RePHILL: Prehospital Blood Product vs. Saline Resuscitation in Trauma (2022)

“Among patients with trauma-related hemorrhagic shock, prehospital resuscitation with red blood cells and lyophilized plasma did not result in a significant difference in a composite of mortality or lactate clearance at 2 hours, as compared with resuscitation with saline.”

  • The RePHILL Trial Investigators

1. Publication Details

  • Trial Title: Prehospital Resuscitation With Red Blood Cell Units and Lyophilized Plasma in Trauma Patients: The RePHILL Randomized Clinical Trial
  • Citation: Crombie N, Woolley T, Munder T, et al. Prehospital Resuscitation With Red Blood Cell Units and Lyophilized Plasma in Trauma Patients: The RePHILL Randomized Clinical Trial. JAMA. 2022;328(13):1311-1321. DOI: 10.1001/jama.2022.17290
  • Published: October 4, 2022, in The Journal of the American Medical Association (JAMA)
  • Author: Nicholas Crombie, M.B., Ch.B., Ph.D.
  • Funding: UK National Institute for Health Research.

2. Keywords

  • Trauma, Hemorrhagic Shock, Prehospital Care, Blood Transfusion, Plasma, Damage Control Resuscitation, Randomized Controlled Trial

3. The Clinical Question

  • In adult trauma patients with hemorrhagic shock (Population), does prehospital resuscitation with packed red blood cells (PRBCs) and lyophilized plasma (Intervention) compared to 0.9% saline (Comparison) improve a composite outcome of mortality or impaired lactate clearance at 2 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The principles of damage control resuscitation, emphasizing early and balanced transfusion of blood products to treat coagulopathy, had become the standard of care inside the hospital. This was based on trials like PROPPR (2015).
  • Knowledge Gap: It was a major clinical and logistical question whether these principles could and should be applied even earlier, in the prehospital setting. The potential benefit of earlier hemostatic resuscitation had to be weighed against the significant logistical challenges and costs of providing blood products in the field.
  • Proposed Hypothesis: The authors hypothesized that a strategy of prehospital PRBCs and plasma would be superior to saline in improving the composite outcome of mortality or impaired lactate clearance.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 4 air ambulance services in the United Kingdom.
  • Trial Period: Enrollment ran from June 2016 to January 2021.
  • Population:
    • Inclusion Criteria: Adult trauma patients with evidence of hemorrhagic shock, defined by a systolic blood pressure < 90 mm Hg and tachycardia > 110 bpm.
    • Exclusion Criteria: Included patients under 16 years of age and those with isolated head injury.
  • Intervention: Patients received prehospital resuscitation with up to 4 units of blood products: 2 units of O-negative PRBCs and 2 units of lyophilized (freeze-dried) plasma.
  • Control: Patients received prehospital resuscitation with up to 1 liter of 0.9% saline.
  • Management Common to Both Groups: All patients received standard prehospital trauma care, including tranexamic acid. Upon hospital arrival, resuscitation was continued according to standard major hemorrhage protocols.
  • Power and Sample Size: The authors calculated that a sample size of 490 patients would be required to have 90% power to detect a 12.5% absolute difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: A composite of mortality or impaired lactate clearance (<20%/hour) at 2 hours after randomization.
    • Secondary Outcomes: Included 30-day mortality, blood product use, and the incidence of complications like ARDS and multi-organ failure.

6. Key Results

  • Enrollment and Baseline: 432 patients were randomized (209 to the blood product group and 223 to the saline group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary composite outcome. The primary outcome occurred in 137 of 209 patients (65.6%) in the blood product group and in 143 of 223 patients (64.1%) in the saline group (p=0.76).
  • Secondary Outcomes: There were no significant differences between the groups in 30-day mortality or in the incidence of ARDS or multi-organ failure.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.76 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: In a pre-specified subgroup analysis of patients with penetrating trauma, there was a suggestion of benefit with the blood product strategy, but this was not statistically significant.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical prehospital question.
  • Generalizability: The pragmatic design makes the findings generalizable to similar advanced, physician-led prehospital trauma systems.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of mortality, although as part of a composite primary endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted in an advanced trauma system with very short prehospital times (median ~40 minutes). The results may not be generalizable to systems with longer transport times, where the benefit of earlier blood product administration might be greater.
  • Other: The primary outcome was a composite endpoint driven largely by the lactate clearance component, which is a physiological surrogate. The trial was underpowered to detect a difference in mortality alone.

10. Conclusion of the Authors

  • The authors concluded that among trauma patients with hemorrhagic shock, prehospital resuscitation with PRBCs and lyophilized plasma did not result in a significant difference in the composite of mortality or impaired lactate clearance compared with resuscitation with saline.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the routine implementation of a complex and expensive prehospital blood product program in trauma systems with short transport times.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with hemorrhagic shock in an advanced trauma system with rapid transport to a trauma center.
    • Actionable Intervention: The results do not support the routine use of prehospital blood and plasma over saline.
  • What This Trial Does NOT Mean: This trial does NOT mean that early blood product resuscitation is not important. It only suggests that in a system where patients can get to the hospital quickly, initiating this therapy in the field may not provide an additional benefit over simply getting them to the hospital faster.
  • Implementation Caveats: The key takeaway is that the decision to implement a prehospital blood program requires a careful consideration of the local system’s transport times, logistics, and cost.

12. Context and Related Studies

  • Building on Previous Evidence: The RePHILL trial (2022) was designed to test whether the principles of in-hospital damage control resuscitation, established by trials like PROPPR (2015), could be successfully and beneficially applied in the prehospital environment.
  • Influence on Subsequent Research: The definitive neutral result of this trial will be highly influential in shaping guidelines for prehospital trauma care, suggesting that for most systems, the priority should remain on “scoop and run” (rapid transport) rather than complex field interventions.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether prehospital blood product resuscitation would be beneficial in systems with much longer transport times (e.g., rural or military settings).
  • Future Directions: Future research may focus on identifying which specific subgroups of patients (e.g., those with penetrating trauma or very prolonged entrapment) might still benefit from prehospital blood, and on the role of other hemostatic adjuncts like whole blood.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a complex and resource-intensive strategy to improve outcomes in the earliest phase of trauma care.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. A key point for interpretation is the short transport time in the study system, which is a major factor in the applicability of the results.
  • Results: The study reported a clear neutral finding for its primary outcome.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to similar, well-organized, urban trauma systems. This is a classic example of a high-quality “negative” trial that provides strong evidence to guide health policy and prevent the widespread adoption of an expensive intervention for which there is no clear benefit in this context.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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