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1.
Fresh frozen plasma transfusion in the neonatal population: A systematic review
Sokou R, Parastatidou S, Konstantinidi A, Tsantes AG, Iacovidou N, Doxani C, Piovani D, Bonovas S, Stefanidis I, Zintzaras E, et al
Blood reviews. 2022;:100951
Abstract
Although fresh frozen plasma (FFP) transfusions are common practice in neonatology, robust evidence on their use is lacking. The aim of this study was to systematically review the literature for data on the practice of FFP transfusions in neonates and their association with neonatal morbidity and mortality. The authors identified 40 studies, which met the inclusion criteria for this review. It was demonstrated that the practice of FFP transfusions significantly varies throughout the world. The majority of FFP transfusions are administered "prophylactically", without evidence of active bleeding. Although FFP transfusions may restore coagulation tests results, they do not alter the clinical outcome of the neonates. Reactions following transfusions are probably underestimated in neonates, often undiagnosed and thus, underreported. High quality RCTs aiming to evaluate the effectiveness of FFP in specific clinical conditions are urgently needed, as they could change long-standing FFP transfusion practices, and help reduce neonatal morbidity and mortality.
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Prehospital plasma is associated with survival principally in patients transferred from the scene of injury: A secondary analysis of the PAMPer trial
Lewis RE, Muluk SL, Reitz KM, Guyette FX, Brown JB, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Yazer MH, et al
Surgery. 2022
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Editor's Choice
Abstract
BACKGROUND We sought to characterize if prehospital transfer origin from the scene of injury (SCENE) or from a referral emergency department (REF) alters the survival benefit attributable to prehospital plasma resuscitation in patients at risk of hemorrhagic shock. METHODS We performed a secondary analysis of data from a recently completed prehospital plasma clinical trial. All of the enrolled patients from either the SCENE or REF groups were included. The demographics, injury characteristics, shock severity and resuscitation needs were compared. The primary outcome was a 30-day mortality. Kaplan-Meier analysis and Cox-hazard regression were used to characterize the independent survival benefits of prehospital plasma for transport origin groups. RESULTS Of the 501 enrolled patients, the REF group patients (n = 111) accounted for 22% with the remaining (n = 390) originating from the scene. The SCENE group patients had higher injury severity and were more likely intubated prehospital. The REF group patients had longer prehospital times and received greater prehospital crystalloid and blood products. Kaplan-Meier analysis revealed a significant 30-day survival benefit associated with prehospital plasma in the SCENE group (P < .01) with no difference found in the REF group patients (P = .36). The Cox-regression verified after controlling for relevant confounders that prehospital plasma was independently associated with a 30-day survival in the SCENE group patients (hazard ratio 0.59; 95% confidence interval 0.39-0.89; P = .01) with no significant relationship found in the REF group patients (hazard ratio 1.03, 95% confidence interval 0.4-3.0). CONCLUSION Important differences across the SCENE and REF cohorts exist that are essential to understand when planning prehospital studies. Prehospital plasma is associated with a survival benefit primarily in SCENE group patients. The results are exploratory but suggest transfer origin may be an important determinant of prehospital plasma benefit.
PICO Summary
Population
Severely injured trauma patients enrolled in the PAMPer trial (n= 501).
Intervention
Thawed plasma (n= 230).
Comparison
Standard pre-hospital air medical care (n= 271).
Outcome
For this secondary analysis of the PAMPer trial, the study population was composed of 390 (78%) patients with an air medical transfer origin from the scene of injury (SCENE) and 111 (22%) patients transferred from an outside referral emergency department (REF). Randomization to plasma or standard of care was equally distributed across each transfer origin group. The SCENE group had higher injury severity and were more likely intubated pre-hospital. The REF group had longer pre-hospital times and received greater pre-hospital crystalloid and blood products. Kaplan-Meier analysis revealed a significant 30-day survival benefit associated with pre-hospital plasma in the SCENE group with no difference found in the REF group. The Cox-regression verified after controlling for relevant confounders that pre-hospital plasma was independently associated with a 30-day survival in the SCENE group with no significant relationship found in the REF group.
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3.
