Abstract
Background
Both group A and AB plasma have been approved for emergency release transfusion in acutely bleeding trauma patients prior to blood grouping being performed. The safety profile associated with this practice has not been well characterized, particularly in patients requiring massive transfusion.
Methods
This secondary analysis of the PROPPR trial examined whether exposure to group A emergency release plasma (ERP) was non-inferior to group AB ERP. We also examined patients whose blood groups were compatible versus incompatible with group A ERP. Outcomes included 30-day mortality and complication rates including systemic inflammatory response syndrome (SIRS), infection, renal injury, pulmonary dysfunction, and thromboembolism.
Results
Of the 680 patients predicted to receive a massive transfusion, 584 (85.9%) received at least 1 unit of ERP. Of the 584 patients analyzed, 462 (79.1%) received group AB and 122 (20.9%) received group A ERP. Using a hazard ratio (HR) of 1.35 as the non-inferiority margin, transfusion with group A versus group AB ERP was not associated with increased thromboembolic rates (HR 0.52, 95% CI 0.31–0.90). Mortality (HR 1.15, 95%CI 0.91–1.45) and non-fatal complication rates (HR 1.24, 95% CI 0.87–1.77) were inconclusive. In the subgroup analysis, transfusion with incompatible ERP (group B or AB patients receiving group A ERP) was not associated with increased nonfatal complications (HR=1.02, 95%CI 0.80–1.30). There were no reported hemolytic transfusion reactions.
Conclusion
The use of emergency release plasma is common in patients requiring massive transfusion and facilitates the rapid balanced resuscitation of patients who have sustained blood loss. Group A emergency release plasma is an acceptable option for patients requiring massive transfusion, especially if group AB emergency release plasma is not readily available.
Study type
Prognostic Level III, Therapeutic / Care Management Level III
Keywords: Emergency release plasma, massive transfusion, PROPPR, transfusion, plasma
Background
The early transfusion of plasma, platelets, and red blood cells (pRBCs) in a balanced ratio has been championed as a best-practice transfusion strategy for trauma patients who have sustained significant blood loss.1 The early delivery of blood components in a balanced fashion has become the primary objective of contemporary massive transfusion protocols.
The early use of plasma during the resuscitation process demands the immediate availability of pre-thawed, dried, or liquid plasma.2–5 The absence of immediately available plasma products requires on-demand thawing of plasma by the blood bank. This leads to a delay of 20–30 minutes for plasma to be thawed, which can significantly alter the outcome of patients in hemorrhagic shock.6 Plasma compatibility with a recipient is conventionally governed by the antibodies contained within the donor’s plasma. Group AB donors typically produce neither anti-A nor anti-B antibodies within their plasma, making them a universal donor. However, maintaining an inventory of pre-thawed group AB plasma is logistically problematic, given that the AB blood group comprises only approximately 4% of the United States blood supply. To alleviate the inherent supply constraints imposed by group AB plasma, there has been increased interest in the use of group A plasma as an alternative universal donor plasma.7–9
Early reports from Zielinski et. al. analyzed the use of group A plasma prior to type and screen in blunt injured patients not requiring massive transfusion, and more recently retrospective multicenter studies have concluded that the use of group A emergency release plasma appears to be non-inferior to group AB emergency release plasma.7,9–11 The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial provides a robust dataset, focused specifically on blood product transfusion, with prospectively collected outcomes data, an area that is notoriously under captured in retrospectively based data. As there were site specific differences in the type of emergency release plasma utilized at participating trauma centers, with centers providing blood products prepared by each site’s blood bank and delivered to the bedside within 10 minutes per the study’s protocol, we investigated whether differences in morbidity and mortality exist in massive transfusion patients receiving group A versus group AB ERP. We hypothesized that utilizing group A plasma as an ERP would not be associated with increased morbidity or mortality compared to group AB plasma.
