Hemorrhage remains a significant cause of preventable death in traumatic injury.1 In patients surviving to hospital admission, hemorrhagic death typically occurs early in the injury course.2,3 For major trauma victims in hemorrhagic shock, early and balanced plasma resuscitation, plasma to red blood cell (RBC) ratio of >1:2, is associated with decreased mortality.4–6 In addition, earlier transfusion of plasma, even within minutes of arrival to a trauma center, has been demonstrated to improve 6-hour survival in the severely injured.4,5 With such a narrow window to optimize resuscitation parameters and potentially mitigate preventable trauma mortality, timely plasma administration is imperative.
To achieve balanced resuscitation goals in the targeted time frame, fresh frozen plasma (FFP) or thawed FFP has been routinely used. In the United States, FFP is plasma that has been separated from whole blood and frozen within 6 to 8 hours of collection. Once thawed, FFP must be used within 24 hours or relabeled as thawed FFP, which can be stored for an additional 4 days.7,8 However, according to these guidelines, in the actively hemorrhaging patient, a 20-minute thaw time for FFP can result in delayed administration, and the 5-day shelf life of thawed FFP limits supply and incurs wastage if it cannot be repurposed. While specialized protocols have been developed for more rapid thawing of plasma,9 unfortunately, the use of such methods is limited because the packaging and special handling required are not feasible across all institutions, with plasma wastage and delay in administration remaining a salient topic.
Liquid plasma (LP), or “never frozen” plasma, is produced from whole blood donation and offers an attractive alternative because it can be easily stored, transported, and immediately transfused, circumventing transfusion delays, and has the potential to reduce wastage because of its 26-day shelf life. While approved by the Food and Drug Administration and used in some European countries since the 1980s, LP has yet to be widely adopted for clinical use in the United States. However, research suggests that LP has an equivalent if not heightened hemostatic10 and safety profile11 compared with thawed FFP. Given these properties of LP, we hypothesized that the use of LP in the massive transfusion protocol (MTP) would improve optimal plasma/RBC ratios, initial plasma transfusion times, and clinical outcomes in the severely injured patient.
PATIENTS AND METHODS
After institutional review board approval, MTP activations from 2016 to 2018 were evaluated using Trauma Quality Improvement Program data from our level 1 trauma center. These data were entered and verified in our institutional trauma registry for all activated trauma patients. Patients aged 16 years or older who had activation of the MTP within the first hour of arrival were included. Activation of the MTP took place at the discretion of the trauma team and attending surgeon. Exclusion criteria included death on arrival before transfusion or patients who did not receive blood products (Fig. 1).
Our institution's trauma MTP is activated when one of the following conditions is met: persistent hemodynamic instability, hemodynamic instability and active bleeding requiring angioembolization or operation, and or blood transfusion in the trauma bay. Emergency blood products, 2 U of O negative RBC's and 2 U of plasma, are brought to the emergency department by the blood bank for all full traumas or when MTP is activated in partial traumas. There is no blood refrigerator or storage of blood products in the emergency department. However, 4 U of O positive RBCs and 6 U of LP are maintained in the operative room refrigerator. Blood components are automatically sent by the blood bank in established ratios (round A and round B). Round A includes 6 U RBCs, 6 U plasma, and 1 plateletpheresis unit. Round B includes 6 U RBCs, 6 U plasma, and 10 U of cryoprecipitate. Subsequent rounds are delivered in 15-minute intervals by the blood bank repeating rounds A and B until termination of the MTP. Thromboelastography or other modalities for real-time goal-directed transfusion are not available at our institution. Blood product units are given together with transfusion ratios guided by MTP until the patient is in the intensive care unit (ICU) at which time baseline measures of coagulation are obtained.
