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.

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.

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.

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.

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).

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.

Abstract

INTRODUCTION Recent randomized clinical trial evidence demonstrated a survival benefit with the use of prehospital plasma in patients at risk of hemorrhagic shock. We sought to characterize the survival benefit associated with prehospital plasma relative to the blood transfusion volume over the initial 24 hours. We hypothesized that the beneficial effects of prehospital plasma would be most robust in those with higher severity of hemorrhage. METHODS We performed a prespecified secondary analysis using data derived from a prospective randomized prehospital plasma trial. Blood component transfusion volumes were recorded over the initial 24 hours. Massive transfusion (MT) was defined a priori as receiving ≥ 10 units of red cells in 24hrs. We characterized the 30-day survival benefit of prehospital plasma and the need for MT and overall 24-hour red cell transfusion volume utilizing Kaplan-Meier survival analysis and Cox proportional hazard regression. RESULTS There were 501 patients included in this analysis with 230 randomized to prehospital plasma with 104 patients requiring MT. Mortality in patients who received MT were higher compared to those that did not (MT vs. NO-MT, 42% vs 26%, p=0.001). Kaplan-Meier survival curves demonstrated early separation in the NO-MT subgroup (log rank p=0.008) with no survival benefit found in the MT group (log rank p=0.949). Cox regression analysis verified these findings. When 24-hour red cell transfusion was divided into quartiles, there was a significant independent association with 30-day survival in patients who received 4-7 units (HR 0.33, 95% CI 0.14-0.80, p=0.013).The survival benefits of prehospital plasma was demonstrated only in patients with red cell requirements below the transfusion level of MT. Patients who received 4-7 units of red cells demonstrated the most robust independent survival benefit attributable to prehospital plasma transfusion. Prehospital plasma may be most beneficial in those patients with moderate transfusion requirements and mortality risk.Secondary AnalysisLevel of Evidence- I.

Abstract

Importance: Both military and civilian clinical practice guidelines include early plasma transfusion to achieve a plasma to red cell ratio approaching 1:1 to 1:2. However, it was not known how early plasma should be given for optimal benefit. Two recent randomized clinical trials were published, with apparently contradictory results. The Prehospital Air Medical Plasma (PAMPer) clinical trial showed a nearly 30% reduction in mortality with plasma transfusion in the prehospital environment, while the Control of Major Bleeding After Trauma (COMBAT) clinical trial showed no survival improvement. Objective: To facilitate a post hoc combined analysis of the COMBAT and PAMPer trials to examine questions that could not be answered by either clinical trial alone. We hypothesized that prehospital transport time influenced the effects of prehospital plasma on 28-day mortality. Design, Setting, and Participants: A total of 626 patients in the 2 clinical trials were included. Patients with trauma and hemorrhagic shock were randomly assigned to receive either standard care or 2 U of thawed plasma followed by standard care in the prehospital environment. Data analysis was performed between September 2018 and January 2019. Interventions: Prehospital transfusion of 2 U of plasma compared with crystalloid-based resuscitation. Main Outcomes and Measures: The main outcome was 28-day mortality. Results: In this post hoc analysis of 626 patients (467 men [74.6%] and 159 women [25.4%]; median [interquartile range] age, 42 [27-57] years) who had trauma with hemorrhagic shock, a Cox regression analysis showed a significant overall survival benefit for plasma (hazard ratio [HR], 0.65; 95% CI, 0.47-0.90; P = .01) after adjustment for injury severity, age, and clinical trial cohort (COMBAT or PAMPer). A significant association with prehospital transport time was detected (from arrival on scene to arrival at the trauma center). Increased mortality was observed in patients in the standard care group when prehospital transport was longer than 20 minutes (HR, 2.12; 95% CI, 1.05-4.30; P = .04), while increased mortality was not observed in patients in the prehospital plasma group (HR, 0.78; 95% CI, 0.40-1.51; P = .46). No serious adverse events were associated with prehospital plasma transfusion. Conclusions and Relevance: These data suggest that prehospital plasma is associated with a survival benefit when transport times are longer than 20 minutes and that the benefit-risk ratio is favorable for use of prehospital plasma. Trial Registration: ClinicalTrials.gov identifiers: NCT01838863 (COMBAT) and NCT01818427 (PAMPer).

Abstract

Background: Trauma-induced coagulopathy is one of the most difficult issues to manage in severely injured patients. The plasma efficacy in treating haemorrhagic-shocked patients is well known. The debated issue is the timing at which it should be administered. Few evidences exist regarding the effects on mortality consequent to the use of plasma alone given in pre-hospital setting. Recently, two randomized trials reported interesting and discordant results. The present paper aims to analyse data from those two randomized trials in order to obtain more univocal results. Methods: A systematic review with meta-analysis of randomized controlled trials (RCTs) of pre-hospital plasma vs. usual care in patients with haemorrhagic shock. Results: Two high-quality RCTs have been included with 626 patients (295 in plasma and 331 in usual care arm). Twenty-four-hour mortality seems to be reduced in pre-hospital plasma group (RR = 0.69; 95% CI = 0.48-0.99). Pre-hospital plasma has no significant effect on 1-month mortality (RR = 0.86; 95% CI = 0.68-1.11) as on acute lung injury and on multi-organ failure rates (OR = 1.03; 95% CI = 0.71-1.50, and OR = 1.30; 95% CI = 0.92-1.86, respectively). Conclusions: Pre-hospital plasma infusion seems to reduce 24-h mortality in haemorrhagic shock patients. It does not seem to influence 1-month mortality, acute lung injury and multi-organ failure rates.Level of evidence: Level IStudy type: Systematic review with Meta-analysis.

Abstract

BACKGROUND After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting. METHODS To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport. The primary outcome was mortality at 30 days. RESULTS A total of 501 patients were evaluated: 230 patients received plasma (plasma group) and 271 received standard-care resuscitation (standard-care group). Mortality at 30 days was significantly lower in the plasma group than in the standard-care group (23.2% vs. 33.0%; difference, -9.8 percentage points; 95% confidence interval, -18.6 to -1.0%; P=0.03). A similar treatment effect was observed across nine prespecified subgroups (heterogeneity chi-square test, 12.21; P=0.79). Kaplan-Meier curves showed an early separation of the two treatment groups that began 3 hours after randomization and persisted until 30 days after randomization (log-rank chi-square test, 5.70; P=0.02). The median prothrombin-time ratio was lower in the plasma group than in the standard-care group (1.2 [interquartile range, 1.1 to 1.4] vs. 1.3 [interquartile range, 1.1 to 1.6], P<0.001) after the patients' arrival at the trauma center. No significant differences between the two groups were noted with respect to multiorgan failure, acute lung injury-acute respiratory distress syndrome, nosocomial infections, or allergic or transfusion-related reactions. CONCLUSIONS In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation. (Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).