Low‐titer group O whole blood in military ground ambulances: Lessons from the Israel Defense Forces initial experience

Cold‐stored low‐titer group O whole blood (LTOWB) has become increasingly utilised in both prehospital and in‐hospital settings for resuscitation of traumatic haemorrhage. However, implementing the use of LTOWB to ground medical teams has been limited due to logistic challenges.


| INTRODUCTION
5][6] The concept of DCR, dictating balanced ratios of packed red blood cells (PRBCs), plasma and platelets-reconstituting the makeup of whole blood, was devised to combat the early coagulopathy of trauma, 5 affecting more than 25% of trauma patients by the time they arrive to the hospital, and conferring a significant increase in mortality. 7,8mer Talmy and Michael Malkin contributed equally to this study and are co-first authors.Sami Gendler and Ofer Almog contributed equally to this study and are co-last authors.
3][14] Additional benefits of whole blood include the higher haematocrit, reduced volume of citrate-containing preservative and improved coagulation activity as compared with balanced component therapy. 15,16However, the use of LTOWB in prehospital settings is met with significant deployment and logistic challenges, and has therefore been used in limited settings, primarily among helicopter emergency medical services. 17,18In October 2017, the American Association of Blood Banks (AABB) 19 approved the use of whole blood as a standard product for patients with severe bleeding, but its use in ground ambulances has remained very limited. 20,21e use of blood products in the prehospital setting has become a fundamental part of remote damage-control resuscitation (RDCR), considering the potential benefit of their use close to the point-ofinjury. 22Since 2018, the Israel Defense Forces Medical Corps (IDF-MC) has instituted a whole blood program, utilising cold-stored LTOWB in its Airborne MedEvac Unit, demonstrating initial safety and logistic feasability. 23In 2022, recognising the benefits of early transfusion of whole blood, the IDF-MC deployed whole blood in ground ambulances for the first time in Israel.Herein, we report on the initial experience, and present a case-series of the first patients receiving LTOWB by ground ambulance teams.

| Setting and design
The IDF-MC provides prehospital trauma care to both civilians and soldiers injured in military or civilian circumstances (i.e., road traffic collision, falls) occurring in proximity to IDF bases.IDF-MC intensive care unit (ICU) ambulances are staffed with paramedic-led teams and provide both point-of-injury and en-route care.These teams are stationed along Israel's borders with varying transport times (Approximately between 30 and 90 min, depending on region).In most military scenarios, these ICU ambulances are tasked with rapidly evacuating patients to the hospital following hand-over from teams providing point-of-injury care.Since the IDF does not operate military hospitals, patients requiring further care are transferred to civilian hospitals, as part of the national health system.
In 2022, the IDF-MC initiated the deployment of low titer coldstored O RhD-positive whole blood (LTOWB) to several ICU ambulances, replacing the previous IDF-MC's standard fluid of choice for trauma resuscitation-freeze-dried plasma (FDP). 24Each of the ICU ambulances were equipped with two units of LTOWB, replaced upon expiry or use.We retrospectively reviewed the IDF Trauma Registry (IDF-TR) to identify cases of whole blood administration by ground ICU ambulance teams, between January and December 2022.In our analysis, we excluded cases of patients administered whole blood for the indication of traumatic cardiac arrest.The IDF-MC Institutional Review Board approved this study (Protocol #: 1948-2018).This manuscript was written and formatted according to the STROBE guidelines for cohort studies. 25

| Products and logistics
All LTOWB units to be used in the IDF were supplied by Magen David National Blood Services (MDABS), Israel's national blood bank, from whole blood donations of male-only O Rh + volunteer donors, with a volume of 450 ± 50 mL, as previously described. 23All whole blood units are collected in CPDA-1, with a maximal expiration of 35-days.
Each unit undergoes an automated screening procedure, and only units with a titer of Anti-A or Anti-B of <1:100 were classified as LTOWB during the study period.Units identified as LTOWB are tagged and do not undergo separation into components, creating an inventory for use by the IDF as well as by several civilian hospitals.
Currently, platelet-sparing leukocyte reduction is not utilised during unit processing as quality control tests performed during the validation of the filtration procedure revealed a significant reduction in the platelet content of the final LTOWB product.Units are supplied to the IDF ICU ambulance teams upon demand, to be used within 21 days from the time of collection.LTOWB units can be issued within 3 days after collection, due to preparation and transport times to the remote military units.Units not utilised during this period are returned to MDABS laboratories, to be discarded.During transport in the ICU ambulances, units are stored in a Cr edo ProMed Cooler™ (Pelican BioThermal, Plymouth, MN), and transferred to monitored, alarm-equipped medical refrigerators (Horizon Series™ HLR105, Helmer Scientific, Noblesville, IN) when the team is on-base.

