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Association of initial lactate levels and red blood cell transfusion strategy with outcomes after severe trauma: a post hoc analysis of the RESTRIC trial
Kosaki, Y., Hongo, T., Hayakawa, M., Kudo, D., Kushimoto, S., Tagami, T., Naito, H., Nakao, A., Yumoto, T.
World journal of emergency surgery : WJES. 2024;19(1):1
Abstract
BACKGROUND The appropriateness of a restrictive transfusion strategy for those with active bleeding after traumatic injury remains uncertain. Given the association between tissue hypoxia and lactate levels, we hypothesized that the optimal transfusion strategy may differ based on lactate levels. This post hoc analysis of the RESTRIC trial sought to investigate the association between transfusion strategies and patient outcomes based on initial lactate levels. METHODS We performed a post hoc analysis of the RESTRIC trial, a cluster-randomized, crossover, non-inferiority multicenter trials, comparing a restrictive and liberal red blood cell transfusion strategy for adult trauma patients at risk of major bleeding. This was conducted during the initial phase of trauma resuscitation; from emergency department arrival up to 7 days after hospital admission or intensive care unit (ICU) discharge. Patients were grouped by lactate levels at emergency department arrival: low (< 2.5 mmol/L), middle (≥ 2.5 and < 4.0 mmol/L), and high (≥ 4.0 mmol/L). We compared 28 days mortality and ICU-free and ventilator-free days using multiple linear regression among groups. RESULTS Of the 422 RESTRIC trial participants, 396 were analyzed, with low (n = 131), middle (n = 113), and high (n = 152) lactate. Across all lactate groups, 28 days mortality was similar between strategies. However, in the low lactate group, the restrictive approach correlated with more ICU-free (β coefficient 3.16; 95% CI 0.45 to 5.86) and ventilator-free days (β coefficient 2.72; 95% CI 0.18 to 5.26) compared to the liberal strategy. These findings persisted even after excluding patients with severe traumatic brain injury. CONCLUSIONS Our results suggest that restrictive transfusion strategy might not have a significant impact on 28-day survival rates, regardless of lactate levels. However, the liberal transfusion strategy may lead to shorter ICU- and ventilator-free days for patients with low initial blood lactate levels.
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Study of Whole blood in Frontline Trauma (SWiFT): implementation study protocol
Antonacci, G., Williams, A., Smith, J., Green, L.
BMJ open. 2024;14(2):e078953
Abstract
INTRODUCTION Uncontrolled bleeding is a major cause of death for patients with major trauma. Current transfusion practices vary, and there is uncertainty about the optimal strategy. Whole blood (WB) transfusion, which contains all components in one bag, is considered potentially advantageous, particularly for resuscitating patients with major bleeding in the prehospital setting. It could potentially improve survival, reduce donor risk and simplify the processes of delivering blood transfusions outside hospitals. However, the evidence supporting the effectiveness and safety of WB compared with the standard separate blood component therapy is limited. A multicentre randomised controlled trial will be conducted, alongside an implementation study, to assess the efficacy, cost-effectiveness and implementation of prehospital WB transfusion in the prehospital environment. The implementation study will focus on evaluating the acceptability and integration of the intervention into clinical settings and on addressing broader contextual factors that may influence its success or failure. METHODS AND ANALYSIS A type 1 effectiveness-implementation hybrid design will be employed. The implementation study will use qualitative methods, encompassing comprehensive interviews and focus groups with operational staff, patients and blood donor representatives. Staff will be purposefully selected to ensure a wide range of perspectives based on their professional background and involvement in the WB pathway. The study design includes: (1) initial assessment of current practice and processes in the WB pathway; (2) qualitative interviews with up to 40 operational staff and (3) five focus groups with staff and donor representatives. Data analysis will be guided by the theoretical lenses of the Normalisation Process Theory and the Theoretical Framework of Acceptability. ETHICS AND DISSEMINATION The study was prospectively registered and approved by the South Central-Oxford C Research Ethics Committee and the Health Research Authority and Health and Care Research Wales. The results will be published in peer-reviewed journals and provided to all relevant stakeholders. TRIAL REGISTRATION NUMBER ISRCTN23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072.
