SGEM#369: Romeo is Bleeding – Does He Need a RePHILL?

Date: June 18th, 2022 Reference: 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. The Lancet Haematology 2022 Guest Skeptic: Dr. Casey Parker is a Rural Generalist that includes in his practice emergency medicine, anaesthesia and critical care. He is also now a fully fledged "sonologist". Casey currently splits his time between Broome, a small rural hospital in the remote Kimberley region of Western Australia, and a large tertiary ED in sunny Perth. Case: You are working in the emergency department (ED) and receive a call from the Advanced Care Paramedics who are at the scene of a stabbing. Apparently, two rival gangs (Jets and Sharks) had a rumble. The young man has been stabbed in the abdomen and lost a lot of blood. The patient is tachycardic (120 beats/minute), hypotensive (80/60 mmHg) and looks very pale. They have two large bore intravenous (IV) access and are planning to bring them to your ED as soon as possible. The paramedic asks you, “we have saline, and we also have red-cells and this fancy new lyophilised plasma.  Should we give our shocked patient saline or plasma / red cells en route to the ED?”  What do you advise him?  Background: The use of fluids in trauma resuscitation has been studied in a number of trials in recent years. A lot of observational data has been collected from the battlefields of Iraq and Afghanistan. The Control of Major Bleeding After Trauma (COMBAT) Trial was published in the Lancet in 2018. It was a pragmatic, randomised, single-centre trial done at the Denver looking at the use of plasma in the prehospital setting. This trial did not show a statistical mortality benefit within 28 days of injury. First10EM and REBEL EM both did a review of the COMBAT trial.  The Prehospital Air Medical Plasma (PAMPer) trial was published in NEJM, also in 2018.  The goal of this trial was to determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock. This trial did report that prehospital administration of plasma was safe and resulted in lower 30-day mortality. PAMPer was reviewed by First10EM and The Bottom Line.  The traditional teaching in trauma is to replace blood with blood products, so we would expect that we should see a benefit if we used blood and plasma instead of saline alone for the initial resuscitation. Clinical Question: In the resuscitation of pre-hospital trauma patients with hemorrhagic shock is there a patient-oriented benefit to using blood and plasma over 0.9% saline? Reference: 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. The Lancet Haematology 2022 Population: Adult patients 16 years of age or older suffering traumatic injury resulting in shock believed to be due to a traumatic haemorrhage. Shock was defined as a systolic BP less than 90 mmHg or an absent radial pulse.  Exclusions: Patients known to refuse blood produces, those who received transfusion of prehospital blood products before assessment for eligibility, pregnancy (known or apparent), isolated head injury without evidence of major haemorrhage, and prisoners.  Intervention: Up to four units of blood products boluses one unit at a time.  Units were alternating between units of O-negative packed red cells (PRBC) or or reconstituted lyophilised plasma to a maximum of two units of either. Comparison: Up to four boluses of 0.9% saline (250ml/bolus) Outcome:  Primary Outcome: Composite outcome of mortality from time of injury to hospital discharge or the failure to clear lactate by 20% within the first two hours after randomisation. Secondary Outcomes: Individual components of the composite primary outcome, fluid volumes, measures of coagulopathy, 30 day mortality and common side effects of transfusion such as reaction and adult respiratory distress syndrome (ARDS) Trial: This was a multi-centre, open-label, concealed, single-blinded, randomised controlled trail Authors’ Conclusions: “The trial did not show that prehospital PRBC–LyoPlas resuscitation was superior to 0.9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Unsure The treatment effect was large enough and precise enough to be clinically significant. No Lack of financial conflicts of interest. Yes Results: The trial randomized 432 participants. Median age was 38 years, 82% were male and 62% of patients had blunt force trauma from a motor vehicle collision.  Key Result: Blood products were not superior to saline for the primary outcome. Primary Outcome: Composite outcome of mortality from time of injury to hospital discharge or the failure to clear lactate by 20% within the first two hours after randomisation. 64% in the blood product group vs 65% of the saline group  Adjusted risk difference –0·025% [95% CI –9.0 to 9.0], p=0·996) Adjusted risk ratio 1.01 [95% CI 0.88 to 1.17] Secondary Outcomes:  Mortality: 43% in the blood products group vs 45% in the saline group (Adjusted risk ratio 0.97 [95% CI 0.78 to 1.20]; p=0·75)  Failure to clear lactate: 50 vs 55% (Adjusted risk ratio 0.94 [95% CI 0.78 to 1.13]; p=0·52) None of the other secondary outcomes reported were statistically different Serious adverse events were similar between both groups 1. Mixing POOs and LOOs: Is it appropriate to place LOOs (lab-oriented outcomes) and POOs (patient-oriented outcomes) together in a composite primary? This trial used a composite primary outcome that included  mortality (a big POO) with lactate clearance (a lab-oriented outcome that may or may not be a surrogate marker for mortality).  Usually one might design a trial with softer LOOs if one were trying to detect a subtle difference in a population where hard patient-oriented outcomes are rare. However, in this trial nearly half of the patients died.  Mortality is very objective and important to patients, and it would therefore seem better to stick with a single primary outcome and power the recruitment to that end. 2. Dose: The RePHILL trial participants received less than a litre of fluid in total prior to arriving in hospital. That could either be all saline in the control group or a mixture of saline and blood products in the intervention group.  The fact that this was a “negative” trial may mean that there truly is no difference between saline and blood products in pre-hospital resuscitation. Or, it could mean that at this dosage there is no detectable potential benefit or potential harm observable. For example, If we only gave 10 mg of aspirin to patients with ST elevated myocardial infarction and observe no mortality benefit, but also no GI bleeds we could conclude that aspirin has no effect. However, we do have high-quality data showing that there is a benefit to giving 162.5mg of aspirin to STEMI patients with a small increase in harm (TheNNT.com). So is the RePHILL trial telling us there is no benefit, or that the doses are not adequate to give an effect that we can observe? This is why it is good to be cautious not to over or under-interpret the data. The most accurate conclusion is that the intervention provided in this cohort of trauma patients with shock did not demonstrate superiority over the control group. This is different than concluding blood products do not work for trauma patients in the prehospital setting.  3. External Validity: This trial used a team of pre-hospital physicians and critical care paramedics in the UK. The team traveled by helicopter or land based rapid response vehicles with a blood product that is relatively new and hard to come by (lyophilised plasma).  If RePHILL had been a positive trial and shown a clear benefit then we would be stuck with the issue of external validity, especially in rural areas like Canada and Australia which are much larger countries geographically.  We do not have the systems or access to this product. It would be very difficult to bring a physical-led plasma wielding team to the roadside in most parts of the world. Rural clinicians know about the tyranny of distance.  The goal should be to get the best medical care to rural patients which can be logistically tough at times. However, it should not be the knowledge of the team that results in lesser care. 4. Too Good to Be True: The original power calculation for RePHILL was based on the consensus that a 10% absolute difference in the primary outcome. This is a large difference for a complex disease like trauma using a simple intervention. However,