A multi-centre randomised controlled trial of pre-hospital blood product administration versus standard care for traumatic haemorrhage. [Short Title: Resuscitation with Pre-HospItaL bLood products - RePHILL]

Problem: "Haemostatic resuscitation" (HR) with high ratios of plasma to red blood cells has become standard hospital practice for traumatic haemorrhage. Supporting evidence is observational and mainly retrospective. Clinical equipoise for in-hospital HR has been lost making a randomised controlled trial impossible. Military medical teams have delivered HR in battlefield casualty retrieval missions. The few studies of pre-hospital blood product (PHBP) resuscitation provide only low-quality observational evidence, have contradictory results and are limited by significant confounding factors. Nonetheless, use of packed red blood cells (PRBC) (without plasma) by UK civilian pre-hospital emergency medical (PHEM) services is increasing. This has associated costs and increases demand for universal donor components. Patients: Adult trauma patients with hypotension (absent radial pulse) due to haemorrhage. Intervention: Lyophilised plasma (LP) is potentially useful in PHEM. Unlike thawed plasma, it is stable, tolerant of temperature variation and quick to reconstitute and administer. The combination of LP and PRBC is an attractive and practical option for HR in PHEM. Comparison: Current standard care for pre-hospital resuscitation of traumatic haemorrhage is the preservation of a palpable radial pulse with limited volumes of crystalloid. Outcomes: Composite primary outcome composed of mortality (allocation to hospital discharge) or inadequate tissue perfusion (assessed as lactate clearance <20%/hr in first two hours after ED admission). Lactate clearance has been shown to be a predictor of mortality in trauma. This composite measure is both a clinically meaningful and patient centred outcome. Secondary and mechanistic outcomes: incidence of trauma-induced coagulopathy and platelet dysfunction on ED arrival, transfusion and fluid requirements and organ failure. Study Design: Multicentre RCT of 490 patients with investigators blinded to treatment allocation prior to recruitment. Sample size & statistical analysis: This study size provides 80% power to detect an absolute reduction in incidence of primary outcome from 20% in the standard care group to 10% in PHBP recipients. Resource allocation: Widespread implementation of PHBP resuscitation has financial and logistical implications and will increase demand for scarce “universal” components, reducing their availability for other patients. This trial will establish if pre-hospital blood product resuscitation is clinically beneficial, thus informing decisions about allocation of these valuable resources. Project stages: Stage 1: Months 1-3 Setup. Activities: Protocol development, regulatory approvals, contracts, staff recruitment Stage 2: Internal pilot studies. Activities: Months 4-6: Single site pilot with West Midlands Ambulance Service Medical Emergency Response Incident Team (WMAS MERIT) Months 7-9: Two site pilot with WMAS MERIT and one East of England Air Ambulance Service Objectives: Confirmation of feasibility, protocol compliance, data capture, recruitment rates. Stage 3: Months 10-39 Main RCT Activities: Recruitment from 6 PHEM services. The overall rate of recruitment is estimated at 15-20 patients per month, derived from review of eligible patients seen by the WMAS MERIT team and comparative activities of other pre-hospital services. Stage 4: Months 40-48 Close out. Activities: Final follow-up, database lock, analysis, report writing