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Two-year outcomes following a randomised platelet transfusion trial in preterm infants
Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, et al
Archives of disease in childhood. Fetal and neonatal edition. 2023
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Editor's Choice
Abstract
OBJECTIVE Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one. DESIGN Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group. SETTING 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland. PATIENTS 660 infants born at less than 34 weeks' gestation with platelet counts less than 50×10(9)/L. INTERVENTIONS Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×10(9)/L (higher threshold group) or 25×10(9)/L (lower threshold group). MAIN OUTCOMES MEASURES Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. RESULTS Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017). CONCLUSIONS Infants randomised to a higher platelet transfusion threshold of 50×10(9)/L compared with 25×10(9)/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants. TRIAL REGISTRATION NUMBER ISRCTN87736839.
PICO Summary
Population
Preterm infants enrolled in the PlaNeT-2/MATISSE trial, at 43 neonatal intensive care units across UK, Netherlands and Ireland (n= 660).
Intervention
Higher platelet transfusion threshold (n= 296).
Comparison
Lower platelet transfusion threshold (n= 305).
Outcome
The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR: 1.54; 95% CI [1.09, 2.17]).
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Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS)
Chock, V. Y., Kirpalani, H., Bell, E. F., Tan, S., Hintz, S. R., Ball, M. B., Smith, E., Das, A., Loggins, Y. C., Sood, B. G., et al
JAMA network open. 2023;6(9):e2334889
Abstract
IMPORTANCE Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. OBJECTIVE To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. DESIGN, SETTING, AND PARTICIPANTS This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. INTERVENTIONS Near-infrared spectroscopy monitoring of Csat and Msat. MAIN OUTCOMES AND MEASURES Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. RESULTS A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). CONCLUSIONS AND RELEVANCE In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01702805.
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The SWiFT trial (Study of Whole Blood in Frontline Trauma)-the clinical and cost effectiveness of pre-hospital whole blood versus standard care in patients with life-threatening traumatic haemorrhage: study protocol for a multi-centre randomised controlled trial
Smith, J. E., Barnard, E. B. G., Brown-O'Sullivan, C., Cardigan, R., Davies, J., Hawton, A., Laing, E., Lucas, J., Lyon, R., Perkins, G. D., et al
Trials. 2023;24(1):725
Abstract
BACKGROUND Early blood transfusion improves survival in patients with life-threatening bleeding, but the optimal transfusion strategy in the pre-hospital setting has yet to be established. Although there is some evidence of benefit with the use of whole blood, there have been no randomised controlled trials exploring the clinical and cost effectiveness of pre-hospital administration of whole blood versus component therapy for trauma patients with life-threatening bleeding. The aim of this trial is to determine whether pre-hospital leukocyte-depleted whole blood transfusion is better than standard care (blood component transfusion) in reducing the proportion of participants who experience death or massive transfusion at 24 h. METHODS This is a multi-centre, superiority, open-label, randomised controlled trial with internal pilot and within-trial cost-effectiveness analysis. Patients of any age will be eligible if they have suffered major traumatic haemorrhage and are attended by a participating air ambulance service. The primary outcome is the proportion of participants with traumatic haemorrhage who have died (all-cause mortality) or received massive transfusion in the first 24 h from randomisation. A number of secondary clinical, process, and safety endpoints will be collected and analysed. Cost (provision of whole blood, hospital, health, and wider care resource use) and outcome data will be synthesised to present incremental cost-effectiveness ratios for the trial primary outcome and cost per quality-adjusted life year at 90 days after injury. We plan to recruit 848 participants (a two-sided test with 85% power, 5% type I error, 1-1 allocation, and one interim analysis would require 602 participants-after allowing for 25% of participants in traumatic cardiac arrest and an additional 5% drop out, the sample size is 848). DISCUSSION The SWiFT trial will recruit 848 participants across at least ten air ambulances services in the UK. It will investigate the clinical and cost-effectiveness of whole blood transfusion versus component therapy in the management of patients with life-threatening bleeding in the pre-hospital setting. TRIAL REGISTRATION ISRCTN 23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072, 21 Dec 2021.
