Prehospital blood transfusion (PHBT) and prehospital low titer O whole blood (LTOWB): A review of studies and practices

Unintentional injuries represent the third leading cause of deaths in the United States1 and the leading cause of death among all individuals between ages of 1–44.2 In one study, exsanguination accounted for 36% of prehospital deaths,3 while in another hemorrhage accounted for 55% of prehospital preventable or potentially preventable deaths.4 Annually, 25,000 civilian deaths are attributable to prehospital hemorrhagic shock.5 In 2017, a retrospective cohort study of 502 US military combat casualties undergoing medical evacuation suggested that prehospital transfusion was associated with improved 24-h and 30-day survival.6 Since then, four randomized trials7-10 compared blood products to control fluids during prehospital transport (published 2018–2022). In 2021, the Trauma, Hemostasis and Oxygenation Research (THOR)—Association for the Advancement of Blood and Biotherapies (AABB) Working Party published its recommendations for a prehospital blood product transfusion program.11 As of September 2023, over 121 emergency medical service (EMS) systems in the United States have implemented prehospital blood transfusion (PHBT) programs—with most (>70%) utilizing low titer O (positive) whole blood (LTOWB).12 In 2024, the AABB initiated an open public comment period (May 31, 2024 through July 30, 2024) for its proposed 1st Edition of Standards for Out of Hospital and Prehospital Transfusion Administration Services.13 Key prospective and retrospective studies related to PHBT as well as real-world models of LTOWB-based PHBT programs are reviewed herein. A MSH search for [prehospital transfusion] with filters: Clinical Trial, Randomized Controlled Trial was conducted in PubMed. The search was then repeated with filters off. Articles were included if blood products were compared to control solution or standard of care in the trauma setting. Pilot or feasibility studies were excluded as their design was not intended to demonstrate a clinical outcome difference; one study was excluded due to non-trauma patient population. For randomized controlled studies, risk of bias assessment was carried out using the Cochrane Risk of Bias tool.14 For non-randomized studies, risk of bias assessment was carried out using the Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) tool.15 Data including study design, age, proportion male, proportion blunt injury mechanism, injury severity score (ISS), and primary outcomes were extracted and discussed. Articles describing existing PHBT programs utilizing LTOWB were retained for further review. Details about their operation were extracted and discussed. The initial search produced 54 results, of which six met inclusion criteria. Of the studies, four were randomized controlled studies7-10 and two were retrospective.6, 16 An additional search without the RCT restriction produced a total of 87 results, from which four additional studies17-20—all retrospective—were identified. Of these four studies, two were excluded owing to (1) a focus on patients with gastrointestinal bleeding rather than trauma20; and (2) a defined intention as pilot study.19 The included studies are summarized in Tables 1 and 2. Notably, the retrospective studies utilized differing variables to develop matched control groups (Table 3). NTA 27% HTI 56% NTA 73%a HTI 35%b Yesc AORS 4.91 [95% CI: 1.51, 16.04] Nod 17.2% vs. 23.1%; p = .36 Yes HRM 0.46 [95% CI: 0.23, 0.91] Yes HRM 0.26 [95% CI: 0.08,0.84] Noc AORS 1.06 [95% CI: 0.42, 2.61] No 13.8% vs. 25.0%; p = .08 Yes HRM 0.51 [95% CI: 0.27, 0.97] Yes HRM 0.39 [95% CI: 0.16,0.92] Risk of bias assessments were conducted and presented in Tables 4 and 5. For the RCTs, personnel became aware of the treatment arm immediately upon opening the assigned treatment container, thus introducing performance bias.7-10 Crombie et al. was halted prior to completion of enrollment targets due to COVID-19 pandemic (under-powered study) and the authors stated that while clinicians assessing outcomes were not informed of group assignments, they might have been able to access them through hospital records, (possible detection bias).9 In Sperry et al., primary outcome data were available for 481 patients, and had to be imputed for 20. The total sample size was therefore fewer than the 504 required under the stated power analysis.7 After 144/150 planned patients had been enrolled, the data safety monitoring board and the FDA approved early termination of the COMBAT study for futility.8 In the conclusion sections of their article abstracts, 2/4 retrospective studies touted improvements in shock index at admission and survival at 24 h but failed to mention an absence of inhospital survival benefit, thus leading to reporting bias.17, 18 This additionally suggests a component of