PURPOSE: Hypocalcaemia upon arrival (HUA) to hospital is associated with morbidity and mortality in the trauma patient. It has been hypothesised that there is an increased incidence of HUA in patients receiving prehospital transfusion as a result of citrated blood products. This research aimed to determine if there was a difference in arrival ionised calcium (iCa) levels in trauma patients who did and did not receive prehospital transfusion. METHODS: We conducted a systematic review and meta-analysis of patients with an Injury Severity Score (ISS) > / = 15 and an iCa measured on hospital arrival. We then derived mean iCa levels and attempted to compare between-group variables across multiple study cohorts. RESULTS: Nine studies reported iCa on arrival to ED, with a mean of 1.08 mmol/L (95% CI 1.02-1.13; I2 = 99%; 2087 patients). Subgroup analysis of patients who did not receive prehospital transfusion had a mean iCa of 1.07 mmol/L (95% CI 1.01-1.14; I2 = 99%, 1661 patients). Transfused patients in the 3 comparative studies had a slightly lower iCa on arrival compared to those who did not receive transfusion (mean difference - 0.03 mmol/L, 95% CI - 0.04 to - 0.03, I2 = 0%, p = 0.001, 561 patients). CONCLUSION: HUA is common amongst trauma patients irrespective of transfusion. Transfused patients had a slightly lower initial iCa than those without transfusion, though the clinical impact of this remains to be clarified. These findings question the paradigm of citrate-induced hypocalcaemia alone in trauma. There is a need for consensus for the definition of hypocalcaemia to provide a basis for future research into the role of calcium supplementation in trauma.

Massive transfusion protocol reactivation as a novel marker of physician team under-triage after injury.

BACKGROUND: Large trauma centers have protocols for the assessment of injury and triaging of care with attempts to over-triage to ensure adequate care for all patients. We noted that a significant number of patients undergo a second massive transfusion protocol (MTP) activation in the first 24 h of care and conducted a retrospective cohort study of patients involved over a 3-year period. METHODS: Transfusion service records of MTP activations 2019-2021 were linked to Trauma Registry records and divided into cohorts receiving a single versus a reactivation of the MTP. Time of activation and amounts of blood products issued were linked to demographic, injury severity, and outcome data. Categorical and continuous data were compared between cohorts with chi-squared, Fisher's, and Wilcoxan tests as appropriate, and multivariable regression models were used to seek interactions (p < .05). RESULTS: MTP activation was recorded for 1884 acute trauma patients over our 3-year study period, 142 of whom (7.5%) had reactivation. Factors associated with reactivation included older age (46 vs. 40 years), higher injury severity score (ISS, 27 vs. 22), leg injuries, and presentation during morning shift change (5-7 a.m., 3.3% vs. 7.7%). Patients undergoing MTP reactivation used more RBCs (5 U vs. 2 U) and had more ICU days (3 vs. 2). CONCLUSIONS: Older patients and those presenting during shift change are at risk for failure to recognize their complex injury patterns and under-triage for trauma care. The fidelity and granularity of transfusion service records can provide unique opportunities for quality assessment and improvement in trauma care.

Novel method for determining when a field-collected donor unit is sufficiently full.

BACKGROUND: Whole blood (WB) collections can occur downrange for immediate administration. An important aspect of these collections is determining when the unit is sufficiently full. This project tested a novel method for determining when a field collection is complete. METHODS: The amount of empty space at the top of WB units, destined to become LTOWB or separated into components, that were collected at blood centers or hospitals was measured by holding a WB unit off the ground and placing the top of a piece of string where the donor tubing entered the bag. The string was marked where it intersected the top of the column of blood in the bag and measured from the top. The WB units were also weighed. RESULTS: A total of 15 different bags, two of which were measured in two different filling volumes, from 15 hospitals or blood centers were measured and weighed. The most commonly used blood bag, Terumo Imuflex SP, had a median string length of 9 mm (range: 2-24 mm) and weighed a median of 565.1 g (range: 524.8-636.7 g). CONCLUSION: Pieces of string can be precut to the appropriate length depending on the type of bag before a mission where field WB collections might be required and a mark placed on the bag before the collection commences to indicate when the unit is full.

Age, admission platelet count, and mortality in severe isolated traumatic brain injury: A retrospective cohort study.