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Balanced resuscitation and earlier mortality end points: bayesian post hoc analysis of the PROPPR trial
Lammers, D., Rokayak, O., Uhlich, R., Sensing, T., Baird, E., Richman, J., Holcomb, J. B., Jansen, J.
Trauma surgery & acute care open. 2023;8(1):e001091
Abstract
INTRODUCTION The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial failed to demonstrate a mortality difference for hemorrhaging patients receiving a balanced (1:1:1) vs a 1:1:2 resuscitation at 24 hours and 30 days. Recent guidelines recommend earlier mortality end points for hemorrhage-control trials, and the use of contemporary statistical methods. The aim of this post hoc analysis of the PROPPR trial was to evaluate the impact of a balanced resuscitation strategy at early resuscitation time points using a Bayesian analytical framework. METHODS Bayesian hierarchical models were created to assess mortality differences at the 1, 3, 6, 12, 18, and 24 hours time points between study cohorts. Posterior probabilities and Bayes factors were calculated for each time point. RESULTS A 1:1:1 resuscitation displayed a 96%, 99%, 94%, 92%, 96%, and 94% probability for mortality benefit at 1, 3, 6, 12, 18, and 24 hours, respectively, when compared with a 1:1:2 approach. Associated Bayes factors for each respective time period were 21.2, 142, 14.9, 11.4, 26.4, and 15.5, indicating 'strong' to 'decisive' supporting evidence in favor of balanced transfusions. CONCLUSION This analysis provides evidence in support that a 1:1:1 resuscitation has a high probability of mortality benefit when compared with a 1:1:2 strategy, especially at the newly defined more proximate time points during the resuscitative period. Researchers should consider using Bayesian approaches, along with more proximate end points when assessing hemorrhage-related mortality, for the analysis of future clinical trials. LEVEL OF EVIDENCE Level III/Therapeutic.
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Volume replacement in the resuscitation of trauma patients with acute hemorrhage: an umbrella review
Gianola, S., Castellini, G., Biffi, A., Porcu, G., Napoletano, A., Coclite, D., D'Angelo, D., Di Nitto, M., Fauci, A. J., Punzo, O., et al
International journal of emergency medicine. 2023;16(1):87
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Editor's Choice
Abstract
BACKGROUND The use of intravenous fluid therapy in patients with major trauma in prehospital settings is still controversial. We conducted an umbrella review to evaluate which is the best volume expansion in the resuscitation of a hemorrhagic shock to support the development of major trauma guideline recommendations. METHODS We searched PubMed, Embase, and CENTRAL up to September 2022 for systematic reviews (SRs) investigating the use of volume expansion fluid on mortality and/or survival. Quality assessment was performed using AMSTAR 2 and the Certainty of the evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS We included 14 SRs investigating the effects on mortality with the comparisons: use of crystalloids, blood components, and whole blood. Most SRs were judged as critically low with slight overlapping of primary studies and high consistency of results. For crystalloids, inconsistent evidence of effectiveness in 28- to 30-day survival (primary endpoint) was found for the hypertonic saline/dextran group compared with isotonic fluid solutions with moderate certainty of evidence. Pre-hospital blood component infusion seems to reduce mortality, however, as the certainty of evidence ranges from very low to moderate, we are unable to provide evidence to support or reject its use. The blood component ratio was in favor of higher ratios among all comparisons considered with moderate to very low certainty of evidence. Results about the effects of whole blood are very uncertain due to limited and heterogeneous interventions in studies included in SRs. CONCLUSION Hypertonic crystalloid use did not result in superior 28- to 30-day survival. Increasing evidence supports the scientific rationale for early use of high-ratio blood components, but their use requires careful consideration. Preliminary evidence is very uncertain about the effects of whole blood and further high-quality studies are required.