survival bias. In their propensity matched cohorts, 2/4 studies had important differences in injury patterns in the PHBT groups compared to matched controls, leading to increased selection bias.6, 17 Comparing PHBT versus Matched Controls: Penetrating Injuries were 58.6% versus 28.8% (p = <.01) in Braverman et al. and percentage of traumatic limb amputation was 73% versus 27% (p = <.001) in Shackelford et al. It must also be noted that most injuries were explosion related and involved a high rate of traumatic amputations and hemorrhagic torso injuries. Although the ISS was matched between the two groups, the PHBT population differed significantly in severity of injury from their own matched comparator group and likely explains the greater use of tourniquets 84% versus 45% (p < .001).6 In a multicenter, phase 3 trial, patients 16 and older with trauma-related hemorrhagic shock and hypotension (SBP ≤90 mmHg or absence of palpable radial pulse) were randomized to receive, in the prehospital setting, either 2 units each of packed RBCs and lyophilized plasma (LyoPlas) or up to 1 liter of normal saline (NS) via the intravenous or intraosseous route. The primary outcome was a composite of episode mortality or impaired lactate clearance. The intended sample size was 490 participants but due to pandemic related disruption, the study was halted early after 432 were randomized out of 580 screened (74%). Prior to randomization, participants had received on average 430 mL of crystalloids and 90% had received tranexamic acid. There was no difference in the composite outcome between groups, which had occurred in 128/199 (64%) of the RBC/LyoPlas group versus 136/210 (65%) of the NS group; adjusted risk difference −0.025% (95% CI: −9.0 to 9.0, p = .996).9 In a randomized controlled trial conducted in France, severely injured adults (≥18) at high risk for hemorrhagic shock and associated coagulopathy (i.e., shock index >1.1 or SBP <70 mmHg) were randomized to receive—en route—up to 1000 mL of lyophilized plasma or saline.10 The primary outcome was the International Normalized Ratio (INR) value at arrival to hospital. Secondary outcomes included transfusion requirements and 30-day survival. From April 1, 2016 through September 30, 2019 (3 years, 5 months), 150/1633 (9%) screened individuals were deemed eligible and randomized; 16 met exclusion criteria and thus 134 constituted the modified intention-to-treat cohort. Both groups received crystalloid—median (IQR) 700 (475–1000) mL in plasma group versus 1000 (700–1350) mL in control group (p = .03)—and the median (IQR) volume of plasma given was 525 (350–800) mL. There was no significant difference in the primary outcome of INR at arrival to hospital nor were there any differences in need for massive transfusion or 30-day survival.10 In the Prehospital Air Medical Plasma (PAMPer) multicenter, phase 3, superiority trial, injured adult patients at risk for hemorrhagic shock were randomized to receive, in the prehospital setting, 2 units thawed plasma or standard of care resuscitation during air medical transport. The primary outcome was mortality at 30 days. Standard of care resuscitation included crystalloids as part of the standard resuscitative protocol. Air transport teams at 13/27 participating air medical bases also carried 2 units of universal donor RBCs on each of their flights. If RBC-stocked transports were assigned to the plasma arm, then plasma would be administered first with RBC following if hypotension persisted and according to local protocol. Of screened individuals, 564/7275 (8%) were eligible for randomization, 501/564 (89%) met all inclusion criteria and none of the exclusion criteria, and data on the primary outcome were available for 481/501 (96%). The primary outcome was lower among those receiving thawed plasma versus standard of care—23.2% versus 33.0%; difference −9.8 percentage points (95% CI: −18.6 to −1.0, p = .03). Of interest, a subgroup analysis showed no improvement in 30-day survival among those receiving prehospital, standard of care treatment involving RBCs versus those randomized to plasma.7 Control of Major Bleeding After Trauma (COMBAT) was a randomized, placebo-controlled prehospital plasma (2 units of AB plasma, approximately 250 mL each) versus normal saline (per standard of care) trial among severely injured adults (>18) with SBP <70 mmHg or SBP <71–90 and HR >108 bpm thought due to acute blood loss.8 Ambulance teams carried frozen plasma (or frozen water dummy units). Plasma was dry-thawed using a plasma warming device (Barkey Plasmatherm, Barkey GmBH & Co. KG, Leopoldshoehe, Germany) adapted for vehicular use and capable of thawing 2 units of plasma in less than 3 min.8, 21 Endpoints included a primary endpoint of mortality at 28 days and a composite secondary endpoint of multiple organ failure (MOF), death, or both by day 