Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS: Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS: From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION: 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. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation.

Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation.

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicles which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to monocytes. GPIbα+-monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-ß1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood in vitro and in vivo Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα+-monocytes adhered to the microcirculation of the TGF-ß1-stimulated cremaster muscle, while in the ApoE-/- model of atherosclerosis, GPIbα+-monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicles transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic.

What fluids are given during air ambulance treatment of patients with trauma in the UK, and what might this mean for the future? Results from the RESCUER observational cohort study.

OBJECTIVES: We investigated how often intravenous fluids have been delivered during physician-led prehospital treatment of patients with hypotensive trauma in the UK and which fluids were given. These data were used to estimate the potential national requirement for prehospital blood products (PHBP) if evidence from ongoing trials were to report clinical superiority. SETTING: The Regional Exploration of Standard Care during Evacuation Resuscitation (RESCUER) retrospective observational study was a collaboration between 11 UK air ambulance services. Each was invited to provide up to 5 years of data and total number of taskings during the same period. PARTICIPANTS: Patients with hypotensive trauma (systolic blood pressure <90 mm Hg or absent radial pulse) attended by a doctor. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the number of patients with hypotensive trauma given prehospital fluids. Secondary outcomes were types and volumes of fluids. These data were combined with published data to estimate potential national eligibility for PHBP. RESULTS: Of 29 037 taskings, 729 (2.5%) were for patients with hypotensive trauma attended by a physician. Half were aged 21-50 years; 73.4% were male. A total of 537 out of 729 (73.7%) were given fluids. Five hundred and ten patients were given a single type of fluid; 27 received >1 type. The most common fluid was 0.9% saline, given to 486/537 (90.5%) of patients who received fluids, at a median volume of 750 (IQR 300-1500) mL. Three per cent of patients received PHBP. Estimated projections for patients eligible for PHBP at these 11 services and in the whole UK were 313 and 794 patients per year, respectively. CONCLUSIONS: One in 40 air ambulance taskings were manned by physicians to retrievepatients with hypotensive trauma. The most common fluid delivered was 0.9% saline. If evidence justifies universal provision of PHBP, approximately 800 patients/year would be eligible in the UK, based on our data combined with others published. Prospective investigations are required to confirm or adjust these estimations.

Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study.

BACKGROUND: Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess the ultra-early, within 1-hour, immune response to trauma and perform an exploratory analysis of its relationship with the development of multiple organ dysfunction syndrome (MODS). METHODS AND FINDINGS: The immune and inflammatory response to trauma was analysed in 89 adult trauma patients (mean age 41 years, range 18-90 years, 75 males) with a mean injury severity score (ISS) of 24 (range 9-66), from whom blood samples were acquired within 1 hour of injury (mean time to sample 42 minutes, range 17-60 minutes). Within minutes of trauma, a comprehensive leukocytosis, elevated serum pro- and anti-inflammatory cytokines, and evidence of innate cell activation that included neutrophil extracellular trap generation and elevated surface expression of toll-like receptor 2 and CD11b on monocytes and neutrophils, respectively, were observed. Features consistent with immune compromise were also detected, notably elevated numbers of immune suppressive CD16BRIGHT CD62LDIM neutrophils (82.07 x 106/l ± 18.94 control versus 1,092 x 106/l ± 165 trauma, p < 0.0005) and CD14+HLA-DRlow/- monocytes (34.96 x 106/l ± 4.48 control versus 95.72 x 106/l ± 8.0 trauma, p < 0.05) and reduced leukocyte cytokine secretion in response to lipopolysaccharide stimulation. Exploratory analysis via binary logistic regression found a potential association between absolute natural killer T (NKT) cell numbers and the subsequent development of MODS. Study limitations include the relatively small sample size and the absence of data relating to adaptive immune cell function. CONCLUSIONS: Our study highlighted the dynamic and complex nature of the immune response to trauma, with immune alterations consistent with both activation and suppression evident within 1 hour of injury. The relationship of these changes, especially in NKT cell numbers, to patient outcomes such as MODS warrants further investigation.

Unilateral Dilated Pupil and Spontaneous Cardiac Arrest with Successful Bystander Resuscitation.

A 75-year-old man collapsed on a golf course and received cardiopulmonary resuscitation from a bystander, including the use of a public automated external defibrillator (AED). The AED was discharged once, with return of spontaneous circulation. An air ambulance crew found the patient haemodynamically stable, with no acute abnormalities on a 12-lead ECG. He had reduced consciousness and a dilated left pupil. On contacting the patient's wife by telephone, she said that he had fallen and hit his head earlier that day. The crew decided to convey the patient to a Major Trauma Centre that had both neurosurgical and cardiology specialist services (rather than the nearest hospital) so that both traumatic brain injury and cardiac pathologies could be addressed if required. A head CT was normal, but coronary angiography demonstrated occlusion of two coronary arteries. These were successfully treated with stenting, and the patient went home two weeks later. He informed medical staff that his left pupil has been permanently dilated since he was a boy following a traumatic ocular injury. This case illustrates the utility of early deployment of an AED as well as the importance of an accurate history and emergency decision-making by prehospital personnel.