PICO Summary
Population
Trauma patients with haemorrhagic shock (14 systematic reviews).
Intervention
Crystalloids, packed red blood cells, fresh frozen plasma, platelets, liquid plasma, lyophilized plasma, low titre 0-negative whole blood.
Comparison
A comparison or combination of the above (including different ratios).
Outcome
For crystalloids, inconsistent evidence of effectiveness in 28- to 30-day survival (primary endpoint) was found for the hypertonic saline/dextran group compared with isotonic fluid solutions with moderate certainty of evidence. Pre-hospital blood component infusion seems to reduce mortality, however, as the certainty of evidence ranges from very low to moderate, the authors are unable to provide evidence to support or reject its use. The blood component ratio was in favour of higher ratios among all comparisons considered with moderate to very low certainty of evidence. Results about the effects of whole blood are very uncertain due to limited and heterogeneous interventions in studies included in systematic reviews.
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Shock index as predictor of massive transfusion and mortality in patients with trauma: a systematic review and meta-analysis
Carsetti, A., Antolini, R., Casarotta, E., Damiani, E., Gasparri, F., Marini, B., Adrario, E., Donati, A.
Critical Care (London, England). 2023;27(1):85
Abstract
BACKGROUND Management of bleeding trauma patients is still a difficult challenge. Massive transfusion (MT) requires resources to ensure the safety and timely delivery of blood products. Early prediction of MT need may be useful to shorten the time process of blood product preparation. The primary aim of this study was to assess the accuracy of shock index to predict the need for MT in adult patients with trauma. For the same population, we also assessed the accuracy of SI to predict mortality. METHODS This systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. We performed a systematic search on MEDLINE, Scopus, and Web of Science from inception to March 2022. Studies were included if they reported MT or mortality with SI recorded at arrival in the field or the emergency department. The risk of bias was assessed using the QUADAS-2. RESULTS Thirty-five studies were included in the systematic review and meta-analysis, for a total of 670,728 patients. For MT the overall sensibility was 0.68 [0.57; 0.76], the overall specificity was 0.84 [0.79; 0.88] and the AUC was 0.85 [0.81; 0.88]. Positive and Negative Likelihood Ratio (LR+; LR-) were 4.24 [3.18-5.65] and 0.39 [0.29-0.52], respectively. For mortality the overall sensibility was 0.358 [0.238; 0.498] the overall specificity 0.742 [0.656; 0.813] and the AUC 0.553 (confidence region for sensitivity given specificity: [0.4014; 0.6759]; confidence region for specificity given sensitivity: [0.4799; 0.6332]). LR+ and LR- were 1.39 [1.36-1.42] and 0.87 [0.85-0.89], respectively. CONCLUSIONS Our study demonstrated that SI may have a limited role as the sole tool to predict the need for MT in adult trauma patients. SI is not accurate to predict mortality but may have a role to identify patients with a low risk of mortality.
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Potential benefits of restrictive transfusion in upper gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials
Teutsch, B., Veres, D. S., Pálinkás, D., Simon, O. A., Hegyi, P., Erőss, B.