28. Between April 1, 2014, and March 31, 2017, 144 patients were randomized (total screened unclear) and 125 formed the as-treated analysis. All 65 patients in the plasma group received 2 units of plasma; 32% received both units during transport; 37% received one in transport, one in ED; 31% started first unit during transport and the second unit was completed in ED. After 144/150 planned patients had been enrolled, the Data Safety Monitoring Board, Institutional Review Board, and FDA approved early termination of the study due to futility as outcomes were no different between groups and were not anticipated to change if the study were to be continued.8 The retrospective studies6, 16-18 utilized either single center or registry datasets to compare outcomes between patients receiving or not receiving prehospital transfusion. Heterogeneity was noted in the variables used to produce matched control groups (Table 3). Studies incorporating airlifted patients included those transported from facilities where transfusion may have already been initiated compared to those transported directly from the scene. Brown and colleagues assessed for an impact in this difference using a subgroup analysis of patients transported directly from the scene—finding additional enhancement in 24-h survival—see Table 2—but no difference in hospital survival.18 Braverman and colleagues assessed via subgroup analysis benefit of PHBT (LTOWB, anti-A, and anti-B < 1:256) among patients with prehospital cardiac arrest—there was no difference in ED mortality and the difference inhospital mortality did not reach statistical significance.17 Shackelford et al. differed from the other studies in that injury patterns were predominantly explosion-related and involved a high rate of traumatic amputations and hemorrhagic torso injuries—whereas the remainder of studies involved predominantly blunt injured patients.6 Among all patients who died within 30 days, 70% occurred within the first hour of Medevac rescue or hospital arrival, including 74% of deaths among nonrecipients and 17% of deaths among PHBT recipients and for those surviving long enough to receive a transfusion, only transfusions initiated within 15 min of Medevac were associated with reduced 24-h mortality.6 Importantly, survival from rescue to arrival at a role 3 hospital (which provides definitive theater support, and advanced capabilities) versus a role 2 hospital was improved among PHBT recipients over nonrecipients.6 A retrospective cohort study of the Pennsylvania Trauma Systems Foundations database explored the primary outcome of 24-h mortality between pediatric patients (aged 0–17 years) patients who received PHBT versus those receiving first transfusion in the emergency department (EDT).16 Of 559 children included, 70 (13%) received PHBT; propensity matching resulted in a weighted cohort of 207 children, including 68/70 PHBT recipients. Both 24 h (16% vs. 27%) and inhospital mortality (21% vs. 44%) were lower in PHBT versus EDT groups, respectively.16 There did not appear to be major safety signals among the various studies reviewed. It is notable, however, that while Sperry and colleagues reported all transfusion reactions to be mild and managed during transport—they do report one individual in the plasma arm with an anaphylactic reaction for which additional information was not provided.7 Crombie et al. reported similar rates of ARDS between the RBC + LyoPlas (6%) and the NS arms (2%).9 In the retrospective studies, rates of ARDS and inhospital complications were similar between study groups.16, 18 Finally, a feasibility study comparing LTOWB to standard of care PHBT showed no transfusion reactions or hemolytic complications, comparable rates of adverse events between groups, and no significant difference in early mortality.22 HSCESD48 San Antonio, Texas 2017 [Mapp JG, et al] SAFD San Antonio, Texas 2018 [Mapp JG, et al] IDF-MC Israel 2018 [Levin D, et al] Anti A/B titer <50 PBCFR Palm Beach, Florida 2022 [Coyle C, et al.] HCDFRS USA (Baltimore-Washington Corridor) 2021 [Levy MJ, et al.] The HCESD48 Fire-EMS is a 9-1-1 service provider with a service territory of 50 square miles and 150,000 residents with 8000 calls per year. Given distance and traffic delays, HCESD48 began a prehospital component therapy program in February 2016, which evolved in 2017 to an LTOWB program. The SAFD is the sole 9-1-1 provider for a 460 square mile service territory and 1.5 million residents.23 The HSCESD48 and CCEMS programs in Harris County, Texas, became the first ground ambulance systems in the United States to carry cold stored LTOWB; in October of 2018, the SAFD began stocking LTOWB as well.23 Retrospective analyses of the HSCESD48 and SAFD programs have been published. The combined HSCESD48/SAFD cohort included 58 patients who met study criteria (>18, nonprisoners, complete data). The