Methods
The data analyzed in the present study were collected prospectively as part of the previously reported PROPPR trial. The PROPPR trial was a pragmatic, phase 3, multisite, randomized clinical trial that compared the effectiveness and safety of a 1:1:1 transfusion ratio of plasma, platelets, and RBCs to a 1:1:2 ratio. In total, 680 severely injured patients predicted to receive a massive transfusion (Assessment of Blood Consumption [ABC] score ≥3) admitted to twelve level I North American trauma centers over a 16 month period between August 2012 and December 2013 were randomized and followed to hospital discharge or up to the 30th day of hospitalization. The primary analysis of the trial and details of the study protocol have been reported previously.1,12
For the present study, patients who received at least one unit of emergency release plasma (ERP) were included in the study analysis. ERP was defined as plasma delivered and infused prior to the patient’s ABO group being known. Of the twelve study sites, nine transfused group AB ERP, two transfused group A ERP (one site provided plasma with low measured anti-B titers at a 1:25 dilution while the other site did not measure anti-B titers), and one site transfused a combination of group A and group AB ERP with unmeasured anti-B titers.4
The primary outcome of interest was in-hospital mortality at 30 days after admission. Secondary outcomes included nonfatal complications, systemic inflammatory response syndrome (SIRS), pulmonary dysfunction (acute lung injury or acute respiratory distress syndrome), acute kidney injury, infection (sepsis, urinary tract/wound/line infection, and ventilator-associated pneumonia), thromboembolic events (TE) (pulmonary embolism, stroke, deep vein thrombosis, and myocardial infarction). Several variables were dichotomized using clinically relevant cutoff points: systolic blood pressure (< 90 mmHg vs. ≥ 90 mmHg), Glasgow Coma Scale score (< 9 vs. ≥ 9), and injury severity score (≤ 25 vs. > 25).
Statistical analysis
Study groups were compared for differences in clinical characteristics, transfusion requirements, and outcomes of interest. Bivariate chi-square (χ2) analysis was performed to test differences in proportions and unpaired Student’s t-test or Wilcoxon test to compare differences between means and medians, respectively. In the PROPPR trial design, there was an expected 12% difference in 30-day mortality between the trial’s two study arms.1 With conservative consideration, the non-inferiority margin was set as 1.35, which represented an 8% difference in 30-day mortality (24% vs 32%). Cox proportional hazard (PH) models were used to compare outcome rates between treatment groups by calculating hazard ratios (HR). Multivariable models were built for two analyses (1) group A versus group AB ERP and (2) identical versus non-identical type A ERP. Except for 30 day mortality, death was treated as a competing risk for all outcomes. Covariates included in the multivariable models included age, ISS > 25, GCS < 9, 3-hour red blood cell (RBC) transfusion, and 3-hour crystalloid infusion. Variables not acting as a confounder and with p >0.05 were excluded from the final model. These additional covariates tested included ED hemodynamics (systolic blood pressure and pulse rate), positive focused assessment of sonography for trauma, randomization group (1:1:1 vs. 1:1:2), injury mechanism (blunt versus penetrating), emergency surgery (any operation required within 6 hours of ED arrival), number of units of transfused emergency release plasma, 3-hour platelet transfusion, and 3-hour plasma transfusion. To take into account correlation of patients clustered in trauma centers, a robust sandwich covariance matrix estimate was used to account for intracluster dependence within trauma centers for analysis (1). Results were reported as raw and adjusted hazard ratios (aHR) [95% confidence intervals (95% CI)]. Variables with 95% CI range less than 1.35 were considered significant. For each model the PH assumption was checked using scaled Schoenfeld residuals. Power analysis for 30-day mortality was performed using PASS14. All other statistical analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC).
Results
Of the 680 patients included in the PROPPR trial analysis, 584 (85.6%) received at least one unit of emergency release plasma. Of these, 122 (20.9%) received group A ERP and 462 (79.1%) received group AB ERP. The median number of transfusions of ERP was 4 units (IQR 2–7) and there was no difference in the number of transfusions of ERP between patients receiving group A and group AB plasma. The median number of plasma transfusions over three hours was 4 units (IQR 2–9). Mortality was higher in patients that required a higher number of units of ERP (19% with < 5 units ERP, 27% with 5 – 10 units ERP, 46% with > 10 units ERP, p < 0.001).