Scientific reports. 2023;13(1):17301
Abstract
The optimal red blood cell (RBC) transfusion strategy in acute gastrointestinal bleeding (GIB) is debated. We aimed to assess the efficacy and safety of restrictive compared to liberal transfusion strategies in the GIB population. We searched PubMed, CENTRAL, Embase, and Web of Science for randomised controlled trials on 15.01.2022 without restrictions. Studies comparing lower to higher RBC transfusion thresholds after GIB were eligible. We used the random effect model and calculated pooled mean differences (MD), risk ratios (RR) and proportions with 95% confidence intervals (CI) to calculate the overall effect size. The search yielded 3955 hits. All seven eligible studies reported on the upper GIB population. Restrictive transfusion did not increase the in-hospital- (RR: 0.94; CI 0.46, 1.94) and 30-day mortality (RR: 0.71; CI 0.35, 1.45). In-hospital- and 28 to 45-day rebleeding rate was also not higher with the restrictive modality (RR: 0.67; CI 0.30, 1.50; RR:0.75; CI 0.49, 1.16, respectively). Results of individual studies showed a lower rate of transfusion reactions and post-transfusion intervention if the transfusion was started at a lower threshold. A haemoglobin threshold > 80 g/L may result in a higher untoward outcome rate. In summary, restrictive transfusion does not appear to lead to a higher rate of significant clinical endpoints. The optimal restrictive transfusion threshold should be further investigated.
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Pre-hospital freeze-dried plasma for critical bleeding after trauma: A pilot randomized controlled trial
Mitra B, Meadley B, Bernard S, Maegele M, Gruen RL, Bradley O, Wood EM, McQuilten ZK, Fitzgerald M, St Clair T, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2023
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Editor's Choice
Abstract
OBJECTIVES Transfusion of a high ratio of plasma to packed red blood cells (PRBC), to treat or prevent acute traumatic coagulopathy, has been associated with survival after major trauma. However, the effect of pre-hospital plasma on patient outcomes has been inconsistent. The aim of this pilot trial was to assess the feasibility of transfusing freeze-dried plasma with red blood cells (RBC) using a randomized controlled design in an Australian aeromedical pre-hospital setting. METHODS Patients attended by Helicopter Emergency Medical Service (HEMS) paramedics with suspected critical bleeding after trauma managed with pre-hospital RBC were randomized to receive two units of freeze-dried plasma (Lyoplas N-w) or standard care (no plasma). The primary outcome was the proportion of eligible patients enrolled and provided the intervention. Secondary outcomes included preliminary data on effectiveness, including mortality censored at 24 hours and at hospital discharge, and adverse events. RESULTS During the study period of 01 June to 31 October 2022, there were 25 eligible patients, of whom 20 (80%) were enrolled in the trial and 19 (76%) received the allocated intervention. Median time from randomization to hospital arrival was 92.5 mins (IQR 68-101.5). Mortality may have been lower in the freeze-dried plasma group at 24h (RR 0.24; 95%CI: 0.03 - 1.73) and at hospital discharge (RR 0.73; 95%CI: 0.24 - 2.27). No serious adverse events related to the trial interventions were reported. CONCLUSIONS This first reported experience of freeze-dried plasma use in Australia suggests pre-hospital administration is feasible. Given longer prehospital times typically associated with HEMS attendance, there is potential clinical benefit from this intervention and rationale for a definitive trial.
PICO Summary
Population
Patients attended by Helicopter Emergency Medical Service (HEMS) paramedics with suspected critical bleeding after trauma (n= 20).
Intervention
Two units of freeze-dried plasma (Lyoplas N-w), (n= 9).
Comparison
Standard care (no plasma), (n= 11).
Outcome
The primary outcome was the proportion of eligible patients enrolled and provided the intervention. Secondary outcomes included preliminary data on effectiveness, including mortality censored at 24 hours and at hospital discharge, and adverse events. Nineteen patients (76%) received the allocated intervention. Median time from randomization to hospital arrival was 92.5 mins (IQR 68-101.5). Mortality may have been lower in the freeze-dried plasma group at 24h (RR 0.24; 95% CI [0.03, 1.73]) and at hospital discharge (RR 0.73; 95% CI [0.24, 2.27]. No serious adverse events related to the trial interventions were reported.