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Colombian Journal of Anestesiology

Print version ISSN 0120-3347On-line version ISSN 2256-2087

Rev. colomb. anestesiol. vol.48 no.3 Bogotá July/Sept. 2020  Epub Oct 15, 2020 

Systematic Review Article

Mortality in civilian trauma patients and massive blood transfusion treated with high vs low plasma: red blood cell ratio. Systematic review and meta-analysis

Henry Oliveros Rodrígueza  * 

Fernando Ríosa  b 

Cristhian Rubioc 

Daniel Martin Arsaniosa 

Andrés Felipe Herazoa 

Luis Mateo Beltrána 

Paloma Garcíaa 

Annie Cifuentesa 

Juliana Muñoza 

Javier Polaníaa 

a School of Medicine, Universidad de La Sabana, Chía, Colombia.

b Clínica Universidad de La Sabana, Chía, Colombia.

c Epidemiology Postgraduate Program, Facultad de Medicina, Universidad de la Sabana, Chía, Colombia.



Massive bleeding in civilian trauma patients leads to dilutional coagulopathy. Transfusion with high plasma:red blood cell (RBC) ratio has been effective in reducing mortality in war trauma patients. However, in civilian trauma the evidence is controversial.


To assess the impact on mortality of high vs low plasma:RBC ratio transfusion, in civilian trauma patients with massive bleeding.


A systematic review and meta-analysis, including observational studies and clinical trials, was conducted. Data bases were systemically searched for relevant studies between January 2007 and June 2019. The main outcome was early (24-hours) and late (30-day) mortality. Fixed and random effects models were used.


Out of 1295 studies identified, 33 were selected: 2 clinical trials and 31 observational studies. The analysis of observational trials showed both decreased early mortality (odds ratio [OR] 0.67; 95% confidence interval [CI], 0.60-0.75) and late mortality (OR 0.79; 95% CI, 0.71-0.87) with the use of high plasma:RBC ratio transfusion, but there were no differences when clinical trials were evaluated (OR 0.89; 95% CI, 0.64-1.26). The exclusion of patients who died within the first 24 hours was a source of heterogeneity. The Injury Severity Score (ISS) altered the association between high plasma:RBC ratio and mortality, with a reduced protective effect when the ISS was high.


The use of high vs low plasma: RBC ratio transfusion, in patients with massive bleeding due to civil trauma, has a protective effect on early and late mortality in observational studies. The exclusion of patients who died within the first 24 hours was a source of heterogeneity.

Keywords: Meta-analysis; Mas sive transfusion; Civilian trau ma; Mortality; Plasma; Red blood cells



El sangrado masivo en los pacientes con trauma civil propicia el desarrollo de coagulopatía dilucional. La transfusión de plasma y glóbulos rojos con una relación alta ha sido efectiva para disminuir la mortalidad en pacientes con trauma de guerra; sin embargo, su evidencia en trauma civil es controversial.


Evaluar el efecto sobre la mortalidad de la transfusión de plasma: glóbulos rojos con relación alta (TPGR-RA) versus baja, en pacientes con sangrado masivo por trauma civil.


Se realizó una revisión sistemática y metaanálisis de estudios observacionales y experimentos clínicos publicados en el periodo de enero de 2007 a junio de 2019. El desenlace principal fue mortalidad temprana (24 horas) y tardía (30 días), utilizando el modelo de efectos fijos y aleatorios.


De 1.295 estudios identificados se incluyeron 33: dos experimentos clínicos y 31 estudios observacionales. El uso de TPGR-RA mostró una disminución de la mortalidad temprana (OR 0,67; IC 95 %, 0,60-0,75) y tardía (OR 0,79; IC 95 %, 0,71-0,87) cuando se analizaron los estudios observacionales, pero no hubo diferencias cuando se evaluaron los experimentos clínicos (OR 0,89; IC 95 %, 0,64-1,26). La exclusión de pacientes que fallecieron en las primeras 24 horas fue una fuente de heterogeneidad. La gravedad del trauma, ISS (por las iniciales en inglés de injury severity score)modificó la asociación entre la TPGR-RA y mortalidad, siendo menor el efecto protector cuando el ISS era alto.