BACKGROUND: We asked whether patients >50 years of age with acute traumatic brain injury (TBI) present with lower platelet counts and whether lower platelet counts are independently associated with mortality. METHODS: We combined trauma registry and laboratory data on a retrospective cohort of all patients ≥18 years of age admitted to our Level 1 US regional trauma center 2015-2021 with severe (Head Abbreviated Injury Score [AIS] ≥3), isolated (all other AIS <3) TBI who had a first platelet count within 1 h of arrival. Age and platelet count were assessed continuously and as groups (age 18-50 vs. >50, platelet normals, and at conventional transfusion thresholds). Outcomes such as mean admission platelet counts and in-hospital mortality were assessed categorically and with logistic regression. RESULTS: Of 44,056 patients, 1298 (3%, median age: 52 [IQR 33,68], 76.1% male) met all inclusion criteria with no differences between younger and older age groups for (ISS; 18 [14,26] vs. 17 [14,26], p = .22), New ISS (NISS; 29 [19,50] vs. 28 [17,50], p = .36), or AIS-Head (4 [3,5] vs. 4 [3,5]; p = .87). Patients aged >50 had lower admission platelet counts (219,000 ± 93,000 vs. 242,000 ± 76,000/µL; p < .001) and greater in-hospital mortality (24.5% vs. 15.6%, p < .001) than those 18-50. In multivariable regression, firearms injuries (OR9.08), increasing age (OR1.004), NISS (OR1.007), and AIS-Head (OR1.05), and decreasing admission platelet counts (OR0.998) were independently associated with mortality (p < .001-.041). Platelet transfusion in the first 4 h of care was more frequent among older patients (p < .001). CONCLUSIONS: Older patients with TBI had lower admission platelet counts, which were independently associated with greater mortality.

Ultramassive Transfusion for Trauma in the Age of Hemostatic Resuscitation: A Retrospective Single-Center Cohort From a Large US Level-1 Trauma Center, 2011-2021.

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. In the last 40 years, ultramassive transfusion (UMT; ≥20 units of red blood cells [RBCs]/24 hours) for trauma has been associated with 50% to 80% mortality; the question remains as to whether the increasing number of units transfused in urgent resuscitation is a marker of futility. We asked whether the frequency and outcomes of UMT have changed in the era of hemostatic resuscitation. METHODS: We performed a retrospective cohort study of all UMTs in the first 24 hours of care over an 11-year period at a major US level-1 adult and pediatric trauma center. UMT patients were identified, and a dataset was built by linking blood bank and trauma registry data, then reviewing individual electronic health records. Success in achieving hemostatic proportions of blood products was estimated as (units of plasma + apheresis-platelets-in-plasma + cryoprecipitate-pools + whole blood]/[all units given] ≥0.5. Demographics, injury type (blunt or penetrating), severity (Injury Severity Score [ISS]), severity pattern (Abbreviated Injury Scale score for head [AIS-Head] ≥4), admitting laboratory, transfusion, selected emergency department interventions, and discharge status were assessed using χ2 tests of categorical association, the Student t-test of means, and multivariable logistic regression. P <.05 was considered significant. RESULTS: Among 66,734 trauma admissions from April 6, 2011 to December 31, 2021, we identified 6288 (9.4%) who received any blood products in the first 24 hours, 159 of whom received UMT (0.23%; 154 aged 18-90 + 5 aged 9-17), 81% in hemostatic proportions. Overall mortality was 65% (n = 103); mean ISS = 40; median time to death, 6.1 hours. In univariate analyses, death was not associated with age, sex, or more RBC units transfused beyond 20 but was associated with blunt injury, increasing injury severity, severe head injury, and failure to receive hemostatic blood product ratios. Mortality was also associated with decreased pH and evidence of coagulopathy at admission, especially hypofibrinogenemia. Multivariable logistic regression showed severe head injury, admission hypofibrinogenemia and not receiving a hemostatic resuscitation proportion of blood products as independently associated with death. CONCLUSIONS: One in 420 acute trauma patients at our center received UMT, a historically low rate. A third of these patients lived, and UMT was not itself a marker of futility. Early identification of coagulopathy was possible, and failure to give blood components in hemostatic ratios was associated with excess mortality.

Effects of pre-freeze pathogen reduction with riboflavin and UV light on red cells stored post-thaw in AS-3 additive solution.

BACKGROUND: Pathogen reduction technology (PRT) may improve the safety of RBCs for transfusion. As the Czech Republic considers PRT, we asked what effects riboflavin and UV light PRT pre-freezing has on the post-thaw recovery and properties of cryopreserved RBCs (CRBCs) after deglycerolization and liquid storage. STUDY DESIGN AND METHODS: 24 Group O whole blood (WB) units were leukoreduced and then treated with riboflavin and UV light PRT (Mirasol, Terumo BCT, USA) before cryopreservation (T-CRBC); 20 similarly-collected units were untreated controls (C-CRBC). Units were processed to RBCs and then cryopreserved with 40% glycerol (wt/vol), frozen at -80°C, stored >118 days, reconstituted as deglycerolized RBC units in AS-3, and stored at 4 ± 2°C for 21 days. One treated unit sustained massive hemolysis during the post-thaw wash process and was removed from data analysis. The remaining units were assessed pre-PRT, post-PRT, and post-thaw-wash on days 0, 7, 14, and 21 for hematocrit, volume, hemoglobin per transfusion unit, pH, % hemolysis, hemoglobin in the supernatant, potassium, phosphorus, NH3 , osmolality, ATP, and 2,3-diphosphoglycerate. RESULTS: PRT with leukoreduction caused a 5% loss of RBC followed by a 24% freeze-thaw-wash related loss for a total 28% loss but treated units contained an average of 45 g of hemoglobin, meeting European Union guidelines for CRBC. T-CRBCs displayed higher post-wash hemolysis, potassium, and ammonia concentrations, and lower ATP at the end of storage. CONCLUSIONS: Cryopreserved RBCs from Riboflavin and UV light-treated WB meet the criteria for clinical use for 7 days after thawing and provide additional protection against infectious threats.

