Introduction
Hemorrhage leading to massive transfusion remains a major cause of potentially preventable deaths [
1]. Massive transfusion and trauma are associated with the development of coagulopathy, which develops secondary to tissue injury, hypoperfusion, dilution, and consumption of clotting factors and platelets [
2]. Coagulopathy, together with hypothermia and acidosis, forms a "lethal triad" associated with a poor prognosis [
3]. Furthermore, an acute coagulopathy of trauma and shock (ACoTS) present already at admission the hospital has been identified also being associated with increased mortality [
3]. Although the early and effective reversal of coagulopathy is acknowledged to be important, the best method to achieve this goal remains controversial [
4].
Recently, the concept of Hemostatic Control Resuscitation (HCR), i.e., providing large transfusions to critically injured patients in an immediate and sustained manner as part of a massive transfusion protocol, has been introduced, with wide implementation of the concept of damage control [
3,
5]. The rationale behind this hemostatic resuscitation concept is that circulating whole blood contains red blood cells, plasma, and platelets at a 1:1:1 ratio, and transfusion of plasma and platelets in an appropriate unit-for-unit ratio has been proposed as a way to both prevent and treat coagulopathy due to massive hemorrhage. A number of retrospective studies have reported the benefit on survival in trauma patients receiving high ratios of fresh frozen plasma (FFP) and platelet concentrates (PLT) in relation to red blood cells (RBC) when compared to those receiving less FFP and PC [
6].
At Rigshopitalet, Haemostatic Control Resuscitation (HCR) encompassing preemptive use of PLT and FFP in tailored transfusion packages immediately upon arrival at the trauma centre with subsequent transfusion therapy directed by the results of thrombelastograph (TEG) analysis throughout the peri- and postoperative period was implemented in 2004 [
7] and the aim of the present study was to investigate the potential effect of HCR on mortality in trauma patients when compared to those treated before the implementation of HCR.
Methods
We undertook a before and after study using historical controls. Patients treated in 2001-3 were compared to patients treated in 2005-7. 2004 was excluded, since HCR for massively bleeding patients was introduced this year, as previously described [
7]. In brief, HCR was introduced including the following services: (i) transfusion packages comprising 5 units of RBCs stored in saline-adenine-glucose-manitol (SAGM) for a maximum of 15 days, 5 units of FFP and 2 units of PLT (buffy coat pool from four donors), to be used before the results of the TEG analysis was available; (ii) storage of thawed, ready-to-use FFP in the blood bank for a maximum of 72 h; (iii) continuous monitoring of the blood transfusion therapy in patients receiving more than 10 RBCs within 24 h; (iv) protocol for monitoring of haemostatic competence with TEG and an intervention algorithm for treatment with FFP and PLT based on the results of the analysis (Appendix 1); and (v) educational program for anesthesiologists concerning functional hemostasis and TEG.
All Consecutive trauma patients admitted to the Trauma Centre, Copenhagen, Rigshospitalet in 2001-3 (n = 1448) and 2005-7 (n = 2553) were identified. All secondary transfers were excluded. All patients receiving ≥1 blood product at admission were then identified by merging data from all trauma patients admitted to the Trauma Centre with data from the blood bank of all patients receiving blood 2001-3 (n = 120) and 2005-7 (n = 209). ISS scores were obtained from the Trauma Audit & Research Network (TARN) data base, and only patients with available ISS were included, which reduced the number of patients to 97 (2001-3) and 156 (2005-7). Admission blood samples were collected from the laboratory data base. LOS and 30 day mortality were obtained from the database of the hospital and the Central Office of Civil Registration. All data were collected and entered into a study database based on unique personal identity number after approval from the Data Protection agency. The resulting database contained ISS, age, gender, time from arrival to first blood product delivery, type and amount of blood products (RBC, FFP and PLT) in the first 6 hours, 6-12, 12-24 hours and total amount during hospital stay, admission hematology and coagulation, LOS and mortality. In the present study, coagulopathy was defined as APTT (or INR) just above normal reference value, which is in accordance with the increase in mortality recently reported by Frith et al [
8] though the authors here used a, for the study created, prothrombin time ratio. Given the increase in mortality with standard coagulation tests just above normal [
8] and the previously reported stronger prognostic value of PTT as compared to PT in trauma patients [
9] we chose to define coagulopathy as APTT above normal reference value.