El uso de TPGR-RA en pacientes con trauma civil y transfusión masiva (TM) tiene efecto protector sobre la mortalidad en los estudios observacionales. La exclusión de pacientes fallecidos en las primeras 24 horas fue causa de heterogeneidad.

Palabras clave: Metaanálisis; Transfusión masiva; Trauma civil; Mortalidad; Plasma; Eritrocitos


The main causes of death in trauma patients during the first 24hours are exsanguination and central nervous system (CNS) injuries. Whenever there massive bleeding involving the CNS, mortality rises to 50% within the first hour.1 Bleeding results in important physiological changes that may even lead to the lethal triad of acidosis, hypothermia, and coagulopathy.2 Coagulation disorders are an independent factor for mortality3 accounting for 30% of the deaths of civilian trauma patients.4 The initial treatment of trauma patients requires surgical damage control and management of the hemorrhagic shock, in order to reduce blood loss to the minimum and restore tissue perfusion.5 These interventions include minimizing the use of crystalloids to prevent organ dysfunction associated with fluid overload-such as dilutional coagul opathy-and early use of blood products.6 These measures are resuscitation with damage control, intended to perform a hemostatic resuscitation to prevent death from exsanguination.7 In trauma patients requiring massive transfusion, the fresh frozen plasma (FFP) to platelets and red blood cells (RBCs) ratio has been studied, which provides the best protective effect. Consequently, there is an increasing number of trials assessing the impact of the FFP:RBC ratio on outcomes such as mortality or multiple organ failure, with controversial results.

Since 2005, the United States Army's Institute of Surgical Research Conference suggested the administra tion of a high ratio (1:1:1) instead of a low ratio (1:1:2).8 Later on, the Prospective, observational, multicenter, major trauma transfusion trial (PROMMTT)9 found that the administration of blood products with a high FFP:RBC ratio was associated with decreased mortality during the first 6 hours after the trauma event. In contrast, the clinical trial Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma (PROPPR),10,11 did not find any mortality reduction at 24 hours and at 30 days; however, there was a lower risk of early death due to exsanguination in patients treated with a high ratio. Moreover, some trials have reported an increase in the number of pulmonary complications and multiple organ failure with a higher FFP input.12,13

Notwithstanding, the consensus to intervene early in coagulopathy, with limited crystalloid use and early treatment with blood products,14 it is not clear however about which plasma: RBC ratio provides the best outcomes. Some observational studies and clinical experiments have compared different FFP:RBC ratios with varying results, attributable to differences in the definition of massive bleeding, early exclusion of deceased patients, and interventions at different time periods.15,16

The objective of this systematic review was to assess the impact on early and late mortality of the administration of high vs low FFP:RBC, in patients with civilian trauma massive bleeding, and to determine the sources of heterogeneity of the trials.


Selection of trials

A systematic literature review was conducted to identify observational studies and clinical controlled trials that addressed the research question, with no language restrictions. The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) recommendations were followed.17 The systematic review protocol was previously registered in PROSPERO (Record ID 111387).

The quality of the observational studies was assessed with the Newcastle-Ottawa scale (NOS),18 and in the case of clinical experiments, the Cochrane collaboration instruc tions were adopted.19 In order to identify the studies, the following e-databases were consulted, between the first week of 1990 and week 40 of 2019: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily Update, Embase, PsycINFO, and Lilacs, using the following search strategy: (trauma OR traumatic OR injur* OR wound*) AND (massive OR major) AND (haemorrhag* OR hemorrhag* OR bleed* ORtransfus* ORblood) AND (plasma OR component) AND (mortal* OR death* OR die OR died). In addition, the structured filters validated for observational studies of the Scottish Intercollegiate Guidelines Network were used, and for controlled clinical trials. The search was manually complemented with the snowball strategy and gray literature search using OpenGrey.