median (IQR) age was 37.5 (27.3–58.0) and 79.3% (95% CI: 67.2%–87.7%) were male. Hemorrhagic shock etiology was nontraumatic in 46.5% (95% CI: 34.3%–59.2%) with gastrointestinal hemorrhage accounting for 66.7% (95% CI: 47.8%–81.4%). Of the traumatic subgroup, penetrating injury accounted for 80.6% (95% CI: 63.7%–90.8%)—which differs from the primarily blunt injured patients in the preceding literature review.23 Including fixed and variable costs, the authors concluded that by year 10 of the program and using an NNT of 10.2, the cost per life saved for the prehospital LTOWB program would be $5136.51; by comparison, and using an NNT of 2.5, the cost per life saved for the prehospital defibrillation program was $1710.09.23 A comparison between LTOWB and matched non-transfused controls from within the San Antonio EMS system was reviewed above.17 The SAFD later conducted a 12-month retrospective review of operations, finding that 248/363 (68.3%) of LTOWB units were transfused with the unused units returned for a zero-percentage wastage rate.24 The IDF-MC began use of freeze-dried plasma in 2013 as a primary volume resuscitation fluid for trauma casualties in field units; this was replaced by LTOWB in June of 2018 as the preferred resuscitation agent for hemorrhagic casualties of the Israeli Defense Forces—Airborne Combat Search and Rescue Unit (IDF-CSAR).25 The authors report that 3171/29,269 (10.8%) screened group O, Rh positive donors met criteria for LTOWB (titers <1:50); units were collected in CPDA-1 permitting an overall 35-day shelf life at 2–8°C storage that was subsequently further limited to 21 days to ensure functional platelet recovery.25 LTOWB units are stored in the IDF-CSAR unit in monitored refrigerators, then transferred into Pelican Credo Cubes (PeliBiothermal, Maple Grove, Minnesota—and validated to maintain a temperature of 4°C for 48 h) prior to air deployment.25 LTOWB units not used by day 21 were discarded; those unused prior to day 21 were returned to the blood center for recovery of red cells. Transfusion of LTOWB could be initiated for patients with injury and at least one sign of hemorrhagic shock (see Table 1).26 Of 1608 of LTOWB units issued to IDF-CSAR 33 (2%) were transfused by day 21. In total, 27 patients with a median (IQR) age of 29 (2–69) received 33 LTOWB units; mechanism of injury was penetrating in 8/27 (29.6%) and 22/27 (81.5%) recipients were male.25 Palm Beach County Fire Rescue (PBCFR) covers a service territory of 1800 square miles and 1.5 million people.27 The agency's 52 rescue trucks and two helicopters transport on average 230 patients by ground daily and respond to approximately 400 aeromedical transports per year.27 PBCFR began prehospital transfusion of LTOWB to trauma patients with suspected hemorrhagic shock in July of 2022. At any given time, the program only stocks 4 units of LTOWB (supplied by One Blood blood center)—with one unit reserved for air transport and the remaining three strategically placed at stations with the highest density of critically injured patients.27 Of interest, the authors note that LTOWB units are stored at 2–9°C (which is outside the acceptable storage temperature of 1–6°C28) in fire stations equipped with Helmer blood refrigerators (Helmer Scientific, Noblesville, Indiana); then transferred to Pelican Credo Coolers (Bound Tree Medical, Dublin, Ohio) for transport to the scene. Continuous temperature monitoring (every 30 min) was accomplished via Temp Stick (Ideal Sciences, Bountiful, Utah) WiFi temperature and humidity sensors. The program additionally utilizes Warrior (Quality in Flow, New Prague, Minnesota) blood warmers and LifeFlow PLUS Blood and Fluid Infusers (410 Medical, Durham, North Carolina)—hand operated rapid infuser devices that permit delivery of a 500 mL LTOWB unit in 3–5 min.27 For the review period, Coyle et al. report LTOWB transfusion to 20/881 (2.3%) trauma activations.27 Patients had a median (IQR) age of 27.5 years (20–32), 17/20 (85%) were male, and 8/20 (40%) LTOWB recipients had a penetrating trauma mechanism.27 Utilization was 20/39 (51%) with 19 units being discarded—18 due to expiration and one due to temperature excursion constituting a 19/39 (49%) wastage rate.27 The HCDFRS provides EMS services for the Baltimore-Washington corridor, serving a population of 325,000 people and responding to over 30,000 requests annually.12 Levy et al. state that "regulatory, administrative, and logistical barriers prevented EMS from receiving blood products from regional health system partners" and that units were instead sourced directly from a regional blood center—Inova Blood Donor Services.12, 29 On the Inova Blood Donor Services website, mention is made of their Field Available Component Transfusion Response (FACT*R) Program, with a link featuring a 2020 ABC news story describing a multivehicle car accident