Type A LP as the initial resuscitation plasma was implemented in April 2017. Post–LP implementation, all trauma MTP activations received LP as the initial plasma product. As part of the protocol, the first 14 plasma units provided are LP after which the transition to thawed FFP occurs. Before this, thawed FFP was solely used. This change in blood product management occurred when the opportunity to use LP became newly available to our institution. Liquid plasma offered an attractive solution to difficulties consistently achieving desired plasma/RBC ratios because of the 20-minute lag time necessary for thawing FFP at our institution. No other protocol changes related to blood management occurred during this period. Therefore, to evaluate plasma/RBC ratios in patients receiving thawed FFP versus LP, MTP patients were compared before and after implementation with respect to the following variables: baseline patient demographics and clinical factors including mechanism of injury (blunt vs. penetrating), Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), arrival Glasgow Coma Scale (GCS), presenting systolic blood pressure (SBP), Trauma and Injury Severity Scoring System probability of survival (Ps) calculation, and emergent operative intervention on admission. Emergent operative intervention was defined as exploratory laparotomy, thoracotomy, open vascular exploration for hemorrhage control, and/or craniotomy on admission. The primary outcome of plasma/RBC ratio in pre-LP and post-LP patients was evaluated at 4 and at 24 hours from hospital arrival. Plasma/RBC ratios were determined by first calculating the product ratio for each patient and then determining the median for the two study groups based on these individual ratios. Initial plasma and RBC transfusion times were calculated in minutes from documented arrival. Secondary outcomes were mortality, 28-day recovery, and patient complications recorded in our trauma registry within 28-days of injury. Recovery was defined as discharge to home, shelter, rehabilitation, or nursing facility within 28 days from injury. Patients who did not survive or who remained hospitalized beyond 28 days were censored at day of death or at 28 days if still alive. Complications included acute kidney injury (AKI), acute respiratory distress syndrome, venous thromboembolism, and those of an infectious nature. Lastly, as type A LP contains anti-B antibodies, which in theory may result in a hemolytic reaction, evidence of ABO incompatibility in post-LP patients was assessed. Records pertaining to serum specimens of post-LP trauma patients with type B and AB blood type were reviewed for evidence of hemolysis within 24 hours post–LP transfusion.
A power analysis was performed to assess our study's ability in detecting our primary outcomes: plasma/RBC ratios and initiation time of plasma transfusion before and after LP implementation. An 80% power and 95% confidence were used for the analysis. Based on published data, we estimated that a per group sample size of 18 was needed to detect a 35% difference in plasma/RBC ratios at both 4 and 24 hours,12 and to detect a 33% difference in plasma transfusion time, a per group sample size of 33 was needed.13
Demographic and outcome data were analyzed using paired t tests and Wilcoxon rank sum tests, as applicable, for continuous variables and Fisher's exact test for categorical variables. Unless otherwise specified, continuous data values are reported as mean ± SD or median (interquartile range [IQR]), and categorical data, as proportions. Statistical significance was defined as an α value of <0.05. Hedge g (Cohen d with adjustment for differing group size) and r (z statistic/√n) were used to calculate effect size for our parametric and nonparametric data, respectively.
Univariable analysis was performed by evaluating the association of sex, age, ISS, GCS, presenting SBP, Ps, and injury mechanism on 4-hour and 24-hour plasma/RBC ratios. Variables with a p value of <0.2 were subsequently included in a multivariable linear regression model to investigate the associations between plasma type (LP or thawed FFP) and transfusion ratios at 4 and 24 hours. For 4-hour transfusion ratios, sex and presenting SBP were significant on univariable analysis. For 24-hour transfusion ratios, sex, presenting SBP, and Ps were significant on univariable analysis. These variables were subsequently included in their corresponding multivariable linear regression models.
To evaluate our secondary outcomes between pre-LP and post-LP patients, that is, mortality, recovery, and patient complications during the first 28-days of admission, Cox proportional hazards regression analysis was performed. To assess independent risk between pre-LP and post-LP groups, secondary outcomes with significant hazard ratios (HRs), 28-day recovery, and AKI were then analyzed using a multivariable Cox proportional hazards regression controlling for sex, age, injury mechanism, ISS, GCS, Ps, presenting SBP, and 4- and 24-hour plasma/RBC ratios. Variables with a p value of <0.2 on univariable analysis were accounted for in the multivariable Cox proportional hazards regression model. Statistical analysis was performed using RStudio (version 1.1.463, RStudio, PBC, Boston, MA) and IBM SPSS Statistics for Windows (version 25.0; IBM Corp., Armonk, NY).
A total of 95 patients met the inclusion criteria and were included in the study; 39 were in the pre-LP group and 56 were in the post-LP group. Over the first 24 hours of admission, 80% (45/56) of patients in the post-LP group received LP as their sole plasma resuscitation fluid. The remaining 20% (11/56) received 14 U of LP initially with subsequent transition to thawed FFP for continued resuscitation. Baseline demographics were similar between the two groups (Table 1). In regards to injury characteristics on admission, presenting SBP, injury mechanism (blunt vs. penetrating), ISS, AIS scores, and need for emergent operative intervention (laparotomy, thoracotomy, craniotomy, and/or open vascular) were similar between groups (Table 1). Compared with the pre-LP group, the post-LP group had a lower Ps estimate (0.70 ± 0.35 vs. 0.53 ± 0.40; p = 0.036).