Inclusion criteria for the studies in this review

The studies that met the following criteria were included: clinical controlled trials or observational cohort, case controlled, studies that should include civilian trauma patients, report the FFP:RBC ratio admin istered, assess the mortality outcome, and embrace the previously established massive transfusion definition of ≥ 10 units in 24 hours, ≥ 6 units in 12 hours, or ≥ 5 units in 4 hours.20

Exclusion criteria for the studies

Any studies with the following characteristics were excluded: (a) studies such as case reports or case series; (b) studies using a historical cohort as the comparator; (c) studies that failed to consider the severity of the patients using scales such as the Injury Severity Score (ISS); and (d) studies, including patients with war or military trauma, or that included patients undergoing pro grammed surgeries.

Data mining

From each study, the information collected included the FFP:RBC ratio used for each one of the comparator groups, the mean age, the severity assessed with the ISS score, and in terms outcomes, mortality at 6,12, and 24 hours and at 30 days after hospital discharge. Two reviewers (HO, DM) independently checked all the abstracts, taking the exclu sion and inclusion criteria into account. Any differences among the studies selected were identified and reconciled, and the studies were independently reviewed as full texts.

Statistical analysis

The quality of the selected observational studies was assessed using the NOS scale,18 and in the case of clinical experiments, the Cochrane collaboration instructions were followed.19 Two reviewers (HO, DM) independently assigned a quality score and settled any disagreements by consensus. High-quality studies were those that obtained 7 or more points in NOS. The heterogeneity of the studies was assessed using the Q of Cochran, the I2, and the Tau index; high heterogeneity was considered as I2 > 50%. The odds ratio (OR) was measured in each study, with their corresponding confidence intervals (CIs). Mortality before 24hours was considered early and at 30 days late. The FFP: RBC ratio used was taken into account both in the intervention and in the comparator, and the accepted high ratio was that defined for each study. A 1:1 ratio represented the same number of units of FFP and RBC; in contrast, a 1:2 meant twice the amount of RBC per FFP unit, and this latter one was a lower ratio. For the combination of early and late mortality outcomes, it was stratified in accordance with the exclusion of deceased patients at 6, 12, and 24hours, in order to assess the differential opportunity to receive therapy for survival. The OR values were obtained for each summary measurement through the fixed effects models of the Mantel and Hansen model; the random effects model by inverse variance, charts, and analyses were conducted using the statistical software STATA 15.0 (StataCorp, College Station, TX).


General findings and quality assessment of the trials

With the search strategy, 1295 studies were identified and 74 of them were selected based on title and abstract; 25 failed to meet the inclusion criteria and an additional 16 were excluded due to various reasons; finally, 33 studies were included for analysis (Fig. 1).

Source. Authors.

Figure 1 Flowchart identification and selection of the trials that met the inclusion criteria. 

Of the studies included, 22 reported mortality in the first 24hours; in other 22, death was reported at 30 days, and 15 studies reported both outcomes. Most of the studies established as high FFP:RBC ratio cut points above 1:1.5 and 1:2. The quality of the observational studies assessed using NOS18 was three points for only one study.21 The rest had scores between 6 and 9, which translates into adequate-good quality. The risk of bias was low in the clinical experiments (Table 1).

Table 1 Overall characteristics of the studies. 