where PHBT was utilized as well as the partnership between Virginia's Fairfax and Loudoun County's EMS and Inova Blood Donor Services.30 The program utilizes purpose-built Credo-ProMed coolers to maintain blood at 1–6°C for >24 h.12, 31 Continuous temperature monitoring is carried out with WiFi enabled, portable monitors which provide mobile device alerting of temperature control issues in real time to the smartphones of authorized EMS individuals.12, 32 One unit of LTOWB was placed on each of the HCDFRS' three supervisor vehicles along with a blood administration infusion set with standard in-line filter, a pressure infuser bag, the LifeFlow Plus hand operated rapid infuser (410 Medical, Durham, NC), and the Qin Flow Warrior Lite Fluid Warmer (Quality in Flow, New Prague, MN).12, 33, 34 A fourth unit is maintained on the most centrally located EMS Supervisor vehicle for immediate resupply if needed. Documentation of transfusions is afforded through a prehospital Electronic Medical Record (EMR—ImageTrendElite, Lakeville, MN). As per the ImageTrend website, the Health Information Hub "facilitates the automatic, bidirectional exchange of data connecting EMS and hospitals".35 EMS providers are able to securely take and embed into the medical record photographs of blood unit labels and patient identifiers. A systematic review of the literature surrounding PHBT was conducted. Two of the RCTs were stopped early—one for failure to accrue due to COVID-19 pandemic9 and another for futility.8 None of the RCTs and only a single retrospective study assessed LTOWB; all studies were impacted by low to moderate degrees of bias. One of the four RCTs demonstrated benefit; three of four retrospective studies demonstrated benefit in early survival while only two of four showed inhospital survival benefit. Analysis groups differed in injury severity patterns and there was heterogeneity in the variables used to construct matched control groups (Table 3). Safety appeared acceptable across all studies. According to Shackelford et al.6 the low sample sizes "generated broad 95% confidence intervals [for mortality reduction] whose upper bounds were close to null – especially for 30-day survival." This was echoed in Brown et al. where the 24-h survival benefit was lost by the measurement point of inhospital survival.18 The PAMPer and COMBAT trials benefitted from a priori harmonization of design, data collection, and data sharing thus permitting combining of data for post hoc analysis.36 It was hypothesized that the disparity in outcomes—with a mortality benefit noted in PAMPer but not in COMBAT—was due to very short ground-transport times in the COMBAT trial rendering neutral the potential benefit of prehospital transfusion.36 The hazard ratio after adjustment for age, injury severity, and trial cohort (PAMPer vs. COMBAT) was 0.65 (95% CI: 0.42–0.90, p = .01) thus favoring lower mortality in the plasma group. Stratified analysis showed twofold higher mortality in control subjects with transport times >20 min (HR 2.12, 95% CI: 1.05–4.30, p = .04) that was absent in those who received prehospital plasma (HR 0.78, 95% CI: 0.40–1.51, p = .46). There was no survival difference between control and plasma groups at ≤20-min transport times but among patients with >20-min transport times, mortality was lower in the plasma group (HR 0.56, 95% CI: 0.40–0.80, p = .01).36 Indeed, while between-group median transport times were similar, a clear difference was noted between PAMPer7—40 to 42 min—and COMBAT8—19–16 min—studies (Table 1). Interestingly, neither Crombie et al. nor Jost et al.—both with transport times >20 min—showed survival benefit in the transfusion arms.9, 10 One potential explanation—at least for Crombie et al. —is the much higher median injury severity scores of its enrollees compared to Sperry et al. (36 vs. 21) and indeed to those of other included studies as well (Tables 1 and 2). This difference in ISS is significant as odds ratio for mortality has been found to jump from 7.04 for an ISS of 15–24 to 55.80 for an ISS of >25.37 Shackelford et al. found that for patients with explosion related injuries enriched for one or more traumatic amputations and hemorrhagic torso injuries, the initiation of PHBT within 15 min of Medevac arrival showed a 24-h survival benefit.6 Such injury patterns differed from those represented in the remainder of studies reviewed—which were predominantly blunt injuries—see Tables 1 and 2. In conclusion, the use of PHBT—whether comprised of standard component therapy, LyoPlas, or LTOWB—is associated with conflicting evidence for survival benefit but reasonable evidence for safety. Large, randomized, controlled trials are required to firmly establish efficacy. Established PHBT programs provide a framework for PHBT adoption, which is expanding rapidly around the country. MHT – Speaker Honoraria, Sanofi.