The regional ethics committee of Copenhagen approved the waiver of consent, as all procedures were part of standard care.
Statistics
Data on patients stratified according to study period or mortality were compared by Wilcoxon Rank Sum and Chi-square test. Early factors associated with blood transfusion within each period were investigated by Spearman correlations, presented by rho and p-values, and differences in these factors between periods were investigated by analysis of covariance (ANCOVA) by including an interaction between period*variable in each model. Furthermore, we investigated factors associated with massive transfusion (MT) by logistic regression analysis, with MT (RBC >10 day 1, n = 66) as dependent variable.
Survival analysis was performed with death as the main endpoint. Follow-up times were calculated from admission date to date of death or censored as alive by the 1 June 2010. Since ~90% of trauma deaths occurred within the first 30 days, only 30-day mortality is reported here. Thirty-day mortality in risk-stratified patients was performed by the Kaplan-Meier method and log-rank test, presented with Chi-square and p-values. Cox proportional-hazards models were done to determine the predictive value for mortality of ISS, age, admission hematology and coagulopathy and early blood transfusion therapy. Significant univariate variables were included in subsequent multivariate models, presented by hazards ratios (HR) with 95% confidence intervals (CI) and p-values. Cases in the two periods were not matched.
Data are presented as medians with inter quartile ranges (IQR) unless otherwise stated. P-values < 0.05 were considered significant. Statistical calculations were performed using SAS 9.1 (SAS Institute Inc., Cary, NC, US) and Kaplan-Meier plots performed using WinSTAT® for Microsoft® Excel version 2009.1 (R. Fitch Software).
Discussion
The main finding of the present study was that a change in transfusion therapy with more aggressive and early administration of plasma and platelets in relation to RBC did not influence survival in the trauma patients investigated, which was also confirmed by multivariate analysis in massively transfused patients.
Recently a substantial number of retrospective studies assessing the influence of ratios of FFP and PLT in relation to RBC have been published in trauma patients reporting on the benefit of ratios approximating 1:1:1 [
11‐
14], which contrasts the findings in the present study. Potential explanation for this difference may be related to the fact that the present study was a before-and- after study where a substantial change in transfusion therapy was implemented, whereas retrospective evaluations not introducing a shift in transfusion practice have previously been reported. Also, a substantial number of studies report on findings from the combat scene and thereby a different kind of trauma patients with higher frequency of penetrating injuries than present in the current study. Our findings however concur with Scalea et al., reporting no survival benefit in patients receiving high FFP:RBC and PLT:RBC-ratios at a major civilian trauma center [
15]. In contrast to the present study, Cotton et al. reported a reduction in mortality after introduction of a massive transfusion (MT) protocol in group of MT patients [
16] and in another study reported a reduction in multiple organ failure (MOF) and postinjury complications in patients transfused according to the MT protocol, though no change in mortality was reported [
17]. Given that conclusions based on retrospective studies like the present are associated with survival (and mortality) bias as compared to conclusions based on prospective efficacy studies, the results presented here should be interpreted with caution.