Reference Outcome mortality n Age ISS High ratio Odds ratio CI (95%) Quality Newcastle- Ottawa (18)
Holcomb et al22 30 days 418 39 33 1:2 1.99 (1.32-2.98) 8
24 hours 418 39 33 1:2 1.81 (0.16-2.81) 8
Sperry et al23 30 days 415 41 34 1:1.5 0.73 (0.45-1.20) 8
12 hours 415 41 34 1:1.5 0.28 (0.10-0.80) 8
Duchesne et al24 24 hours 135 33 27 1:1 0.05 (0.02-0.13) 8
Maegele et al25 30 days 713 41 41 1:1 0.51 (0.36-0.71) 8
24 hours 713 41 41 1:1 0.34 (0.22-0.41) 8
Gunter et al26 30 days 259 34 25 2:3 0.43 (0.24-0.76) 6
Kashuk et al27 24 hours 140 35 36 1:2 0.54 (0.27-1.06) 6
Teixeira et al28 30 days 383 32 31 1:2 0.37 (0.26-0.60) 7
Snyder et al29 24 hours 134 39 33 1:2 0.48 (0.24-0.96) 7
Dente et al30 30 days 73 35 29 1:1 0.56 (0.20-1.55) 6
24 hours 73 35 29 1:1 0.37 (0.11-1.23) 6
Zink et al31 30 days 452 33 31 1:1 0.43 (0.22-0.83) 6
6 hours 452 33 31 1:1 0.07 (0.01-0.55) 6
Mitra et al32 30 days 331 42 36 1:1.5 0.93 (0.49-1.74) 9
4 hours 331 42 36 1:1.5 0.32 (0.10-1.08) 9
Shaz et al33 30 days 190 37 27 1:2 1.18 (0.66-2.10) 6
24 hours 190 37 27 1:2 1.8 (0.92-3.54) 6
Lustenberger et al34 24 hours 229 40 37 1:1.5 0.08 (0.04-0.16) 7
Spoerke et al35 30 days 529 NA NA 1:4 0.39 (0.25-0.62) 7
24 hours 529 NA NA 1:4 0.29 (0.16-0.52) 7
Rowell et al36 30 days 704 40 32 1:2 0.71 (0.53-0.96) 9
24 hours 704 40 NA 1:2 0.54 (0.38-0.76) 9
Peiniger et al37 30 days 1250 41.8 42 1:2 2.11 (1.65-2.69) 9
24 hours 1250 41.8 42 1:2 3.29 (2.52-4.29) 9
Magnotti et al38 24 hours 103 38 32 1:2 0.39 (0.17-0.89) 7
Borgman et al39 30 days 659 43 34 1:2 0.61 (0.44-0.85) 8
24 hours 659 43 34 1:2 0.47 (0.33-0.68) 8
Biasi et al40 24 hours 393 39 32 1:3 1.54 (0.93-2.54) 6
Spinella et al41 30 days 461 38 40 1:2 0.74 (0.40-1.35) 6
Wafaisade et al42 30 days 1362 45 36 1:1 0.66 (0.51-0.85) 8
24 hours 1362 45 36 1:1 0.51 (0.36-0.73) 8
Brown et al43 6 hours 604 43 37 1:1.5 0.37 (0.14-0.95) 6
Sharpe et al44 30 days 135 37 32 1:1.5 0.46 (0.23-0.94) 7
Duchesne et al45 24 hours 451 38 23 1:2 0.38 (0.22-0.65) 9
Simms et al46 3 hours 151 33 29 1:1.4 0.19 (0.08-0.45) 6
Guidry et al47 6 hours 234 35 25 1:2 0.63 (0.35-1.14) 9
Nascimento et al48 30 days 69 41 35 1:1 4 (1.03-16.3)
Kudo et al49 30 days 15 60 25 1:1.5 0.8 (0.10-6.35) 7
6 hours 15 60 25 1:1.5 1 (0.11-8.95) 7
Kim et al50 30 days 100 47 32 1:2 0.61 (0.26-1.46) 8
24 hours 100 47 32 1:2 0.08 (0.02-0.39) 8
Rubén Peralta et al21 30 days 77 34 29 1:1.5 0.2 (0.07-0.55) 3
24 hours 77 34 29 1:1.5 0.15 (0.05-0.45) 3
Stanworth et al51 24 hours 298 38 28 1:2 0.35 (0.19-0.65) 9
Holcomb et al11 30 days 680 34 26 1:1 0.81 (0.57-1.15) *
24 hours 680 34 26 1:1 0.71 (0.47-1.09)
Endo et al52 30 days 1777 NA NA 1:1.25 0.85 (0.60-1.21) 8

* RCT = randomized controlled trials.

Source: Authors.