Table 1 shows demographic, clinical characteristics, and outcomes of patients that received group A versus group AB plasma. There were differences in blood group distribution, initial systolic blood pressures, injury severity, and percentage of patients with blunt versus penetrating mechanism of injury. Patients that received group A ERP had significantly higher 3-hour transfusion rates of packed red blood cells (median 10 units versus 7 units, p < 0.001), plasma (median 6 units vs. 4 units, p = 0.009), and platelets (median 1 units versus 6 units, p < 0.001). Patients in the group A ERP group also received higher volumes of crystalloid (4.1 liters vs. 3.1 liters, p < 0.001). Bivariate outcomes are reported in the table.
Table 1.
Baseline demographics and clinical characteristics of patients requiring massive transfusion who received ≥1 unit of non-identical group A vs. AB emergency release plasma
| Total (n=584) | Group A ERP (n=122) | Group AB ERP (n=462) | p-value | |
|---|---|---|---|---|
| Age, Median (IQR) | 34.0 (24–51) | 32 (24–51) | 35 (25–51) | 0.62 |
| Male sex, n (%) | 464 (79.5) | 102 (83.6) | 362 (78.4) | 0.20 |
| Blood type, n (%) | 0.02 | |||
| A | 173 (29.6) | 26 (21.3) | 147 (31.8) | |
| AB | 24 (4.1) | 10 (8.2) | 14 (3.0) | |
| B | 103 (17.6) | 24 (19.7) | 79 (17.1) | |
| O | 284 (48.6) | 62 (50.8) | 222 (48.1) | |
| ED Hemodynamics | ||||
| SBP (mmHg), Mean ± SD | 103.9 ± 32.4 | 112.7 ± 33.8 | 101.7 ± 31.6 | 0.001 |
| SBP < 90 mmHg, n (%) | 250 (36.8) | 34 (27.9) | 216 (38.6) | 0.04 |
| Pulse rate, Mean ± SD | 113.1 ± 28.4 | 116.3 ± 31.1 | 112.2 ± 27.6 | 0.16 |
| GCS < 9, n (%) | 207 (35.4) | 37 (30.3) | 170 (36.8) | 0.18 |
| ISS, Median (IQR) | 26 (18–41) | 25 (17–34) | 29 (18–41) | 0.02 |
| Blunt mechanism, n (%) | 316 (54.1) | 55 (45.1) | 261 (56.5) | 0.02 |
| Positive FAST, n (%) | 181 (31.0) | 26 (21.3) | 155 (33.6) | 0.01 |
| Emergency Surgery, n (%) | 466 (79.8) | 102 (83.6) | 364 (78.8) | 0.23 |
| Randomization group (1:1:1), n (%) | 294 (50.3) | 61 (50.0) | 229 (49.6) | 0.93 |
| ERP (u), Median (IQR) | 4 (2–7) | 3 (3–6) | 4 (2–7) | 0.25 |
| Transfusion (first 3 hours) | ||||
| RBC (u), Median (IQR) | 8 (5–13) | 10 (7–17) | 7 (5–11) | < 0.001 |
| Plasma (u), Median (IQR) | 4 (2–9) | 6 (3–10) | 4 (2–8) | 0.02 |
| Platelets (u), Median (IQR) | 1 (1–2) | 1 (1–2) | 1 (0–2) | 0.002 |
| Crystalloid (L), Median (IQR) | 3 (1.3–4.6) | 3.8 (2.2–5.5) | 2.5 (1–4.3) | < 0.001 |
| Outcomes | ||||
| Mortality, n (%) | 141 (24.1) | 30 (24.6) | 111 (24.0) | 0.90 |
| Nonfatal complication, n (%) | 482 (82.5) | 112 (91.8) | 370 (80.1) | 0.002 |
| SIRS, n (%) | 390 (66.8) | 93 (76.2) | 297 (64.3) | 0.01 |
| Infection, n (%) | 257 (44.0) | 56 (45.9) | 201 (43.5) | 0.64 |
| Renal, n (%) | 142 (24.3) | 34 (27.9) | 108 (23.4) | 0.30 |
| Pulmonary, n (%) | 117 (20.0) | 33 (27.1) | 84 (18.2) | 0.03 |
| VTE, n (%) | 91 (15.6) | 12 (9.8) | 79 (17.1) | 0.05 |
Emergency surgery was defined as surgery within 6 hours of ED arrival; ERP: emergency release plasma; ED: emergency department; SBP: systolic blood pressure; GCS: Glasgow coma scale; ISS: injury severity score; FAST: focused assessment with sonography for trauma; RBC: red blood cells; SIRS, systemic inflammatory response syndrome; renal: acute kidney injury and acute renal failure; pulmonary: acute respiratory distress syndrome and acute lung injury; VTE: venous thromboembolism (DVT+PE); IQR: interquartile range; u: units; L: liters