Transfusion of ABO-group identical red blood cells following uncrossmatched transfusion does not lead to higher mortality in civilian trauma patients.

BACKGROUND: Questions persist about the safety of switching non-group O recipients of group O uncrossmatched red blood cells (RBC) or low titer group O whole blood (LTOWB) to ABO-identical RBCs during their resuscitation. METHODS: The database of an earlier nine-center study of transfusing incompatible plasma to trauma patients was reanalyzed. The patients were divided into three groups based on 24-h RBC transfusion: (1) group O patients who received group O RBC/LTOWB units (control group, n = 1203), (2) non-group O recipients who received only group O units (n = 646), (3) non-group O recipients who received at least one unit of group O and non-group O units (n = 562). Fixed marginal effect of receipt of non-O RBC units on 6- and 24-h and 30-day mortality was calculated. RESULTS: The non-O patients who received only group O RBCs received fewer RBC/LTOWB units and had slightly but significantly lower injury severity score compared to control group; non-group O patients who received both group O and non-O units received significantly more RBC/LTOWB units and had a slightly but significantly higher injury severity score compared to control group. In the multivariate analysis, the non-O patients who received only group O RBCs had significantly higher mortality at 6-h compared to the controls; the non-group O recipients of O and non-O RBCs did not demonstrate higher mortality. At 24-h and 30-days, there were no differences in survival between the groups. CONCLUSION: Providing non-group O RBCs to non-group O trauma patients who also received group O RBC units is not associated with higher mortality.

Cryopreservation of apheresis platelets treated with riboflavin and UV light.

BACKGROUND: Pathogen reduction technology (PRT) is increasingly used in the preparation of platelets for therapeutic transfusion. As the Czech Republic considers PRT, we asked what effects PRT may have on the recovery and function of platelets after cryopreservation (CP), which we use in both military and civilian blood settings. STUDY DESIGN AND METHODS: 16 Group O apheresis platelets units were treated with PRT (Mirasol, Terumo BCT, USA) before freezing; 15 similarly collected units were frozen without PRT as controls. All units were processed with 5-6% DMSO, frozen at - 80 °C, stored > 14 days, and reconstituted in thawed AB plasma. After reconstitution, all units were assessed for: platelet count, mean platelet volume (MPV), platelet recovery, thromboelastography, thrombin generation time, endogenous thrombin potential (ETP), glucose, lactate, pH, pO2, pCO2, HCO3, CD41, CD42b, CD62, Annexin V, CCL5, CD62P, and aggregates > 2 mm and selected units for Kunicki score. RESULTS: PRT treated platelet units had lower platelet number (247 vs 278 ×109/U), reduced thromboelastographic MA (38 vs 62 mm) and demonstrated aggregates compared to untreated platelets. Plasma coagulation functions were largely unchanged. CONCLUSIONS: Samples from PRT units showed reduced platelet number, reduced function greater than the reduced number would cause, and aggregates. While the platelet numbers are sufficient to meet the European standard, marked platelets activation with weak clot strength suggest reduced effectiveness.

Drivers of blood use in paediatric trauma: A retrospective cohort study.

OBJECTIVES: We asked whether age or injury severity drives blood use patterns in paediatric trauma. BACKGROUND: Transfusion for paediatric trauma care is complicated by known developmental differences in coagulation and injury patterns. METHODS/MATERIALS: We linked 10 years of Trauma Registry and blood bank data, 2011-2020, for all acute trauma patients aged <18 treated at a large US Level 1 adult and paediatric trauma centre. We assessed age, injury severity and mechanism for association with any blood use, use within the first 4 h of care, and resuscitation balance, using grouped-age Chi-square and multivariable regression models. RESULTS: Of 60 066 acute trauma arrivals at our centre in the study period, 7979 (13.3%) met inclusion criteria. Median age (IQR) was (7.6[2.4-14.5]); 6230(78.1%) were < 15 years old; 590(7.4%) received any blood products; and 128(1.6%) died. Among the 5842(73.2%) patients with impact-related injury, 2023(34.6%) met standards for severe injury (New Injury Severity Score [NISS] ≥ 16); 541(9.3%) were transfused, 171(31.6%) in the first 4 h and 72(13.3%) using ≥3 units of products in the first hour. Firearms injuries were the most severe, most likely to be transfused urgently, using balanced resuscitation, and to die (p < 0.001 for all). Multivariable logistic regression showed any blood use as strongly associated with NISS (Odds Ratio 1.124832; p < 0.0001; 95% CI 1.11-1.13) but not with age (OR 0.98; p = 0.07; 95% CI 0.96-1.00). CONCLUSION: Transfusion in the care of acute paediatric trauma is uncommon (<10% of injured minors in our cohorts received any blood products), and injury severity, particularly firearms injury-not age-drove transfusion.