Both the 4- and 24-hour plasma/RBC ratios improved in the post-LP group (1:1.80 vs. 1:1.46, p = 0.025, and 1:1.72 vs. 1:1.23, p = 0.0055) (Table 2). In addition, in the post-LP group, median RBC transfusion volumes at both 4 and 24 hours decreased (9 U [IQR, 6–17 U] vs. 6 U [IQR, 3–12 U], p = 0.035, and 13 U [IQR, 6–18 U] vs. 7 U [IQR, 3–15 U]; p = 0.034) (Table 2). According to univariable analysis, to assess LP versus thawed FFP transfusion and improvement in 4- and 24-hour plasma/RBC ratios, sex and presenting SBP were associated with plasma/RBC ratios (p < 0.2) and were entered into the multivariable linear regression model. In addition, Ps was associated with 24-hour plasma/RBC ratios (p < 0.2) and also entered into the 24-hour multivariable model. Age, GCS, ISS, and mechanism of injury did not correlate to 4- and 24-hour plasma/RBC ratios (p > 0.2). In our multivariable linear regression model, which adjusted for potential confounders found in the univariable analysis, improvement in 4- and 24-hour plasma/RBC ratios remained significant in post-LP compared with pre-LP patients (p = 0.028 and p = 0.0092, respectively) (Table 3). Platelet and cryoprecipitate transfusion volumes were similar between groups (Table 2).
After LP implementation, a 69% decrease in the time of initial plasma administration and a 79% decrease in time from initial RBC administration to plasma administration occurred (71 minutes [IQR, 58–104 minutes] vs. 22 minutes [IQR, 13–49 minutes] and 58 minutes [IQR, 44–70 minutes] vs. 12 minutes [IQR, 6–25 minutes], respectively; both p < 0.0001)(Table 2). In addition, the median number of RBC units transfused before plasma administration decreased by 50% (4 U [IQR, 4–8 U] vs. 2 U [IQR, 1–2 U], p < 0.0001) (Table 2).
Several secondary outcomes (mortality, ICU length of stay [LOS], hospital LOS, and complications) were notably better in the post-LP group than in the pre-LP group. Hospital LOS and incidence of AKI were reduced by 43% and 89%, respectively, post-LP implementation (p < 0.03) (Table 1). On Cox proportional hazards regression analysis, to account for survivors bias, post-LP implementation was associated with a favorable 28-day recovery (HR, 2.61; confidence interval [CI], 1.37–5.00; p = 0.0037) and reduced odds of AKI (HR, 0.11; CI, 0.013–0.89; p = 0.039) (Table 4). The groups were similar in terms of ICU LOS, incidence of acute respiratory distress syndrome, venous thromboembolism, infectious complications, and mortality (Tables 1 and 4). Twenty-four-hour mortality in the pre-LP group (n = 8) was all due to hemorrhage, and of the 19 deaths in the post-LP group, 16 were hemorrhagic and 3 were secondary to traumatic brain injury. The median 24-hour time of death was similar between both groups (102 minutes [IQR, 35–372 minutes] vs. 101 minutes [IQR, 38–242 minutes], p = 0.89) (Table 1).
On univariable Cox proportional hazards regression evaluating the association between LP versus thawed FFP transfusion and 28-day recovery, male sex, older age, and higher ISS were associated with reduced likelihood of recovery (p < 0.2). Presenting SBP, GCS, Ps, mechanism of injury, and 4- and 24-hour transfusion ratios did not correlate with 28-day recovery (p > 0.2). On univariable Cox proportional hazards regression, to assess LP versus thawed FFP transfusion and odds of AKI development, lower presenting SBP and higher ISS were associated with increased odds of AKI (p < 0.2). Sex, age, GCS, Ps, mechanism of injury, and 4- and 24-hour transfusion ratios did not correlate with development of AKI (p > 0.2). In our multivariable Cox proportional hazards regression, models adjusted for potential confounders from univariable analysis, greater 28-day recovery, and reduced incidence of AKI remained in the post-LP group (HR, 3.16; 95% CI, 1.60–6.24; p < 0.001 and HR, 0.092; 95% CI, 0.011–0.77; p = 0.027, respectively) (Table 5).