Post-injury Complement C4 Activation is Associated with Adverse Outcomes and is Potentially Influenced by Plasma Resuscitation
Schaid TR Jr, Hansen KC, Sauaia A, Moore EE, DeBot M, Cralley AL, Erickson C, Silliman CC, Banerjee A, Ghasabyan A, et al
The journal of trauma and acute care surgery. 2022
Abstract
BACKGROUND Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators remain unclear. Recently the anaphylatoxin C4a has been shown to bind to thrombin receptors. While plasma-based resuscitation has been shown to modify the endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought to characterize the activation of complement after injury and the effect of fresh frozen plasma (FFP) on this inflammatory response. We hypothesized that trauma induces C4 activation, which is associated with worse outcomes and influenced by FFP resuscitation. METHODS Blood was collected from injured patients at a single Level I Trauma Center enrolled in the COMBAT randomized clinical trial. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. For the present observational study, concentrations of complement proteins were analyzed at multiple time points, compared between treatment groups, and correlated with outcomes. RESULTS C4 activation occurred over the first six hours post-injury with peak activation 6-24 hours. Tissue hypoperfusion, defined as base deficit >10 mEq/L, and requirement for massive transfusion were associated with greater C4 activation. C4 activation was associated with mortality, multiple organ failure, and longer ventilator requirement. Additionally, temporal trends of C1q, factor B, and C3 by outcome groups support the prevailing theory of primary classical pathway activation with alternative pathway amplification. Resuscitation with FFP over the first six hours was associated with increased C4 activation at 12 and 24 hours. CONCLUSIONS C4 activation has an important inflammatory role post-injury, and FFP has the potential to augment this complement activation during resuscitation. EVIDENCE Level III, Prognostic/Epidemiological.
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Prothrombin Complex Concentrate for Trauma Induced Coagulopathy: A Systematic Review and Meta-Analysis
Kao TW, Lee YC, Chang HT
Journal of acute medicine. 2021;11(3):81-89
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Editor's Choice
Abstract
BACKGROUND Optimal management for trauma-induced coagulopathy (TIC) is a clinical conundrum. In conjunction with the transfusion of fresh-frozen plasma (FFP), additional administration of prothrombin complex concentrate (PCC) was proposed to bring about further coagulative benefit. However, investigations evaluating the efficacy as well as corresponding side effects were scarce and inconsistent. The aim of this study was to systematically review current literature and to perform a meta-analysis comparing FFP+PCC with FFP alone. METHODS Web search followed by manual interrogation was performed to identify relevant literatures fulfilling the following criteria, subjects as TIC patients taking no baseline anticoagulants, without underlying coagulative disorders, and reported clinical consequences. Those comparing FFP alone with PCC alone were excluded. Comprehensive Meta-analysis software was utilized, and statistical results were delineated with odd ratio (OR), mean difference (MD), and 95% confidence interval (CI). I(2) was calculated to determine heterogeneity. The primary endpoint was set as all-cause mortality, while the secondary endpoint consisted of international normalized ratio (INR) correction, transfusion of blood product, and thrombosis rate. RESULTS One hundred and sixty-four articles were included for preliminary evaluation, 3 of which were qualified for meta-analysis. A total of 840 subjects were pooled for assessment. Minimal heterogeneity was present in the comparisons (I(2) < 25%). In the PCC + FFP cohort, reduced mortality rate was observed (OR: 0.631; 95% CI: 0.450-0.884, p = 0.007) after pooling. Meanwhile, INR correction time was shorter under PCC + FFP (MD: -608.300 mins, p < 0.001), whilst the rate showed no difference (p = 0.230). The PCC + FFP group is less likely to mandate transfusion of packed red blood cells (p < 0.001) and plasma (p < 0.001), but not platelet (p = 0.615). The incidence of deep vein thrombosis was comparable in the two groups (p = 0.460). CONCLUSIONS Compared with FFP only, PCC + FFP demonstrated better survival rate, favorable clinical recovery and no elevation of thromboembolism events after TIC.
PICO Summary
Population
Patients with trauma induced coagulopathy (3 studies, n= 840).
Intervention
Prothrombin complex concentrate and fresh-frozen plasma (PCC + FFP).
Comparison
Fresh-frozen plasma (FFP).
