Introduction

Transfusion in trauma (I won’t abbreviate that) has evolved at a rapid pace over the last decade and it can be hard to keep up with the latest evidence. I also find it useful to think about the story of how the science has developed to lead us to our current practice. The purpose of this post is to provide a narrative of how we have arrived at the contemporary approach to transfusion in trauma. So…let’s see if you remember your PROMMTT from your PAMPER. 

A (very) distilled history of transfusion would note that early transfusions were largely driven by the need to treat bleeding pathology, including wounded soldiers, and that initially, these transfusions were with whole blood. As technology advanced and transfusion requirements changed within the population, blood was fractionated into components, and since the 1970s the vast majority of transfusions have been as such. It is worth mentioning that this is very much a high-income country phenomenon; the majority of transfusions in large parts of the world remain as whole blood. If you read the literature from the major conflicts of the first half of the last century up until the Vietnam War whole blood transfusion was lauded amongst surgeons. 

So how did we get to 2 litres of crystalloid I hear you ask? The possible origin of this comes from Shires and Canizro (1973). I have included some excerpts from their paper ‘Fluid Resuscitation in the Severely Injured’ below (let me know if you want a PDF copy). My interpretation is that the authors argued that the rapid infusion of lactated Ringer’s solution whilst awaiting cross-matching would provide support the circulation and also reduce the volume of whole blood required. In fairness to them, the authors reported very good outcomes ‘This decrease in the rate of transfusion reactions, combined with the prompt correction of associated extracellular fluid volume deficits and restoration of blood flow, has virtually eliminated oliguric renal failure as a complication of shock.’ I would encourage everyone to read this paper. I think we should be careful to use ‘dogma’ as a pejorative; even ‘dogmatic’ practices are usually a result of a lot of hard work and often good contemporary science. It is important to read the first line of this excerpt.

In the early 1990s, the concept of damage control emerged and revolutionised the approach to caring for the critically injured. Originally the concept of damage control was used by naval fleets to describe the rapid, and temporary, repair of a damaged warship until it could be taken to a place of safety to be definitively repaired. This translated well to the bleeding trauma patient; efforts are to preserve life first and foremost and definitive intervention can be performed later at a time of more favourable physiology. The damage control approach was born out of a recognition that conventional, definitive, surgical approaches often led to coagulopathy, hypothermia, and acidosis – otherwise known as the ‘lethal triad’. When this concept was first introduced, it largely applied to surgical interventions and subsequent medical care, and as such was described as damage control surgery (DCS). DCS is best summarised as an approach that emphasises abbreviated surgical procedures, followed by a period of physiological optimisation in intensive care facilitating definitive surgical repair at a later date. Almost as soon as DCS had been conceptualised it evolved to include non-operative interventions and changed in name to damage control resuscitation (DCR). This rapid evolution was largely driven by the identification of acute traumatic coagulopathy. In 2003 Brohi published a study of one thousand eight hundred and sixty-seven trauma patients and demonstrated that around one in four patients arrived at the emergency department with an established endogenous coagulopathy. This endogenous coagulopathy was termed acute traumatic coagulopathy but appeared to be compounded by resuscitation strategies at the time which revolved around large-volume crystalloid infusion. Cue the dawn of the contemporary research of transfusion in trauma!

So what’s happened since 2006 (14 years of key papers) in transfusion in trauma

2006 Malone (PMID 16763487) A review of massive transfusion protocols. Evaluated the likelihood of preventing or correcting coagulopathy addressed by the numbers of units of plasma and platelets administered. Very few institutions had massive transfusion protocols, and those that were present were designed to treat dilutional coagulopathy. The authors argued that prevention is better than cure, and advocated for the study of a simple transfusion protocol targeting ratios of 1:1:1 RBC:plasma:platelets.

2007 Borgman (PMID 18090009) Retrospective review of 246 US military patients receiving >10U RBCs in 24 hours. Three groups were formed based on the ratio of plasma to RBC ratios; low 1:8, medium 1:2.5, high 1:1.4). Mortality across the three groups was 65%, 34%, and 19% respectively. Almost all of these patients had sustained penetrating injuries. There were fewer early deaths and deaths from haemorrhage in the high ratio group, and they received less crystalloid, fewer RBCs, and more cryoprecipitate. 

2007 Gonzalez (PMID 17215741) Retrospective review of data from a single Level 1 US trauma centre. 97 patients over 4 years received treatment as per an ICU protocol at the institution. Patients arrived to the hospital coagulopathic and on admission to ICU were coagulopathic. The pre-ICU resuscitation strategy was crystalloid and RBC heavy, and FFP was not given until after 6 units of RBC. ICU resuscitation was also crystalloid and RBC heavy, but FFP was matched to RBC administration. Coagulopathy normalised whilst on the ICU. The authors suggested the study of earlier administration of 1:1 RBC:plasma. 

