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.

Abstract

INTRODUCTION Low titer group O whole blood (LTOWB) resuscitation is increasingly common in both military and civilian settings. Data regarding the safety and efficacy of prehospital LTOWB remains limited. METHODS We performed a single center, prospective, cluster randomized, prehospital thru in-hospital whole blood pilot trial for injured air medical patients. We compared standard prehospital air medical care including red cell transfusion and crystalloids followed by in-hospital component transfusion to prehospital and in-hospital LTOWB resuscitation. Prehospital vital signs were used as inclusion criteria (SBP ≤ 90 mmHg and HR ≥ 108 bpm) or (SBP ≤ 70 mmHg) for patients at risk of hemorrhage. Primary outcome was feasibility. Secondary outcomes included 28-day and 24 hour mortality, multiple organ failure, nosocomial infection, 24 hr transfusion requirements and arrival coagulation parameters. RESULTS Between November 2018 thru October 2020, 86 injured patients were cluster randomized by helicopter base. The trial has halted early at 77% enrollment. Overall, 28-day mortality for the cohort was 26%. Injured patients randomized to prehospital LTOWB (n = 40) relative to standard care (n = 46) were similar in demographics and injury characteristics. Intent to treat Kaplan-Meier survival analysis demonstrated no statistical mortality benefit at 28 days (25.0% vs. 26.1%, p = 0.85). Patients randomized to prehospital LTOWB relative to standard care had lower red cell transfusion requirements at 24 hours (p < 0.01) and a lower incidence of abnormal thromboelastographic measurements. No transfusion reactions during the prehospital or in-hospital phase of care were documented. CONCLUSION Prehospital through in-hospital LTOWB resuscitation is safe and may be associated with hemostatic benefits. A large-scale clinical trial is feasible with protocol adjustment and would allow the effects of prehospital LTOWB on survival and other pertinent clinical outcomes to be appropriately characterized. LEVEL OF EVIDENCE II, Cluster randomized pilot trial.

Abstract

BACKGROUND Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage. METHODS We performed a secondary analysis of all scene patients from the STAAMP trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders. RESULTS A total of 763 patients were included. Patients receiving prehospital blood had higher injury severity scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared to the TXA only and neither groups at 6.6% and 7.4% respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared to neither (HR 0.65; 95%CI 0.45-0.94, p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24 h mortality compared to neither (HR 0.39; 95%CI 0.17-0.88, p = 0.02). CONCLUSIONS For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients. LEVEL OF EVIDENCE Therapeutic, Level III.

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

IMPORTANCE In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES The primary outcome was 30-day all-cause mortality. RESULTS In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02086500.

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

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

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

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

MINI: Hemorrhage is the primary cause of preventable trauma death. Secondary analyses of scene patients from the PAMPer trial demonstrated that prehospital packed red blood cell and plasma had the greatest reduction in 30-day mortality compared with crystalloid-only resuscitation. Patients with hemorrhagic shock should receive prehospital blood products when available, preferably packed red blood cell and plasma. OBJECTIVE The aim of this study was to determine whether prehospital blood products reduce 30-day mortality in patients at risk for hemorrhagic shock compared with crystalloid only resuscitation. SUMMARY OF BACKGROUND DATA Hemorrhage is the primary cause of preventable death after injury. Large volume crystalloid resuscitation can be deleterious. The benefits of prehospital packed red blood cells (PRBCs), plasma, or transfusion of both products among trauma patients is unknown compared with crystalloid. METHODS Secondary analysis of the multicenter PAMPer trial was performed on hypotensive injured patients from the scene. The trial randomized 27 helicopter bases to prehospital plasma or standard resuscitation. Standard resuscitation at the sites was equally divided between crystalloid and crystalloid + PRBC. This led to 4 prehospital resuscitation groups: crystalloid only; PRBC; plasma; and PRBC+plasma. Cox regression determined the association between resuscitation groups and risk-adjusted 30-day mortality. The dose effect of resuscitation fluids was also explored. RESULTS Four hundred seven patients were included. PRBC+plasma had the greatest benefit [hazard ratio (HR) 0.38; 95% confidence interval (95% CI) 0.26-0.55, P < 0.001], followed by plasma (HR 0.57; 95% CI 0.36-0.91, P = 0.017) and PRBC (HR 0.68; 95% CI 0.49-0.95, P = 0.025) versus crystalloid only. Mortality was lower per-unit of PRBC (HR 0.69; 95% CI 0.52-0.92, p = 0.009) and plasma (HR 0.68; 95% CI 0.54-0.88, P = 0.003). Crystalloid volume was associated with increased mortality among patients receiving blood products (HR 1.65; 95% CI 1.17-2.32, P = 0.004). CONCLUSION Patients receiving prehospital PRBC+plasma had the greatest mortality benefit. Crystalloid only had the worst survival. Patients with hemorrhagic shock should receive prehospital blood products when available, preferably PRBC+plasma. Prehospital whole blood may be ideal in this population.