What is the REPHILL Trial?
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Introduction
Traumatic hemorrhage is a leading cause of preventable death in trauma patients. Early intervention with blood products in the pre-hospital setting has been hypothesized to improve outcomes by addressing shock and coagulopathy sooner. However, the optimal pre-hospital use of blood products in major trauma has remained uncertain, with conflicting evidence from previous trials [1, 2]. The Resuscitation with Pre-Hospital Blood Products (RePHILL) trial aimed to investigate this critical question.
Background
The RePHILL trial was designed to determine whether the pre-hospital administration of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) is superior to 0.9% sodium chloride (saline) in improving tissue perfusion and reducing mortality in adult patients experiencing trauma-related haemorrhagic shock [1]. Previous research in both military and civilian settings suggested that early transfusion might improve survival, but robust evidence from randomized controlled trials was lacking [2]. Challenges in conducting such trials include logistical complexities, the limited shelf-life of fresh frozen plasma, and the rapid transport times often seen in established trauma networks [2].
Methods
RePHILL was a multicentre, open-label, parallel-group, randomized, controlled, phase 3 superiority trial conducted across four civilian pre-hospital critical care services in the UK. The trial enrolled adults (aged ≥16 years) presenting with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of a palpable radial pulse) [1].
Participants were randomly assigned in a 1:1 ratio to receive either:
•Intervention Group: Up to two units each of PRBC and LyoPlas.
•Control Group: Up to 1 L of 0.9% sodium chloride.
Both treatments were administered via the intravenous or intraosseous route. Sealed treatment packs, identical in external appearance, were prepared by blood banks and distributed according to a randomization schedule stratified by site [1].
The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. Secondary outcomes included individual components of the primary outcome, early survival, and transfusion-related complications [1, 2].
Recruitment for the trial ran from November 29, 2016, to January 2, 2021. The trial was stopped before reaching its intended sample size of 490 participants due to disruptions caused by the COVID-19 pandemic, ultimately enrolling 432 participants (209 in the PRBC-LyoPlas group and 223 in the 0.9% sodium chloride group) [1].
Findings
The median follow-up period was 9 days (IQR 1 to 34) for the PRBC-LyoPlas group and 7 days (0 to 31) for the 0.9% sodium chloride group. The study population was predominantly male (82%) and white (62%), with a median age of 38 years (IQR 26 to 58). Most injuries resulted from road traffic collisions (62%), with participants presenting with severe injuries (median Injury Severity Score 36, IQR 25 to 50). Prior to randomization, participants had received an average of 430 mL of crystalloid fluids and tranexamic acid (90%) [1].
The composite primary outcome occurred in 128 (64%) of 199 participants in the PRBC-LyoPlas group and 136 (65%) of 210 in the 0.9% sodium chloride group. The adjusted risk difference was -0.025% (95% CI -9.0 to 9.0), with a p-value of 0.996, indicating no statistically significant difference between the two groups [1].
Regarding individual components of the primary outcome and other secondary outcomes (e.g., early survival), point estimates were consistent with a potential benefit from PRBC/LyoPlas, but the confidence intervals were wide, encompassing both potential benefits and harms. Bayesian exploratory analysis indicated a probability of 71.2% to 88.2% for episode mortality benefit and 81.3% to 86.9% for lactate clearance benefit, but the 95% credible intervals crossed zero [2].
Participants in the PRBC/LyoPlas group had higher haemoglobin levels upon hospital admission and received cumulatively more blood products overall compared to the control group. However, RePHILL did not find evidence that pre-hospital transfusion improved oxygen delivery as measured by lactate levels or lactate clearance [2].
Transfusion-related complications within the first 24 hours post-Emergency Department (ED) arrival were similar across both groups (PRBC-LyoPlas: 11 [7%] of 148; 0.9% sodium chloride: 9 [7%] of 137; adjusted relative risk 1.05 [95% CI 0.46-2.42]). Serious adverse events included acute respiratory distress syndrome (6% in PRBC-LyoPlas vs. 2% in saline) and other rare events, but no treatment-related deaths were reported [1].
Interpretation and Conclusion
The RePHILL trial concluded that pre-hospital resuscitation with PRBC-LyoPlas was not superior to 0.9% sodium chloride for adult patients with trauma-related haemorrhagic shock [1]. Several factors may explain these findings:
•Established Trauma Network: The study was conducted in a civilian setting with a well-established major trauma network, where pre-hospital critical care teams already provide advanced life support, potentially diluting the impact of early blood product administration [2].
•Rapid Transport Times: The national trauma network aims for transfer to a major trauma center within 60 minutes. A significant proportion of participants had transport times under 20 minutes, which some post-hoc analyses suggest may limit the survival benefit of pre-hospital transfusion [2].
•LyoPlas vs. Fresh Frozen Plasma: The trial used freeze-dried LyoPlas due to logistical challenges. While LyoPlas has similar biological efficacy to fresh frozen plasma, some secondary analyses suggest fresh frozen plasma in combination with red cells might reduce mortality more effectively [2].
•Patient Population: The civilian participants in RePHILL were older, more severely injured, and had a higher proportion of blunt traumatic injuries compared to military studies that suggested benefit from pre-hospital blood transfusion [2].
The trial highlights the need for further research to identify specific patient characteristics that might benefit from pre-hospital transfusion and to define optimal outcomes for future transfusion trials in major trauma. The decision to implement routine pre-hospital transfusion requires careful consideration by all stakeholders [1]. The trial also demonstrated that pre-hospital RBC use did not lead to substantial wastage (2%), providing assurance regarding resource management [2].
References
[1] Crombie, N., Doughty, H. A., Bishop, J. R. B., et al. (2022). Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. The Lancet Haematology, 9(4), e250-e261. Available at: https://pubmed.ncbi.nlm.nih.gov/35271808/
[2] Crombie, N., Doughty, H. A., Bishop, J. R. B., et al. (2022). Discussion - Resuscitation with pre-hospital blood products in adults with trauma-related haemorrhagic shock: the RePHILL RCT. National Center for Biotechnology Information (NCBI) Bookshelf. Available at: https://www.ncbi.nlm.nih.gov/books/NBK599232/