There were no reported acute hemolytic transfusion reactions. There were three febrile non-hemolytic transfusion reactions (all three received group AB ERP). One patient developed transfusion associated circulatory overload and died on hospital day 1 with a cause of death attributable to severe neurologic injuries. This patient was type O, received four units of group AB ERP, 11 additional units of group specific plasma, 16 units of pRBCs, and 18 units of platelets.
We tested the non-inferiority of group A vs. group AB ERP for all of the outcomes and the results are detailed in Figure 1. On bivariate analysis, the risk of mortality in patients receiving group A ERP was found to be non-inferior (HR=1.01, 95% CI 0.83–1.24), however on multivariate analysis the result was inconclusive (HR=1.15, 95% CI 0.91–1.45). Patients receiving group A ERP had a non-inferior rate of thromboembolic events on both univariate (HR=0.55, 95%CI 0.34–0.89) and multivariate analyses (HR=0.52, 95%CI 0.31–0.90). The distribution of thromboembolic events were as follows: group A ERP group had 3 (2.5%) deep vein thrombosis (DVT), 5 (4.1%) pulmonary embolism (PE), 1 (0.8%) myocardial infarction (MI), and 4 (3.2%) cerebral vascular accidents (CVA). The group AB ERP group had 41 (8.9%) DVT, 37 (8.0%) PE, 1 (0.2%) MI, and 16 CVA (3.5%). The results for the other outcomes including nonfatal complications, SIRS, infection, AKI, and pulmonary complications were inconclusive (Figure 1). In a subgroup of patients that received only ERP without subsequent type-specific plasma transfusion (32.4% of group AB ERP and 26.1% of group A ERP), there was a higher rate of SIRS in patients receiving group A ERP on bivariate chi-square analysis (74.3% vs. 54.2%, p = 0.03).
Figure 1.
Association between receiving group A versus group AB emergency release plasma and time to death or various complications among trauma patients requiring massive transfusion protocol.
HR, Hazard ratio; CI, confidence interval; SIRS, systemic inflammatory response syndrome; renal: acute kidney injury and acute renal failure; pulmonary: acute respiratory distress syndrome and acute lung injury. Covariates in adjusted model included: age, first systolic blood pressure, GCS <9, number of units of ERP transfused, 3 hour red blood cell (RBC) transfusion, and 3 hour crystalloid infusion.
Group B or AB patients (n=34) that received incompatible group A ERP were compared to group A or O patients (n=88) that received compatible group A ERP. There were no differences between these two groups with regards to baseline demographics or clinical characteristics. (Table 2). The nonfatal complication rate was found to be non-inferior in patients receiving non-compatible group A ERP (HR=1.02, 95%CI 0.80–1.30), however no significant association was found between transfusion with compatible versus incompatible emergency release plasma and any of the other outcomes that were analyzed including mortality. (Figure 2)
Table 2.
