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Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial
Crombie N, Doughty HA, Bishop JRB, Desai A, Dixon EF, Hancox JM, Herbert MJ, Leech C, Lewis SJ, Nash MR, et al
The Lancet. Haematology. 2022
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Abstract
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.
PICO Summary
Population
Patients aged 16 years old or older with trauma-related haemorrhagic shock enrolled in the resuscitation with pre-hospital blood products (RePHILL) trial, based across four UK prehospital critical care services (n= 432).
Intervention
Packed red blood cells and lyophilised plasma (PRBC-LyoPlas, n= 209).
Comparison
Sodium chloride (n= 223).
Outcome
The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. The composite primary outcome occurred in 128 (64%) of 199 patients receiving PRBC-LyoPlas and 136 (65%) of 210 receiving sodium chloride. The rates of transfusion-related complications in the first 24 hours after emergency department arrival were similar (PRBC-LyoPlas eleven (7%) of 148 compared with sodium chloride nine (7%) of 137). 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 the sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the sodium chloride group (abnormal liver function test). There were no treatment-related deaths.
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Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis
Walsh M, Merkel PA, Peh CA, Szpirt WM, Puechal X, Fujimoto S, Hawley CM, Khalidi N, Flossmann O, Wald R, et al
The New England journal of medicine. 2020;382(7):622-631
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Abstract
BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m(2) of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).
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Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial
Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, Dezoysa J, Ives N, Clark WF, Quillen K, et al
Trials. 2013;14:73
Abstract
BACKGROUND Granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) are small vessel vasculitides collectively referred to as anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). AAV is associated with high rates of morbidity and mortality due to uncontrolled disease and treatment toxicity. Small randomized trials suggest adjunctive plasma exchange may improve disease control, while observational evidence suggests that current oral glucocorticoid doses are associated with severe infections in patients with AAV. A randomized study of both plasma exchange and glucocorticoids is required to evaluate plasma exchange and oral glucocorticoid dosing in patients with AAV. METHODS/DESIGN PEXIVAS is a two-by-two factorial randomized trial evaluating adjunctive plasma exchange and two oral glucocorticoid regimens in severe AAV. Five hundred patients are being randomized at centers across Europe, North America, Asia, and Australasia to receive plasma exchange or no plasma exchange, and to receive standard or reduced oral glucocorticoid dosing. All patients receive immunosuppression with either cyclophosphamide or rituximab. The primary outcome is the time to the composite of all-cause mortality and end-stage renal disease.PEXIVAS is funded by the National Institute of Health Research (UK), the Food and Drug Administration (USA), the National Institutes of Health (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). Additional in-kind supplies for plasma exchange are provided by industry partners (TerumoBCT, Gambro Australia, and Fresenius Australia). DISCUSSION This is the largest trial in AAV undertaken to date. PEXIVAS will inform the future standard of care for patients with severe AAV. The cooperation between investigators, funding agencies, and industry provides a model for conducting studies in rare diseases. TRIAL REGISTRATION Current Controlled Trials: (ISRCTN07757494) and clinicaltrials.gov: (NCT00987389).