Finally, our review of nine post-LP patients with blood group type B or AB found no evidence of incompatibility with type A LP. Documented serology reports within 24 hours of transfusion with type A LP were available for all patients and demonstrated no signs of hemolysis.
In severely injured patients requiring massive transfusion, prompt and balanced administration of blood product components is imperative to mitigate trauma-induced coagulopathy and fatal hemorrhage. The use of plasma as a primary resuscitative fluid has been championed, with trauma centers creating protocols to facilitate immediate access for patients presenting in hemorrhagic shock. Nevertheless, even when such integrated protocols are implemented, obstacles to rapid plasma administration persist, in particular, the inherent limitations of thaw time and storage of FFP. The immediate availability of LP has the potential to obviate such delays. With the implementation of type A LP into our institution's MTP, we sought to evaluate its impact on plasma/RBC ratios and clinical outcomes. We hypothesized that its use in the MTP would improve optimal plasma/RBC ratios, initial plasma transfusion times, and clinical outcomes in the severely injured patient.
We found that implementation of LP as the primary plasma resuscitation fluid improved plasma/RBC ratios and reduced time of initial plasma administration in trauma patients requiring MTP activation. In addition, we found a coinciding reduction in RBC transfusion volumes during the first 24 hours of admission. Patients in the post-LP group also demonstrated improved 28-day recovery and reduced odds of AKI, suggesting an association between LP implementation and improved clinical outcomes.
Despite data suggesting not only a survival benefit with the early use of plasma4,5 but also reduced mortality with higher plasma/RBC ratios,4,5,14–18 a reported 67% of hemorrhaging trauma patients do not receive plasma within 30 minutes of admission, and 10% still do not receive plasma by 3 hours.5 The immediate availability of LP offers a way to effectively meet these transfusion parameter goals. We found a 69% decrease in time from arrival to plasma administration and a 79% decrease in time from initial RBC transfusion to plasma administration. In addition, with adoption of our LP protocol, plasma/RBC ratios were improved both at 4- and 24-hour time intervals. Thus, the use of LP as the primary plasma resuscitation product can optimize timing and volume of plasma transfusion when incorporated into MTPs, mitigating delay.
In our study, improved plasma/RBC ratios and plasma administration times also coincided with a reduction in RBC units transfused in the post-LP group. Prior studies evaluating high plasma/RBC ratios have also demonstrated reduced blood transfusion requirement with high plasma/RBC ratio compared with low plasma/RBC ratio.4,6,15,18,19 Moreover, research suggests the initial hemostatic profile of LP to be superior to that of thawed frozen plasma (FP)10 potentially contributing to the reduced RBC product usage in our post-LP group.
While storage time data were not available to evaluate any potential influence plasma age might have had on our study outcomes, the ability of LP to retain its hemostatic potential longer than thawed FP is part of the perceived benefit of using LP. Liquid plasma appears to sustain its hemostatic profile five times longer than thawed FP, retaining more than 88% of initial clotting factors (aside from factors V and VIII) and demonstrating elevated levels of platelet microparticles by the 26-day expiration.10 In addition, prior research from Sweden, where LP has been in use for several decades, has demonstrated no correlation between longer LP storage time and increased mortality.11 Thus, the hypothesized benefit of LP is due not only to its immediate transfusion potential but also its heightened hemostatic profile to thawed FP, regardless of product age.
Beyond hemostasis, the advantage of early plasma administration in hemorrhagic trauma also appears secondary to preservation and, potentially, reconstitution of the endothelial glycocalyx, which is pathologically shed in hypoxia, ischemia reperfusion injury, sepsis, and hemorrhagic shock.20–24 Studies comparing LP to frozen plasma have found LP to possess equivalent if not superior endothelial stabilizing properties.10,25 Faster correction of shock indices, from implementation of predefined MTPs and higher plasma/RBC ratios, is associated with reduce LOS and multiorgan failure,26,27 while higher volume RBC transfusion is associated with immunosuppression, infection, and increased risk of postinjury organ failure.28 Earlier administration of LP appears to heighten preservation and stabilization of the vascular endothelium and glycocalyx, contributing to faster correction of hemorrhagic shock and avoidance of organ injury. Our study supports these prior findings, as we observed improved 28-day recovery (HR, 3.16) and reduced odds of AKI (HR 0.092) in the post-LP group.