Outcome
In the PCC + FFP cohort, reduced mortality rate was observed (OR: 0.631) after pooling. Meanwhile, international normalized ratio correction time was shorter under PCC + FFP (MD: -608.300 mins), whilst the rate showed no difference. The PCC + FFP group was less likely to mandate transfusion of packed red blood cells and plasma, but not platelet. The incidence of deep vein thrombosis was comparable in the two groups.
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Forgot calcium? Admission ionized-calcium in two civilian randomized controlled trials of pre-hospital plasma for traumatic hemorrhagic shock
Moore HB, Tessmer MT, Moore EE, Sperry JL, Cohen MJ, Chapman MP, Pusateri AE, Guyette FX, Brown JB, Neal M, et al
The journal of trauma and acute care surgery. 2020
Abstract
BACKGROUND Randomized clinical trials(RCTs) support the use of pre-hospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most pre-hospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent pre-hospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that pre-hospital plasma is associated with hypocalcemia, which in turn is associated with lower survival. METHODS We studied patients enrolled in two institutions participating in pre-hospital plasma RCTs (Control=Standard-of-care; Experimental=Plasma), with i-Ca collected prior to calcium supplementation. Adults with traumatic hemorrhagic shock(SBP≤70 mmHg or 71-90mmHg+HR≥108bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca<1.0mmol/L. RESULTS Of 160 subjects(76% men), 48% received pre-hospital plasma, median age 40years(IQR:28-53), 71% suffered blunt trauma, median ISS=22(IQR:17-34). Pre-hospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Pre-hospital plasma recipients had significantly higher rates of hypocalcemia compared to controls (53% vs 36%, Adjusted Relative Risk, aRR=1.48; 95%CI: 1.03-2.12, p=0.03). Severe hypocalcemia was significantly associated with decreased survival(Adjusted Hazard Ratio:1.07;95%CI:1.02-1.13, p=0.01) and massive transfusion(aRR= 2.70;95%CI:1.13-6.46, p=0.03), after adjustment for confounders(randomization group, age, ISS, and shock index). CONCLUSION Pre-hospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in pre-hospital hemotherapy. LEVEL OF EVIDENCE
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Forgot calcium? Admission ionized-calcium in two civilian randomized controlled trials of prehospital plasma for traumatic hemorrhagic shock
Moore HB, Tessmer MT, Moore EE, Sperry JL, Cohen MJ, Chapman MP, Pusateri AE, Guyette FX, Brown JB, Neal MD, et al
J Trauma Acute Care Surg. 2020;88(5):588-596
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Abstract
BACKGROUND Randomized clinical trials (RCTs) support the use of prehospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most prehospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent prehospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that prehospital plasma is associated with hypocalcemia, which in turn is associated with lower survival. METHODS We studied patients enrolled in two institutions participating in prehospital plasma RCTs (control, standard of care; experimental, plasma), with i-Ca collected before calcium supplementation. Adults with traumatic hemorrhagic shock (systolic blood pressure ≤70 mm Hg or 71-90 mm Hg + heart rate ≥108 bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca of 1.0 mmol/L or less. RESULTS Of 160 subjects (76% men), 48% received prehospital plasma (median age, 40 years [interquartile range, 28-53 years]) and 71% suffered blunt trauma (median Injury Severity Score [ISS], 22 [interquartile range, 17-34]). Prehospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Prehospital plasma recipients had significantly higher rates of hypocalcemia compared with controls (53% vs. 36%; adjusted relative risk, 1.48; 95% confidence interval [CI], 1.03-2.12; p = 0.03). Severe hypocalcemia was significantly associated with decreased survival (adjusted hazard ratio, 1.07; 95% CI, 1.02-1.13; p = 0.01) and massive transfusion (adjusted relative risk, 2.70; 95% CI, 1.13-6.46; p = 0.03), after adjustment for confounders (randomization group, age, ISS, and shock index). CONCLUSION Prehospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in prehospital hemotherapy. LEVEL OF EVIDENCE Therapeutic, level II.