2008 Maegele (PMID 18557827) Retrospective review of German trauma registry. 713 patients were divided into three groups based on RBC:FFP ratios of >1.1, 0.9-1.1, <0.9. Mortality rates were higher at 6 hours, 24 hours, and 30 days in patients who received a ratio 1:>1.1. Mortality was lowest in the group receiving a ratio of 1:<0.9. The authors supported further study of aggressive early use of FFP. 

2008 Holcomb (PMID 18791365) Retrospective review of 466 patients receiving massive transfusion transported to one of 16 level 1 US trauma centres. The study compared groups formed by combinations of high or low ratios of plasma and platelets to RBCs. Plasma and platelet ratios to RBC and injury severity were predictors of mortality. The group with the best survival had high ratios of both platelets and plasma to RBCs. This group had increased survival at 6 hours, 24 hours, and 30 days. There were more ICU, ventilator, and hospital-free days associated with higher ratios. 

2008 Gunter Jr (PMID 18784564) Retrospective review of populations pre- and post-introduction of a trauma exsanguination protocol at a single level 1 US trauma centre. Comparisons were made between patients who received FFP:RBC ratios of 2:3 and platelet:RBC ratios of 1:5 with those who did not reach those ratios. 259 patients were included in the study. An FFP:RBC of 2:3 or greater was associated with a reduction in mortality (41% vs 62%) and regression analysis found that the ratio of FFP:RBC is an independent predictor of mortality. Similarly, a higher ratio of platelets:RBC was associated with lower mortality (38% vs 61%).

2013 PROMMTT (PMID 23560283) Prospective cohort study in adult trauma patients receiving at least 1 unit RBC within 6 hours of admission and at least 3 units within 24 hours. The study was set across 10 US level 1 trauma centres. Patients with ratios of plasma:RBC or and platelets:RBC <1:2 were 3-4 times more likely to die than those patients that received a ratio of 1:1 or higher. 

2015 PROPPR ( 25647203) A multicentre RCT comparing plasma:platelet:RBC ratios of 1:1:1 vs. 1:1:2. The primary outcomes were 24 hour and 30 day all cause mortality. No difference in mortality at either time point, however 1:1:1 ratio resulted in more haemostasis and fewer deaths due to exsanguination and no differences in adverse events.

2015 CRYOSTAT 1 (PMID 25991760) Unblinded RCT at two UK MTCs in adult trauma patients with active bleeding. The aim of the study was to assess the feasibility of administering cryoprecipitate within 90 minutes of admission. Fibrinogen is essential for clot integrity, and levels have been shown to fall rapidly in traumatic haemorrhage. The study demonstrated that patients randomised to receive expedited cryoprecipitate did so in a median time of 60 minutes vs a median time of 108 minutes in the standard care group. Fibrinogen concentrations were also higher in the experimental arm. 

2018 COMBAT PMID (30032977) Single-centre randomised trial investigating the use of pre-hospital plasma. Consecutive trauma patients with haemorrhagic shock were assessed on scene and randomised to receive either two units of plasma or normal saline (volume determined by ‘haemodynamic need’). It should probably be noted that some patients in the plasma group also received additional normal saline pre-hospital, presumably due to clinical instability, and also pre-hospital times were 16-19 minutes(!). The primary endpoint was 28-day mortality. 65 patients were randomised to receive plasma and 60 received saline. There was no difference in mortality between the two groups. 

2018 PAMPER (PMID 30044935) Multicentre RCT assessing pre-hospital plasma vs. standard care. The primary outcome was 30-day mortality. Set across 27 pre-hospital aeromedical transport services. 501 patients were randomised with 230 in the plasma arm and 271 in the standard care arm. Mortality was lower in the plasma arm (23.2% vs 33%). Additionally, the plasma group had lower mortality at 24 hours, lower mortality across most prespecified subgroups, and received fewer blood products overall. The survival benefit appeared to occur after 3 hours and persisted until day 30. The NNT = 10! Concern over the plausibility of the effect (10% reduction in mortality) from just two units of plasma – raises the possibility of confounders. 

2021 iTACTIC (PMID 33048195) This was a slightly different kind of trial and one that I will discuss elsewhere in the future. iTACTIC was a multicentre RCT that didn’t investigate different ratios of blood products, but rather investigated whether the transfusion of blood products was better guided by conventional lab tests (INR, fibrinogen, platelets) or by viscoelastic assays (TEG/ROTEM). The primary outcome was the number of patients alive and free of massive transfusion at 24 hours, and the study did not find a difference between the two groups. Interestingly there was a very strong signal that resuscitation guided by viscoelastic studies reduced mortality in patients with severe traumatic brain injury.

2022 REPHILL (PMID 35271808) Multicentre RCT of RBC and lyophilised plasma vs. normal saline for pre-hospital resuscitation of haemorrhagic shock. Patients either received up to 4 units (2 RBC + 2 plasma) of blood products or up to 4 250mL bags of normal saline. Primary outcome was a composite of mortality between injury and discharge, failure to reach a lactate clearance of >/= 20%, or both. There was no difference between the experimental and control arms (64% vs 65%). Mortality was similar in both groups (43 vs 45%) as was the failure to clear lactate (50% vs 55%). There was a signal of benefit for early survival with blood products but overall there was no mortality benefit.