Despite lower odds of AKI in our post-LP group, acute respiratory distress syndrome, infection, and venous thromboembolic events were not reduced in the post-LP group. This may be related to the threshold at which injury to these organ systems is detected. The kidney is particularly sensitive to ischemia, and thus, the benefits of faster hemostasis may be more readily detectable in this organ (reduced AKI) as compared with the other organ systems evaluated. We also did not detect a 24-hour mortality difference, despite a trend toward increased 24-hour mortality in the post-LP group. However, this trend is not unexpected, considering that the post-LP group had a lower probability of survival.
At our institution, real-time or point-of-care evaluation of the coagulation system is not available; thus, the initial trauma resuscitation relies on blood product administration according to current recommended ratios. It is estimated that point-of-care testing for international normalized ratio and partial thromboplastin is used only by 37% of United States trauma centers with only 9% routinely using thromboelastography.29 In nontrauma centers, rural hospitals, and resource-limited institutions, access to these tests is likely much lower. Thus, as a majority of hospitals rely on adherence to blood product ratio guidelines during resuscitation of the hemorrhaging patient, methods to optimize transfusion ratios and administration times remain crucial. However, preemptively thawing FFP to adhere to transfusion guidelines can result in increased plasma wastage.30 With integration of LP into the MTP, our blood bank observed a drop in wasted frozen plasma. In the years proceeding LP implementation, we had an average of 176 wasted frozen plasma units annually compared with 60 wasted units during our post-LP study period, a more than 50% reduction in plasma wastage. The adoption of LP as the initial resuscitation plasma provided an effective strategy to optimize transfusion goals while reducing waste.
Lastly, as part of our institutional protocol, while awaiting blood type characterization, type A LP is used in the emergency trauma setting. Ideally, group AB plasma is used because it is universally compatible. However, blood group AB is rare within North America and concern for nonsustainable use of type AB plasma in the emergent setting has led numerous trauma centers to adopt type A plasma as the initial resuscitative plasma until blood group is determined.31,32 Studies have demonstrated the use of type A thawed plasma as an alternative universal donor in the emergency setting with no increased risk for transfusion-related complications.32–34 In our study, patients with blood type B or AB who received type A LP demonstrated no evidence of hemolytic reaction within 24 hours posttransfusion, supporting current literature in demonstrating the safety of type A LP as an initial resuscitation plasma.
Our study has several limitations. As a retrospective study, it relies on previously collected data not specifically intended to address our study hypothesis and does not allow for determination of causation, and with the use of historical patient groups, there might be unaccounted factors impacting our findings. However, transition to LP use did not coincide with any additional institutional changes to blood management or protocols aimed at improving resuscitation ratios. In addition, we do not have data on what percent of the resuscitation was MTP guided over the 4- and 24-hour periods, potentially impacting the comparisons of plasma/RBC ratios. However, because our actual MTP protocol did not change throughout the duration of the study, the only change being the switch from FFP to LP, this would make a significant difference in percentage MTP between study groups less likely. The practice of giving several units of plasma to “catch-up” on plasma/RBC ratios for 24 hours can impact 24-hour product ratios. However, our comparison of 4- and 24-hour ratios allowed evaluation of the catch-up phenomenon. In both the pre-LP and post-LP groups, there was minimal difference in the 4- and 24-hour plasma/RBC ratios, a catch-up of approximately a quarter unit of plasma in each group, suggesting negligible and likely clinically insignificant catch-up phenomenon. Lastly, while our study was appropriately powered to examine our primary aims, that is, the impact of LP implementation on optimizing plasma/RBC ratios and plasma transfusion times, it was not powered to evaluate differences in our secondary outcomes (length of stay, complications, and mortality). Thus, the sample size should be taken into account when considering the association between LP implementation and our secondary outcomes. In addition, these outcomes are subject to survivor's bias, and while we attempted to account for this in our analyses, this bias should be considered in interpretation of our outcomes.
In massive hemorrhage, the immediacy of plasma administration and ability to quickly achieve optimal plasma/RBC ratios may provide clinical benefits. Our study demonstrates that initial resuscitation with LP optimizes early plasma administration, improves adherence to transfusion ratio guidelines, and is associated with improved patient outcomes (improved 28-day recovery and reduced AKI). Furthermore, LP offers a solution to inherent delays and wastage with FFP while also obviating ABO blood group incompatibility. As such, the addition of LP as the initial plasma resuscitation fluid in trauma center MTPs should be strongly considered.
G.B., C.C., V.L.N., and G.P.V. contributed to the study design, data analysis, data interpretation, and article preparation.
We thank Pamela Derish, MA, UCSF Department of Surgery, for her review of this article.
The authors declare no conflicts of interest.
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