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Freeze-dried plasma in major haemorrhage: a systematic review
Feuerstein SJ, Skovmand K, Moller AM, Wildgaard K
Vox sanguinis. 2020
Abstract
BACKGROUND AND OBJECTIVES Freeze-dried plasma (FDP) has logistical advantages in terms of storage and reconstitution time compared to fresh-frozen plasma. In vitro studies show FDP to be equivalent to fresh-frozen plasma regarding coagulation and clotting capacities. FDP is used in an increasing number of countries. We wanted to evaluate the clinical effects of FDP in major haemorrhage compared to standard care. METHODS MEDLINE, Embase, Central, Biosis Previews, WHO ICTRP, Clinical Trials and Open Grey were systematically searched from inception until September 2018, without language restriction. Studies were eligible if they examined haemorrhagic adult patients transfused with FDP. Our primary outcome was mortality. Two reviewers independently assessed studies for eligibility, extracted data and assessed bias. RESULTS Nine studies were eligible for inclusion. Three studies had a comparison group: one was a randomized controlled trial and two were before and after comparisons. Six studies were uncontrolled. A total of 606 patients received FDP, while 72 patients received non-FDP transfusion. In total, five minor adverse effects were documented. Two studies compared FDP to fresh-frozen plasma and found no difference in 30-day mortality between the groups. The included studies were heterogenous and had several methodological weaknesses, such as no control group, missing data or no protocol. CONCLUSIONS The available research does not document the clinical effects of FDP. We cannot recommend or discourage use of FDP in major haemorrhage on base of available research.
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CHARACTERIZATION OF UNEXPECTED SURVIVORS FOLLOWING A PREHOSPITAL PLASMA RANDOMIZED TRIAL
Gruen DS, Guyette FX, Brown JB, Daley BJ, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Yazer MH, Neal MD, et al
J Trauma Acute Care Surg. 2020
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Editor's Choice
Abstract
BACKGROUND Prehospital plasma improves survival for severely injured trauma patients transported by air ambulance. We sought to characterize the unexpected survivors, patients who survived despite having high predicted mortality following traumatic injury. METHODS The Prehospital Air Medical Plasma (PAMPer) trial randomized severely injured patients (n=501) to receive either standard care (crystalloid) or two units of prehospital plasma followed by standard care fluid resuscitation. We built a generalized linear model to estimate patient mortality. Area under the receiver operating characteristic curve (AUC) was used to evaluate model performance. We defined unexpected survivors as patients who had a predicted mortality >50% and survived to 30 days. We characterized patient demographics, clinical features, and outcomes of the unexpected survivors. Observed to expected (O/E) ratios and Z-statistics were calculated using model-estimated mortality for each cohort. RESULTS Our model predicted mortality better than ISS or RTS parameters and identified 36 unexpected survivors. Compared to expected survivors, unexpected survivors were younger (33 [24, 52] vs. 47 [32, 59] years, P=0.013), were more severely injured (ISS 34 [22, 50] vs. 18 [10, 27], P<0.001), had worse organ dysfunction and hospital resource outcomes (MOF, ICU and hospital length of stay, and ventilator days), and were more likely to receive prehospital plasma (67 vs. 46%, P=0.031). Nonsurvivors with high predicted mortality were more likely to receive standard care resuscitation (P<0.001). Unexpected survivors who received prehospital plasma had a lower observed to expected mortality than those that received standard care resuscitation (O/E 0.56 [0.33-0.84] vs. 1.0 [0.73-1.32]). The number of prehospital plasma survivors (24) exceeded the number of predicted survivors (n=10) estimated by our model (P<0.001). CONCLUSIONS Prehospital plasma is associated with an increase in the number of unexpected survivors following severe traumatic injury. Prehospital interventions may improve the probability of survival for injured patients with high predicted mortality based on early injury characteristics, vital signs, and resuscitation measures.Secondary Analysis LEVEL OF EVIDENCE II.
PICO Summary
Population
Severely injured patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial (n=501).
Intervention
Two units of prehospital plasma followed by standard care fluid resuscitation (n=230).
Comparison
Standard care (crystalloid) (n=271).