Baseline demographics, clinical characteristics, and outcomes of massive transfusion patients receiving ≥1 unit of compatible versus incompatible emergency release group A plasma
| Total (n=122) | Compatible Recipient group A/O (n=88) | Incompatible Recipient group AB/B (n=34) | p-value | |
|---|---|---|---|---|
| Age, Mean ± SD | 38.0 ± 16.7 | 37.7 ± 16.8 | 38.7 ± 16.5 | 0.76 |
| Male sex, n (%) | 102 (83.6) | 73 (83.0) | 29 (85.3) | 0.75 |
| Blood type, n (%) | ||||
| A | 26 (21.3) | 26 (29.6) | ||
| AB | 10 (8.2) | 10 (29.4) | ||
| B | 24 (19.7) | 24 (70.6) | ||
| O | 62 (50.8) | 62 (70.4) | ||
| ED Hemodynamics | ||||
| SBP (mmHg), Mean ± SD | 112.7 ± 33.8 | 112.5 ± 30.0 | 113.0 ± 42.3 | 0.94 |
| SBP < 90 mmHg, n (%) | 76 (62.3) | 57 (64.8) | 19 (55.9) | 0.36 |
| Pulse rate, Mean ± SD | 116.4 ± 31.1 | 115.6 ± 32.1 | 118.4 ± 28.8 | 0.65 |
| GCS < 9, n (%) | 15 (6–15) | 15 (7–15) | 14 (3–15) | 0.16 |
| ISS, Median (IQR) | 25 (17–34) | 25 (17–34) | 25 (17–34) | 1.00 |
| Blunt mechanism, n (%) | 55 (45.1) | 42 (47.7) | 13 (38.2) | 0.75 |
| Positive FAST, n (%) | 26 (21.1) | 19 (21.5) | 7 (20.6) | 0.90 |
| Emergency Surgery, n (%) | 102 (83.6) | 74 (84.1) | 28 (82.4) | 0.81 |
| Randomization group (1:1:1), n (%) | 61 (50.0) | 45 (51.1) | 16 (47.1) | 0.68 |
| ERP (u), Median (IQR) | 3 (3–6) | 3 (3–6) | 6 (3–8) | 0.10 |
| Transfusion (first 3 hours) | ||||
| RBC (u), Median (IQR) | 10.0 (7–17) | 10 (6–17) | 10 (8–17) | 0.38 |
| Plasma (u), Median (IQR) | 6.0 (3–10) | 5.5 (2–9.5) | 6 (3–11) | 0.28 |
| Platelets (u), Median (IQR) | 1.0 (1–2) | 1 (1–2) | 1 (1–2) | 0.31 |
| Crystalloid (L), Median (IQR) | 3.78 (2.2–5.5) | 3.73 (2.0–5.4) | 3.9 (2.6–6) | 0.46 |
| Outcomes | ||||
| Mortality, n (%) | 30 (24.6) | 20 (22.7) | 10 (29.4) | 0.44 |
| Nonfatal complication, n (%) | 112 (91.8) | 79 (89.8) | 33 (97.1) | 0.28 |
| SIRS, n (%) | 93 (76.2) | 66 (75.0) | 27 (79.4) | 0.61 |
| Infection, n (%) | 56 (45.9) | 38 (43.2) | 18 (52.9) | 0.33 |
| Renal, n (%) | 34 (27.8) | 26 (29.6) | 8 (23.5) | 0.50 |
| Pulmonary, n (%) | 33 (27.1) | 21 (23.9) | 12 (35.3) | 0.21 |
| VTE, n (%) | 12 (9.8) | 9 (10.2) | 3 (8.8) | 0.81 |
Emergency surgery was defined as surgery within 6 hours of ED arrival; ERP: emergency release plasma; ED: emergency department; SBP: systolic blood pressure; GCS: Glasgow coma scale; ISS: injury severity score; FAST: focused assessment with sonography for trauma; RBC: red blood cells; SIRS, systemic inflammatory response syndrome; renal: acute kidney injury and acute renal failure; pulmonary: acute respiratory distress syndrome and acute lung injury; VTE: venous thromboembolism (DVT+PE); IQR: interquartile range; u: units; L: liters
Figure 2.
