The main objectives of this study were to evaluate the effect of prehospital RCP transfusion (RCP arm) on 24-h mortality and 30-day mortality compared to prehospital RBC transfusion only (RBC arm) and prehospital RBC plus plasma transfusion (RBC + P arm). Our results showed that prehospital plasma transfusion was associated with lower odds of death at 24 h compared to RBC alone (after adjusting for type of injury, age and prehospital observational markers) and that addition of plasma to RBC resuscitation (versus RBC only) brought greater benefit for penetrating injury than blunt injury. At 30 days, there was no difference in survival between the three arms, indicating that the effect of plasma transfusion is greatest in the short term, but there is potential for residual confounding in longer-term outcomes.
The concept of providing damage control resuscitation to trauma bleeding patients shifted to the prehospital environment following publication of the PROPR trial [2] and several observational studies showing survival benefits in patients who received transfusion at the scene of injury [1, 6]. This body of evidence changed prehospital resuscitation practice in the UK, and by the time we started this study, most services had moved to providing RBC and plasma prehospital, meaning that we could not include a prospective RBC arm in our study (a limitation). During the same period, several RCTs were published in this field, aiming to establish the role of RBC and plasma transfusion in prehospital resuscitation. Currently, the role of plasma transfusion in addition to RBC in prehospital hemostatic resuscitation (versus RBC) is poorly understood and remains an ongoing discussion [12].
Two RCTs (PAMPer and COMBAT) that evaluated the effect of prehospital plasma transfusion on 24-h and 30-day mortality provided conflicting results, with PAMPer showing overall survival benefits with prehospital plasma transfusion [9], while COMBAT showed no difference in survival [8]. In this study, we saw that addition of plasma to RBC transfusion prehospital was associated with lower odds of death at 24 h (compared to RBC alone), which is similar to the PAMPer result [9]; however, unlike PAMPer, we saw no association with addition of prehospital plasma to RBC transfusion on 30-day mortality. Previous studies [6] that have evaluated the impact of RBC only transfusion versus saline resuscitation in prehospital setting and the REPHILL trial [7] have also shown a similar pattern of survival benefits with transfusion improving early survival, but having no impact on overall survival. A systematic review on the use of prehospital blood product resuscitation in trauma also showed no overall survival benefit, but there was some evidence for improved survival at 24 h [20]. These results may not be surprising, as from the recent analysis of RCTs, we know that approximately 75% of deaths from bleeding occur within 6 h of injury or hospital admission [21], and beyond 24 h traumatic brain injury or multiorgan failure with sepsis is the main causes of deaths [22].
The post hoc analysis of PAMPer and COMBAT trials showed that the benefit from plasma is primarily seen in blunt injury patients who had a transport time of > 20 min [13]. The results of this study appear contrasting, although caution is needed when comparing results, as the fundamental differences in study designs, population and methods make comparisons difficult. Firstly the ‘standard of care’ arm in the COMBAT trial was 0.9% saline [8], while in PAMPer trial, it was either RBC transfusion (13 of the 27 air medical services), or crystalloid-based resuscitation only [9]. The PAMPer trial had higher rates of blunt injury (73% control vs 81% intervention), which is similar to the RBC + P (80%) arm, whereas penetrating injury was predominant in the COMBAT trial (54% intervention vs. 47% control), comparable to the RBC (45%) and RCP (48%) arms of this study. The typical transport time in the COMBAT study was 16–19 min, while in the PAMPer trial, it was 39–52 min. In this study, the transport time was longer for all three arms with the median time ranging between 80 and 97 min. The injury severity scores (ISS) of patients in PAMPer (median 22) and COMBAT (median 27) trials are lower than in this study (median 30 to 33), and indeed, this reflected the overall differences in baseline mortality at both 24-h and 30-day between studies. These sources of variation could explain the differences in results between studies.
One major area of future prehospital research should be to better identify the group of patients that are most likely to benefit from prehospital plasma transfusion. Understanding the coagulopathy of different types of injuries and the mechanism whereby plasma transfusion corrects these coagulopathies is key to addressing this important topic [12]. In addition to providing clotting factor replacement, plasma is also an ideal volume expander in the intravascular space and several in vitro studies have now shown that plasma also has a homeostatic effect on endothelial function and innate immune system activation, leading to an improved inflammatory response to injury compared with crystalloid resuscitation [23,24,25,26]. Further analysis of the COMBAT study showed that prehospital plasma resuscitation reduces the incidence of hyperfibrinolysis [27]. We were not able to measure this in our study, but it is a possible mechanism by which early plasma transfusion corrects the coagulopathy of penetrating injury patients and better diagnostic tests are required to prove this.
While these data suggest that plasma has benefits on coagulation and endothelium, there remain logistical challenges with providing prehospital blood transfusion. The main advantages of administering a combined component like RCP or whole blood, versus separate components, are the additional logistical benefits on scene, such as shorter transport time to hospital and the reduced number of processes, personnel and resources required to administer blood prehospital. Based on the results of this study, these advantages were not translated into clinical benefits for the RCP arm, and this is likely due to the same transfusion content of prospective arms in this study (i.e., RCP and RBC + P) and any potential benefits (if these exist) from shortening the prehospital transport time might be too small to detect given the current sample. Either way, our results show that the clinical benefit from prehospital plasma transfusion appears to be consistent, irrespective of the mode of transfusion (separately or combined), which may give reassurance to services deciding on the best plasma component/product to use prehospital [28]. If the results of upcoming whole blood trials show no benefits with a whole blood component in prehospital environments, then the RCP component could become the frontrunner for prehospital services in the UK to treat traumatically injured bleeding patients, considering its logistical benefits and equivalent effect on outcomes with current standard practice. In this scenario, extending its shelf life to beyond 14 days would be a priority for reducing hospital blood wastage [18, 29].
Strengths and limitations
A key strength of the study is that the data for plasma arms were prospectively collected by several air ambulance services in England, with information being directly retrieved from patients’ case notes and not from administrative databases. Further, the design of the study did not rely on patient consent for data collection, a potential source of selection bias. Some limitations, however, should be recognized. Firstly, this was an observational study, and its conclusions are not as definitive as those from a randomized controlled trial for evaluating a strategy. Secondly, the sample size for the RBC arm was smaller than the other two arms, due to the data being collected from a single site, and furthermore, the data for the RBC arm were collected at a different period compared to plasma arms and it could be argued that overall treatment of bleeding patients would have changed over time, influencing the survival independent of transfusion. However, the similarities in patients’ characteristics and their outcomes between RBC and RCP arms mitigate these concerns. Further, the implementation of RCP transfusion in London happened the day after cessation of RBC transfusion, and during the study period, the London region did not implement any other major intervention in prehospital environments for treatment of bleeding that could have materially impacted survival. Thirdly, there were some demographic differences between arms, with patients in the RBC and RCP arms being younger than the RBC + P arm and having a higher incidence of penetrating injury and a shorter prehospital transit time, all of which could have contributed to survival outcomes independently of the intervention. The analysis adjusted for these confounding factors as well as differences between services and sites, and evidence for the existence of overall benefit from RCP, compared to RBC alone, remained. Lastly, given the long transport times and the high ISS seen in our cohort, it would have been interesting to evaluate the impact of operative versus non-operative management, but this information was not collected.