Outcome
The generalized linear model to estimate patient mortality predicted mortality better than ISS or RTS parameters and identified 36 unexpected survivors. Compared to expected survivors, unexpected survivors were younger, were more severely injured, had worse organ dysfunction and hospital resource outcomes, and were more likely to receive prehospital plasma (67 vs. 46%). Non-survivors with high predicted mortality were more likely to receive standard care resuscitation. Unexpected survivors who received prehospital plasma had a lower observed to expected mortality than those that received standard care resuscitation. The number of prehospital plasma survivors (24) exceeded the number of predicted survivors (10) estimated by the model.
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French lyophilized plasma versus normal saline for post-traumatic coagulopathy prevention and correction: PREHO-PLYO protocol for a multicenter randomized controlled clinical trial
Jost D, Lemoine S, Lemoine F, Lanoe V, Maurin O, Derkenne C, Franchin Frattini M, Delacote M, Seguineau E, Godefroy A, et al
Trials. 2020;21(1):106
Abstract
BACKGROUND Post-trauma bleeding induces an acute deficiency in clotting factors, which promotes bleeding and hemorrhagic shock. However, early plasma administration may reduce the severity of trauma-induced coagulopathy (TIC). Unlike fresh frozen plasma, which requires specific hospital logistics, French lyophilized plasma (FLYP) is storable at room temperature and compatible with all blood types, supporting its use in prehospital emergency care. We aim to test the hypothesis that by attenuating TIC, FLYP administered by prehospital emergency physicians would benefit the severely injured civilian patient at risk for hemorrhagic shock. METHODS/DESIGN This multicenter randomized clinical trial will include adults severely injured and at risk for hemorrhagic shock, with a systolic blood pressure < 70 mmHg or a Shock Index > 1.1. Two parallel groups of 70 patients will receive either FLYP or normal saline in addition to usual treatment. The primary endpoint is the International Normalized Ratio (INR) at hospital admission. Secondary endpoints are transfusion requirement, length of stay in the intensive care unit, survival rate at day 30, usability and safety related to FLYP use, and other biological coagulation parameters. CONCLUSION With this trial, we aim to confirm the efficacy of FLYP in TIC and its safety in civilian prehospital care. The study results will contribute to optimizing guidelines for treating hemorrhagic shock in civilian settings. TRIAL REGISTRATION ClinicalTrials.gov, NCT02736812. Registered on 13 April 2016. The trial protocol has been approved by the French ethics committee (CPP 3342) and the French Agency for the Safety of Medicines and Health Products (IDRCB 2015-A00866-43).
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10.
Evaluation of effect of scheduled fresh frozen plasma on ECMO circuit life: A randomized pilot trial
McMichael ABV, Zimmerman KO, Kumar KR, Ozment CP
Transfusion. 2020
Abstract
BACKGROUND Factor consumption is common during ECMO complicating the balance of pro and anticoagulation factors. This study sought to determine whether transfusion of coagulation factors using fresh frozen plasma (FFP) increased ECMO circuit life and decreased blood product transfusion. Secondly, it analyzed the association between FFP transfusion and hemorrhagic and thrombotic complications. STUDY DESIGN AND METHODS Thirty-one pediatric ECMO patients between October 2013 and January 2016 at a quaternary care institution were included. Patients were randomized to FFP every 48 hours or usual care. The primary outcome was ECMO circuit change. Secondary outcomes included blood product transfusion, survival to decannulation, hemorrhagic and thrombotic complications, and ECMO costs. RESULTS Median (interquartile range [IQR]) number of circuit changes was 0 (0, 1). No difference was seen in percent days without a circuit change between intervention and control group, P = .53. Intervention group patients received median platelets of 15.5 mL/kg/d IQR (3.7, 26.8) vs 24.8 mL/kg/d (12.2, 30.8) for the control group (P = .16), and median packed red blood cells (pRBC) of 7.7 mL/kg/d (3.3, 16.3) vs 5.9 mL/kg/d (3.4, 18.7) for the control group, P = .60. FFP transfusions were similar with 10.2 mL/kg/d (5.0, 13.9) in the intervention group vs 8.8 (2.5, 17.7) for the control group, P = .98. CONCLUSION In this pilot randomized study, scheduled FFP did not increase circuit life. There was no difference in blood product transfusion of platelets, pRBCs, and FFP between groups. Further studies are needed to examine the association of scheduled FFP with blood product transfusion.