Association between receiving compatible (recipient group A or O) versus incompatible (recipient group B or AB) emergency release group A plasma and time to death or various complications among trauma patients requiring massive transfusion protocol.
HR, Hazard ratio; CI, confidence interval; SIRS, systemic inflammatory response syndrome; renal: acute kidney injury and acute renal failure, pulmonary: acute respiratory distress syndrome and acute lung injury. Covariates in adjusted model included: age, first systolic blood pressure, GCS <9, number of units of ERP transfused, 3 hour red blood cell (RBC) transfusion, and 3 hour crystalloid infusion.
Of the three centers that provided group A ERP, one site provided plasma with measured low anti-B antibody titers in a 1:25 dilution. The titration is performed in the blood bank from segments removed from the A plasma units slated to be used for emergency release. The other two centers provided group A ERP with unmeasured titers (n=71). Patients in the low-titer subgroup had lower ERP transfusion rates (median 3 units vs. 5 units, p = 0.03). Patients in the unmeasured titer subgroup received more crystalloid fluid (median 9.5L vs. 6.0L in the first 24 hours, p < 0.001), although 24 hour transfusion rates of pRBCs, plasma, and platelets were not significantly different (Supplemental table 1). Patients in the low-titer subgroup had significantly lower rates of documented SIRS (64.5% vs. 84.5%, p = 0.01), but had higher rates of acute kidney injury (37.7% vs. 21.1%, p = 0.05) on univariate chi-square analysis.
Discussion
This secondary analysis of the PROPPR trial adds to the growing body of literature cautiously supporting the use of group A emergency release plasma when used for the resuscitation of patients who have not yet had their ABO group categorized. We analyzed 584 of the 680 patients who received at least one unit of emergency release plasma in the PROPPR trial and observed that transfusion with group A emergency release plasma was not associated with increased rates of mortality, end organ failure, or hemolytic transfusion reactions although true non-inferiority could not be shown in the multivariable analysis.
Group AB plasma, which is considered universal due to its lack of anti-A or anti-B antibodies, has historically been utilized for emergency release purposes due to its low risk of hemolytic transfusion reactions. However, given the scarcity of group AB plasma consequent to the low prevalence of group AB male donors in the general US population and the increasing demand for pre-thawed or liquid plasma, many trauma centers throughout the country have difficulty meeting transfusion demands when solely utilizing group AB plasma for emergency release purposes.9 Group A plasma offers a practical solution to this issue of supply and demand as it is easier for blood banks to supply group A plasma due to the higher prevalence of group A donors in the general population.
There have been significant concerns regarding the risk of hemolysis resulting from transfusion with ABO group incompatible plasma, particularly in patients requiring massive transfusion.13 In our analysis, which included 584 patients requiring massive transfusion, there were no reported cases of acute hemolytic transfusion reactions. This finding is in agreement with the recent literature that acute hemolytic transfusion reactions are rarely associated with plasma transfusion, including patients requiring massive transfusion volumes.9,11 This may be attributable to a decreased susceptibility to hemolysis due to a reduction in volume and dilution of autologous RBCs due to bleeding plus transfusion with group O RBCs,9 the presence of soluble B substance that neutralizes anti-B present in group A plasma,14 and naturally low levels of anti-B antibodies in group A plasma.15
In this study, despite large differences in baseline clinical characteristics and larger volumes of transfusion of all blood components in patients receiving group A emergency release plasma. There were no easily identifiable causes for the increased transfusion rates among centers that provided group A ERP. It is unlikely to have been the result of a physiologic effect attributable to ERP as the quantities of pRBCs, platelets, and crystalloid over the first 3 hours of hospital admission were higher as well. We found a higher proportion of penetrating injuries in centers that provided group A ERP, however rates of shock on ED arrival were lower.