2023 PRBC/PLASMA (PMID 36650557). Comparison of a combined unit of red cell and plasma (RCP) against RBC alone, or RBC and plasma separately. 295 received patients RCP, 223 received RBC alone, and 391 received RBC and plasma. Patients receiving either RCP or RBC and plasma had lower odds of death at 24-hours compared to those receiving RBC alone. This difference was amplified by penetrating injury and not seen in blunt injury. 

2023 PROCOAG (PMID 36942533) Multicentre RCT of the benefit of using 4-factor prothrombin complex concentrate (4F-PCC) vs placebo (normal saline) on reducing the 24-hour all blood product use. Patients were resuscitated as per the European guidance on bleeding in trauma and the experimental interventions were given in addition as close to admission as possible. 324 patients were included in the final analysis with no difference between the groups in the number of RBCs transfused, however there were more thromboembolic events in the group receiving the 4F-PCC

Results Awaited: CRYOSTAT 2 Building on CRYOSTAT 1 (obviously), this was an international, pragmatic, multi-centre, parallel group, randomized controlled trial, which ran at all of the major trauma centres in England and at 8 international centres. It designed to answer whether the addition of early cryoprecipitate to the current standard of care Major Haemorrhage Protocol (MHP) improves survival from major trauma haemorrhage. The study has stopped recruiting and I understand analysis is near completion so watch this space.

Ongoing: Study of Whole Blood in Frontline Trauma (SWIFT) This is a pre-hospital trial of whole blood (RBCs, plasma, and platelets) in a single product compared to individual transfusions of red cells and plasma.

The Current State of Play

The snapshot below is from the NICE Major Trauma guidance (2016). It’s hard to argue that much has changed despite a phenomenal amount of research; we can still broadly agree and adhere to most of the points in the guidance below. The eagle-eyed might notice that there is no mention of platelets, and from personal and wider anecdotal experience we know that platelets can be slow to reach the patient. I think there is a feeling that we aim for 1:1:1, but how often this is achieved at the time of resuscitation (vs. topped up to 1:1:1 by 24 hours)? I don’t know the answer to that, and I also don’t know if it makes a difference, but logically rapid transfusion of unmatched red cells, or red cells and plasma but without platelets or cryoprecipitate feels intuitively like it might be worse than a balanced transfusion from the off.

Hopefully, this has provided a whistle-stop tour of transfusion in trauma and how we have arrived at our current standard of care. In the US there is a substantial amount of work involving the use of low titer O-neg whole blood with promising results, expect much more on this in the future. In the UK, were have a slight issue with whole blood due to historic vCJD, however as the SWIFT trial is demonstrating NHS blood transfusion has developed a whole blood product. What I find most fascinating is that the conversations ongoing in the trauma community are the same that were being had in the 1990s, the 1970s, and the 1940s!

We are always standing on the shoulders of giants, and sometimes nothing in medicine is really that new. We have seen a move from whole blood transfusions at the start of the last century, to crystalloids, to component therapy, to component therapy in ratio resembling whole blood, and now we’re back at whole blood – hopefully, this will be the last turn of this particular wheel! What is more interesting is the signals coming from early (per-hospital) use of blood products and the potential benefits – this is clearly the area to keep an eye on. We also know that different injury patterns behave differently, so perhaps we can expect to see more nuanced studies of particular populations (blunt, penetrating, head injured). Our approach to transfusion in trauma will continue to evolve and we will develop nuanced approaches to transfusion in different groups of patients. Trauma is not a homogenous disease and the difficulty ahead is identifying which group will benefit from whole blood, which group will benefit from targeted factor replacement via viscoelastic assays, and which patients don’t have any transfusion!

Cheers

Rich

References

1. Malone et al. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma. 2006 60(6 Suppl):S91-6. 
2. Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. 2007 63(4):805-13.Gonzalez et al  Fresh frozen plasma should be given earlier to patients requiring massive transfusion 2007 62(1):112-9
3. M Maegele et al. Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox Sang. 2008 95(2):112-9
4. Holcomb et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008 248(3) 447-58
5. Gunter Jr et al. Optimizing outcomes in damage control resuscitation: identifying blood product ratios associated with improved survival. J Trauma. 2008 65(3) 527-34
6. Holcomb et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg 2013 148(2) 127-36
7. Holcomb et al. 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: the PROPPR randomized clinical trial. JAMA 2015 313(5) 471-82.
8. Curry et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015 115(1) 76-83
9. Moore et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet 2018 392(10144):283-291
10. Sperry et al. Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. NEJM 2018 379(4):315-326
11. Baksaas-Aasen et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med 2021 47(1):49-59
12. Crombie et al. Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol 2022 9(4):e250-e261
13. Tucker et al. Association of red blood cells and plasma transfusion versus red blood cell transfusion only with survival for treatment of major traumatic hemorrhage in prehospital setting in England: a multicenter study. Crit Care 2023 27(1):25
14. Bout et al. Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial JAMA. 2023 ahead of print