MicroRNAs as Novel Biomarkers for the Diagnosis and Prognosis of Mild and Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is the leading cause of death and disability in people younger than 45 in Western countries. Despite many studies, no reliable biomarkers have been found to assess TBI severity and predict recovery. MicroRNA (miRNA) profiling has become widely used to identify biomarkers and therapeutic targets. Through use of the TaqMan Array Human MicroRNA A+B Cards, the expression of 754 miRNAs was analyzed in serum of five mild TBI (mTBI) patients with extra-cranial injury (EC), five severe TBI (sTBI) patients with EC, and five healthy volunteers (HV) at 1 day and 15 days post-injury. The aim was to find candidate biomarkers able to discriminate between mTBI and sTBI. Following this, it was possible to select 10 miRNAs for further study in an enlarged validation cohort of 120 patients by using single TaqMan assays at the following time-points: T0-1 h, T4-12 h, T48-72 h, and 15 days from the injury. Analysis revealed two miRNAs (miR-425-5p and miR-502) that were significantly downregulated (p < 0.05) in mTBI at early time-points and are ideal candidates for diagnosis of mTBI, and two miRNAs (miR-21 and miR-335) that were significantly upregulated (p < 0.01) and are valid biomarkers for the diagnosis of sTBI. In addition, miR-425-5p was a strong predictor of 6-month outcome at T0-1 h and T4-12 h, while miR-21 was predictive of the outcome at T4-12 h. The panel of selected miRNAs shows promise as biomarkers to discriminate mTBI from sTBI. In addition, the selected miRNAs represent new potential therapeutic targets.

Prehospital rapid sequence induction following trauma in the era of regional networks for major trauma.

OBJECTIVE: Rapid sequence induction (RSI) provides prompt airway control during emergency evacuation of trauma patients. Physicians may be tasked to travel with paramedic ambulance crews to the scene of injury when RSI is more likely to be required. This study investigates whether there are any differences in the practice of prehospital RSI during emergency retrievals for trauma since the establishment of the regional Major Trauma Network (MTN) in March 2012. METHODS: A retrospective observational study examined prehospital records for all trauma patients from September 2010 to January 2015 at a Major Trauma Centre in Birmingham, UK. Prehospital physician availability increased from 12 to 24 h after March 2012, and tasking became centralized. Data included demographics, mechanism of injury, crew personnel, and details of RSI. The periods before and after the establishment of the regional MTN were compared. RESULTS: There were 5244 patients: 1432 (27.3%) before and 3812 (72.7%) after March 2012. Of the patients, 67.2% were male. The most common injuries were road traffic collisions (45.0%). Physicians were more likely to be present after (2345 missions, 61.5%) than before (529 missions, 36.9%) March 2012 (P<0.01). RSI was performed 434 (8.3%) times and was more likely during the latter than the former period [359 (9.4%) vs. 75 (5.2%), P<0.01]. Successful tracheal intubation was achieved in 99% of occasions. CONCLUSION: The establishment of regional MTNs enables centrally tasked, 24-h physician availability for emergency trauma patients. There has been an increase in physician presence on emergency missions and increased frequency of RSI for at-risk trauma patients at times when there may previously have been an unmet requirement.

Prehospital anaesthesia performed by physician/critical care paramedic teams in a major trauma network in the UK: a 12†month review of practice.

INTRODUCTION: In the West Midlands region of the UK, delivery of pre-hospital care has been remodelled through introduction of a 24 h Medical Emergency Response Incident Team (MERIT). Teams including physicians and critical care paramedics (CCP) are deployed to incidents on land-based and helicopter-based platforms. Clinical practice, including delivery of rapid sequence induction of anaesthesia (RSI), is underpinned by standard operating procedures (SOP). This study describes the first 12 months experience of prehospital RSI in the MERIT scheme in the West Midlands. METHODS: Retrospective review of the MERIT clinical database for the 12 months following the launch of the scheme. Data was collected relating to the number of RSIs performed; indication for RSI; number of intubation attempts; grade of view on laryngoscopy and the base speciality/grade of the operator performing intubation. RESULTS: MERIT teams were activated 1619 times, attending scene in 1029 cases. RSI was performed 142 times (13.80% of scene attendances). There was one recorded case of failure to intubate requiring insertion of a supraglottic airway device (0.70%). In over a third of RSI cases, CCPs performed laryngoscopy and intubation (n=53, 37.32%). Proficiency of obtaining Grade I view at laryngoscopy was similar for physicians (74.70%) and CCPs (77.36%). Intubation was successful at the first attempt in over 90% of cases. CONCLUSIONS: This study demonstrates that operation within a system that provides high levels of exposure, underpinned by comprehensive and robust training and governance frameworks, promotes levels of performance in successful prehospital RSI regardless of base speciality or profession.

'Interception': a model for specialist prehospital care provision when helicopters are not available.

The deployment of specialist teams to incident scenes by helicopter and the delivery of critical care interventions such as Rapid Sequence Induction of anaesthesia to patients are becoming well-established components of trauma care in the UK. Traditionally in the UK, Helicopter Emergency Medical Services (HEMS) are limited to daylight operations only. The safety and feasibility of operating HEMS services at night is a topic of debate currently in the UK HEMS community. Within the West Midlands Major Trauma Network, the Medical Emergency Response Incident Team (MERIT) provides a physician-led prehospital care service that responds to incidents by air during daylight hours and by Rapid Response Vehicle during the hours of darkness. The MERIT service is coordinated and supported by a dedicated Major Trauma Desk manned by a HEMS paramedic in the ambulance service control room. This case illustrates the importance of coordination and integration of specialist resources within a major trauma network to ensure the expedient delivery of HEMS-level care to patients outside of normal flying hours.