Mortality rates were nearly identical between the two groups on bivariate analysis. Mortality rates in recipients of group A ERP were non-inferior on univariate proportional hazards analysis, although the results for the multivariable analysis were inconclusive. This was most likely attributable to the small number of patients that received group A ERP, and had the study been higher powered the result would have likely reached significance.
We found a decreased rate of thromboembolism in patients receiving group A plasma. The major difference in thromboembolic complications between groups was in rates of diagnosis of DVTs, which may reflect differences in institutional practices regarding prophylaxis or surveillance rather than a protective effect conferred by group A plasma. We did observe a significantly increased risk of pulmonary complications in patients receiving group A ERP on bivariate analysis although this effect was not significant in the PH analysis. We attributed this result to patients who were transfused group A ERP having received higher amounts of crystalloid. Robinson et. al recently showed that crystalloid, but not blood product, transfusion is independently associated with an increased risk of acute respiratory distress syndrome.16
Approximately 85% of patients receiving group A emergency release plasma are group O or group A, and thus are considered compatible, meaning that there are no antibodies in donor plasma expected to cause a significant immunologic response. Incompatible recipients, either group B or AB blood groups, are considered to be at an increased risk for transfusion reactions and its attendant morbidity. However, recipients of incompatible ERP were observed in this study to have a non-inferior complication burden. A higher than expected proportion of our study group received incompatible group A plasma. Based upon blood group prevalence, 15% would be predicted compared to the 27% we observed. Stevens et al. found higher RBC and plasma transfusion rates in patients who received incompatible plasma and hypothesized that this may be due to greater availability of ERP in institutions that utilize group A plasma.11
We did not find a significant difference in ERP transfusion rates between patients receiving group A versus group AB ERP or in patients receiving incompatible versus compatible group A ERP. However, all of the centers that contributed data for the present study had to meet strict criteria with regards to blood product access and the length of time between patient arrival and time to first transfusion of blood products. The majority of trauma centers in the US are not able to provide large numbers of blood products as expediently and issues with plasma wastage, which has been reported to be as high as 25% with ERP may place further restrictions on the ability of trauma centers to supply an adequate quantity of group AB ERP.4 Thus the provision of group A ERP may lead to a faster and more balanced resuscitation.
Studies quantifying antibody titers in group A plasma have shown that more than 85% of units are within a safe range. In a study from the Mayo Clinic Blood Donor Center, the median anti-B titer was 16, the maximum positive titer dilution was 512, and greater than 90% of donors had a titer of 64 or less. 8 While titers less than 64 are generally considered to have a low risk of hemolysis, there is currently no consensus among donor centers regarding the cutoff between high versus low titer levels for plasma. Given the relative safety of group A plasma and the low rate of high titers, many centers that utilize group A plasma do not routinely determine the anti-B titer range of their group A plasma stores.
We found a 20% higher rate of SIRS in patients that received group A ERP without subsequent type-specific plasma transfusion and a similar 20% increased rate of SIRS in patients that received group A ERP with unmeasured titers. While this difference may be partially attributable to transfusion with high-titer ERP, significant differences in transfusion practices between the groups, including pointedly higher crystalloid use and ERP transfusion rates in centers that that provided ERP with unmeasured titers, significantly confound the findings and limit our ability to make recommendations regarding the appropriateness of measuring anti-B titers prior to transfusion. As more centers adopt the use of group A ERP, further research on this topic is currently warranted.