Summary measurements of mortality assessment

When analyzing the 31 observational studies (n = 13924), the use of a high FFP:RBC ratio was associated with lower early mortality (OR 0.67; 95% CI, 0.60-0.75) and late (OR 0.79; 95% CI, 0.71-0.87), but with a significant heterogeneity for both estimates, with an I2 of 91.9% and 86.3%, respectively. There were no differences between the groups when assessing the clinical (n =749) (OR 0,89; 95% CI, 0.64-1.26) and the heterogeneity was high (I2 79.8%). The observational studies took into account the potential differences due to the exclusion of deceased patients over the first 24hours following admission, and hence the summary measurements were stratified (6,12, and 24 hours and studies that did not exclude the deceased patients). The result was that by not excluding the death over the first 24hours, the protective effect on early mortality was maintained (OR 0.58; 95% CI, 0.38-0.89), but that was not the case for late mortality (OR 0.72; 95% CI, 0.46-1.11) (Fig. 2).

Source: Authors.

Figure 2 Effect of high vs low FFP:RBC ratio on mortality. (A) Mortality at 24 hours in observational studies. (B) 30-days mortality in observational studies. (C) Mortality in clinical experiments. FFP = fresh frozen plasma, RBC = red blood cell. 

Heterogeneity assessment

As shown in Table 2, when mortality was stratified in accordance with the exclusion of deceased patients at 6,12, and 24hours, the heterogeneity decreased in all categories as compared against the global I2. Additional stratifications were conducted, keeping in mind the time at which the transfusion was initiated (4,6,12, and 24hours); no reduced heterogeneity was observed in the studies.

Table 2 Summary of early and late mortality measurements based on the exclusion of patients with massive bleeding. 

* With P < 0.05. Source: Authors.


To assess the ISS and age with the association between high FFP:RBC and early and late mortality, a meta-regression was conducted using the random effects model. As shown in Fig. 3, as the ISS value increases, the strength of the association between a high FFP:RBC ratio and mortality reduction. This can be inferred from the value of the slope ß0 = 1.6 for early mortality and ß0 = 1.7 for late mortality. However, the CIs are wide and contain the zero value.

Source: Authors.

Figure 3 Meta-regression of the ISS effect on the association between high FFP:RBC ratio and mortality. FFP = fresh frozen plasma, ISS = Injury Severity Score, RBC = red blood cell. 

Publications bias

The publication bias assessment used the funnel chart and Egger's test to determine the asymmetry via lineal regression. An asymmetry was found mainly for the studies that assessed the late mortality outcome. This asymmetry could be due to a very high heterogeneity, to the quality differences and to the size of the trials (Fig. 4).

Source: Authors.

Figure 4 Assessment of publication bias in studies reporting early and late mortality (A and B, respectively). 


In this meta-analysis, the use of a high FFP:RBC ratio in civilian trauma patients and massive transfusion was associated with a lower mortality risk over the first 34 hours to 30 days when the observational studies were evaluated. There were no significant differences when conducting clinical experiments. When the outcome was stratified based on the exclusion of deceased patients over the first 24 hours, the protective effect was maintained only for early mortality but not for late mortality; this may be due to the survival bias. Furthermore, the ISS changed the association between a high FFP:RBC ratio and mortality, being lower when the ISS was high.

Resuscitation of severe trauma patients and major bleeding has experienced significant changes, including the restricted use of crystalloids, surgical damage control, and balanced ratio transfusions, that are intended to match the total blood, an approach known as damage control resuscitation.53 This particular strategy has been associated with lower requirements of blood products, decreased inflammation, and probably improved survival.

Despite all of these, the ideal FFP:RBC ratio is still controversial. The literature published between 2007 and 2015, based on observational studies, found that high ratios have a protective effect on mortality and hence the scientific associations issue recommendations based on this guideline.54 However, these studies must be inter preted with caution because of their design. Rahouma et al15 suggest some limitations with regards to the survival bias because several studies ignored the exact time of the blood products transfusion; hence, it might be possible that balanced ratios (high) could have been administered to the patients who survived the first hours, that is, the less severe. Our meta-analysis supports the possibility of survival bias in the observational studies, because when the outcomes were stratified in accordance with the exclusion of deceased patients over the first 24 hours, the early mortality protective effect declined and was non-existent for the late mortality.