It has previously been reported that not only the ratio of FFP:RBC and PLT:RBC are important for survival but also the timing of the administration of FFP and PLT, as patients receiving early FFP and PLT therapy displayed improved survival [
18]. In the present study, administration of FFP and PLT commenced within the first five min after arrival at the trauma center in the late period as compared to 28 min in the early period, but this did clearly not improve survival in this cohort of patients. It should however be noted, that in the study by Riskin et al. patients receiving early administration of blood transfusions transfusion commenced much later than those receiving transfusions late in the present study. The lack of improvement of survival in trauma patients in the present study contrasts the finding in patients undergoing surgery for a ruptured abdominal aortic aneurysm (rAAA) previously reported [
19], which may be related to the different extent of tissue injury between these cohorts. In the present study approximately 30% of the patients demonstrated coagulopathy at admission as evaluated by APTT>35 s, which was associated with a 3-fold increase in mortality in accordance with that previously reported by Brohi et al.[
20,
21]. Patients with a rAAA rarely present with coagulopathy upon admission [
19] thus supporting the notion that the bleeding pathophysiology of these patients differ from that in severely injured trauma patients. In the present study, APTT was a strong and independent predictor of higher mortality in massively transfused patients, and even higher APTT in patients presenting with coagulopathy (APTT above normal) was an independent predictor of mortality whereas APTT could not predict mortality in patients presenting with a normal APTT. The findings of the present study could indicate that the devastating effects of trauma and subsequent hypoperfusion occurring immediately after the trauma and before arrival at the trauma center may not be reversed by transfusion therapy alone despite achievement of normal haemostatic competence early in the resuscitation phase, as previously reported [
22].
Furthermore, earlier transfusion and increased amounts of FFP and PLT did in this study not reduce the rate of MT patients since this was comparable in the two periods. However, due to the retrospective nature of this study, a cause-effect relationship between MT and different variables cannot be established.
Interestingly, we found that in the early period hemoglobin was the main factor that triggered early blood transfusion whereas higher ISS (or injury severity since ISS is a derived figure that was not available at the time point of admission) was a significant factor that triggered early transfusion in the late period. Furthermore, higher age was in the late period associated with longer time to first transfusion and transfusion of less FFP and hence a lower FFP:RBC ratio, indicating that patients with an advanced age received less aggressive transfusion therapy, which not is recommended in the hospital transfusion guidelines and consequently an effect introduced by the treating physicians. It is, however, unclear whether this practice negatively affected outcome in these individuals since in all groups studied, age was independently associated with outcome which is in alignment with previous reports [
9,
23]. The negative predictive value of higher age for survival following trauma is likely explained in part by the increase in co-morbidity and a higher frequency of patients on medications with advanced age, which may negatively influence hemostasis [
24] and cardiovascular adaptability. Furthermore, it is well established that systemic inflammatory response syndrome (SIRS) is a particularly serious problem in the aging population and this relates to increased production of pro-inflammatory cytokines [
25,
26]. Recently, it was reported that advanced age is associated with a decrease in thrombomodulin and activated protein C in an animal model, suggesting that also the anticoagulation system is negatively affected by older age, making the individual more pro-thrombotic [
27]. The findings of the present study however demonstrate that the negative predictive value of advanced age for survival is independent of presence or absence of coagulopathy, indicating that more general impairment of adaptation mechanisms may explain the excess mortality during critical illness including ACoTS.
This study has several limitations. Obviously it is a retrospective study not a prospective, the injury pattern (blunt vs. penetrating) has not been investigated, the amount of infused prehospital fluid has not been stated and might differ due to restrictive fluid resuscitation in period two. Also, given the limited number of patients included in this study the exclusion of more than twice the number of patients in the late group as compared to the early group may have influenced the results presented considerably.
In conclusion, the present study demonstrated that a change in transfusion therapy with more aggressive and early administration of FFP and PLT in relation to RBC did not influence survival in the trauma patients investigated, indicating that the devastating effects of trauma and subsequent hypoperfusion cannot be reversed by transfusion therapy alone. Prospective studies addressing the effect of various means of Hemostatic Control Resucitation in trauma patients presenting bleeding requiring transfusion are desperately needed.
Acknowledgements
The authors would like to thank Claus F. Larsen MD DMSc, Vibeke U. Dahl and Jan Olsen, The Trauma Centre Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark for help collecting data to the database.
Financial statement: The authors have no commercial interest related to this article.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
JD, HJ and CHJ: have made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; SRO: has made substantial contributions to analysis and interpretation of data; PIJ has made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. All authors have been involved in drafting the manuscript and have given final approval of the version to be published.