There were significant limitations associated with this study. The PROPPR trial was not designed to answer questions regarding the use of emergency release plasma. With our sample size, we only achieved the power of 0.39 for 30-day mortality. The large confidence intervals in the analyses are also indicative of the study being underpowered to detect non-inferiority. The PROPPR study protocol did not mandate that all centers were to standardize the group of ERP provided thus there was no way to verify the consistency with which group A or group AB plasma was transfused prior to type and screen. The misclassification of ERP may have biased our findings and increased the risk of type 2 error. Additionally, there were known and unknown differences between centers in transfusion and trauma resuscitation practices that may have biased outcomes. While we attempted to adjust for these differences in the multivariable analysis, it is difficult to quantify the proportion of variability in results attributable to ERP versus differences in patient and institution level characteristics. Many of the findings in this study may be due to differences across centers with regards to blood bank protocols, resuscitation practices, and definitions for outcomes. Although the data were derived from a randomized clinical trial, we stratified based on trauma center and the benefits of a randomized study design were not extended to our analysis. This study was underpowered to detect subtle differences in hemolytic transfusion reactions, which are a rare occurrence in clinical practice and would require sample sizes much larger than the current study to show statistical significance. Lastly, trauma patients requiring massive transfusion receive numerous medications and transfusions, and typically undergo multiple invasive procedures. To ascribe causality to a single component of resuscitation in these patients is a complex determination and beyond the ability of a single, nonrandomized, study.
We conclude that the use of emergency release plasma is common in patients requiring massive transfusion. Providing group A ERP can facilitate the early and balanced resuscitation of patients requiring massive transfusion at trauma centers worldwide. As more centers adopt the use of group A ERP, further studies are warranted regarding the appropriateness of determining anti-B titer levels prior to transfusion. Group A emergency release plasma is an acceptable option for patients requiring massive transfusion, especially if group AB emergency release plasma is not readily available.
Supplementary Material
Acknowledgements
We appreciate the biostatistical support from Dr. Li Ding MD MPH and the Southern California Clinical and Translational Science Institute.
Disclosure
The authors disclose no conflicts of interest. This work was supported with grant U01HL077863 from the US National Heart, Lung, and Blood Institute and funding from the US Department of Defense, the Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR-120612).
Contributor Information
Amory de Roulet, Division of General Surgery, Department of Surgery, New York Presbyterian Queens, Flushing, New York.
Jeffrey Kerby, Division of Trauma, Burns and Surgical Critical Care, Department of Surgery, School of Medicine, University of Alabama, Birmingham, Alabama.
Jordan Weinberg, Division of General Surgery, Department of Surgery, Dignity Health Medical Group Arizona, Phoenix, Arizona.
Richard Lewis, Department of Surgery, University of Tennesse Health Science Center, Memphis, Tennessee.
Jay Hudgins, Department of Pathology, LAC+USC Medical Center, University of Southern California, Los Angeles, California.
Ira Shulman, Department of Pathology, LAC+USC Medical Center, University of Southern California, Los Angeles, California.
Erin Elizabeth Fox, Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, University of Texas Health Science Center, Houston, Texas.
John B Holcomb, Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, University of Texas Health Science Center, Houston, Texas.
Karen Brasel, Division of Trauma, Critical Care and Acute Care Surgery, School of Medicine, Oregon Health and Science University, Portland, Oregon.
Eileen Bulger, Division of Trauma and Critical Care, Department of Surgery, School of Medicine, University of Washington, Seattle, Washington.
Mitchell Cohen, Department of Surgery, University of Colorado, Denver, Colorado.
Bryan Cotton, Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, University of Texas Health Science Center, Houston, Texas.
Timothy Fabian, Division of Trauma and Surgical Critical Care, Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Terence O’Keeffe, Division of Trauma, Critical Care and Emergency Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.
Sandro Rizoli, Trauma and Acute Care Service, St. Michael’s Hospital, Toronto, Ontario, Canada.
Thomas Scalea, R Adams Crowley Shock Trauma Center, University of Maryland, Baltimore, Maryland.
Martin Schreiber, Division of Trauma, Critical Care and Acute Care Surgery, School of Medicine, Oregon Health and Science University, Portland, Oregon.
Kenji Inaba, Division of Trauma and Critical Care, LAC+USC Medical Center, University of Southern California, Los Angeles, California.
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