There are other potential variables apart from the FFP: RBC ratio that may influence the mortality outcome; for instance, the early and timely administration of blood products (FFP in particular). So only by improving the transfusion protocol for patients with massive bleeding, has it been possible to report decreases in mortality from 45% to 19%.55 These appreciations were tested in a clinical experiment. Holcomb et al in the PROPPR trial10,11 found no significant differences in mortality at 24 hours and 30 days, though homeostasis was achieved faster and there were less deaths as a result of exsanguination in the group treated with a high ratio. Moreover, the authors claim that about 15% of the deaths were due to traumatic brain injury, which could have contributed to the absence of differences.

The PROPPR trial11 also showed that the administra tion of higher than 1:1 ratio had no additional benefiting mortality, which is a consistent finding with the result of this meta-analysis, since we stratified based on different FFP:RBC ratios, we did not identify that as a source of heterogeneity. With regards to other sources of heterogeneity suggested by other authors, such as time of initiation of the administration of blood products,56 the total number of units transfused, and the amount of crystalloids administered,44,57 these became study limitations and made it impossible to stratify based on these variables because they were not reported.

Our study has its limitations. First, the volume of crystalloids administered over the first few hours is unknown and this is a risk factor for coagulopathy and death;52,58 however, this is a limitation typical of individual studies, since these variables are not reported. Neither is the use of other interventions assessed, such as cryoprecipitates, prothrombin complex concentrate, fibrinogen concentrates, and tranexamic acid. Moreover, the definition of massive transfusion includes a very long period of observation (up to 24hours), which could delay the onset of adequate therapy and favor the survival bias. This has shorten the time to diagnosis of MT to just a few hours (critical threshold for the administration of three units in one hour)59,60 and to adopt massive bleeding prediction models such as: modified shock index,61 Assessment of Blood Consumption score ABC62 Trauma Associated Severe Hemorrhage Score TASH,63 Schreiber Score64 Emergency Transfusion Score ETS,65 and the Prince of Wales Hospital Score PWH.66 The final goal of this reasoning is to reduce the observation period and start hemostatic resuscitation early.63

Although the right blood products ratio continues to be a valid query, its generalized use has been questioned, because of the risk of acute pulmonary injury and multiple organ failure. Along these lines, the proposal is to individualize treatment and direct transfusion support based on a therapy guided by objectives, aimed at achieving normal hemostasis, since it has been able to reduce bleeding, decrease the amount of blood products used, and improve other outcomes.67 To this end, "bedside" coagulation tests are conducted with viscoelastic methods (VEM) and based on the results, the specific blood products used are determined. Some authors suggest a mixed strategy that comprises transfusion therapy with high ratio during the early massive bleeding, and then make some adjustments in accordance with a VEM algorithm (thromboelastography or thromboelastometry).68


The use of high FFP:RBC ratio in civilian trauma patients and massive transfusion was associated with a lower mortality risk in the first 24 hours and at 30 days when the observational trials were assessed. There were no signifi cant differences when analyzing the clinical experiments. When the outcomes were stratified in accordance with the exclusion of deceased patients over the first 24hours, a protective effect was maintained only for early mortality, with no differences in late mortality. The studies identified showed an increased heterogeneity resulting from multi ple sources; one of the most relevant ones was the exclusion of patients who die early, before the first 24 hours after the trauma event, which represents a survival bias. Other sources of heterogeneity, such as the severity of the trauma, changed the use of blood products and mortality, as evidenced in the meta-regression.


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How to cite this article: Oliveros Rodríguez H, Ríos F, Rubio C, Arsanios DM, Herazo AF, Beltrán LM, García P, Cifuentes A, Muñoz J, Polanía J. Mortality in civilian trauma patients and massive blood transfusion treated with high vs low plasma: red blood cell ratio. Systematic review and meta-analysis. Colombian Journal of Anesthesiology. 2020;48:126-137.

Copyright © 2020 Sociedad Colombiana de Anestesiología y Reanimación (S.C.A.R.E.). Published by Wolters Kluwer. This is an open access article under the CC BY-NC-ND license (

Funding The authors have no funding to disclose.

Conflicts of interest The authors have no conflicts of interest to disclose.

* Correspondence: Universidad de La Sabana, Campus Puente del Común, km 7.5 Autopista Norte de Bogotá, Chía, Colombia. E-mail:

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