| Training and administration protocol
For the initial rollout, several ICU ambulances were selected to be equipped with LTOWB.Paramedics manning these teams, underwent dedicated instruction and certification for the administration of LTOWB by a medical officer from the IDF Trauma and Combat Medicine Branch.The instructional sessions included an overview of the rationale for use of whole blood, indications, administration protocols, storage principles and diagnosis and treatment of adverse events, in accordance with the corresponding clinical practice guideline (CPG). 26ereafter, paramedics were required to achieve a passing score in a multiple-choice examination assessing the principles of LTOWB through a series of knowledge-based questions and clinical vignettes.
Administration of whole blood by IDF paramedics was predicated on approval of an on-call physician (Board-certified specialist in emergency medicine/anaesthesia/general surgery), abiding by the indications for volume resuscitation as detailed below.Each use was subject to immediate reporting and recording on both casualty cards and our prehospital trauma registry.

| Whole blood administration CPG
The IDF-MC CPGs for Remote Damage Control Resuscitation 26 instruct use of the best available resuscitation fluid in patients deemed to present with one or more signs of profound shock (Figure 1).The primary indication is a systolic blood pressure measurement of ≤90 mmHg in a trauma patient.If blood pressure is unmeasurable due to clinical presentation or technical reasons, unpalpable radial pulse or altered mental status, estimated not to result from head injury or medication administration, are used as indications.Administration of fluids through a blood warmer (Warrior, QinFlow Ltd.) is recommended via both the intravenous or  were injured in military circumstances, all from gunshot wounds, while two sustained blunt injuries in civilian road traffic collisions.Table 1 describes the characteristics, presentation, and outcomes of the patients included in the case-series.

| Prehospital presentation, treatment, whole blood indication and hospital outcomes
The median initial heart rate at presentation was 120 (IQR 99-141), systolic blood pressure was unmeasurable for four patients (Range 90-97 among measured) and digital pulse oximetry unmeasurable for three patients.The median Glasgow Coma Scale at presentation was 14 (IQR 12.5-15).LTOWB was administered after a hypotensive measurement (≤90 mmHg) in two cases.In the remaining five cases, the indication for volume resuscitation was altered mental status, in the absence of head injury or premedication with unmeasurable blood pressure.Whole blood was administered through intravenous access in 6/7 cases and was administered through a blood warmer in 5/7 cases.The median time from injury to LTOWB administration was Upon hospital arrival, six of seven patients underwent damage control laparotomy and three were started on a massive transfusion protocol (Table 1).All patients except one survived to discharge following ICU admission.One patient, a 59-year-old male with a grade 5 liver laceration, died during ICU stay following angioembolization.
Table 2 presents the vital signs and laboratory measures of the LTOWB recipients upon hospital admission.

| DISCUSSION
This small case series presents the initial experience of the IDF-MC in deploying LTOWB in ground ambulances, for the first time in Israel.
This series demonstrates that administration of LTOWB by paramedic-lead ICU ambulance teams is feasible, and based on current evidence, could be safe and potentially improve outcomes of patients with severe traumatic haemorrhage.The hospital data of patients in this case-series demonstrates that they were indeed seriously wounded, suffered from severe bleeding, and that prehospital LTOWB transfusion was indeed indicated.
Although currently limited, our experience with LTOWB comes at a crucial time in the debate over prehospital utilisation of blood products.The benefits of whole blood (albeitfresh whole blood), demonstrated in several observational studies, 29,30 along with its increased utilisation in civilian settings [9][10][11]17 have raised the prospects of deploying whole blood in the prehospital military setting. Therecently published RePHILL 31 trial, has brought into question the benefits of prehospital PRBC and plasma.Of note is that the study population, setting and outcomes of the RePHILL trial differ substantially from our current report.Specifically, our cohort is characterised by a higher proportion of penetrating injuries and shorter times to blood administration and transport times as compared with the RePHILL trial, along with utilisation of whole blood units as opposed to PRBC and plasma.
Based on the current evidence on the benefits and safety of whole blood, 9,10,17,22,23,29,[32][33][34] we chose to implement its use in the prehospital setting, with the aim of continuing to evaluate our data along with growing evidence on its use.
Five of the patients in this study suffered from single or multiple gunshot wounds, resulting in severe bleeding and signs of profound shock, and six underwent damage control laparotomy.As compared with previous publications on the use of whole blood for trauma resuscitation, this case-series seems to be more reflective of combat injuries observed on the battlefield.Perkins et al. 35 compared the use of fresh-whole blood versus platelets, with penetrating trauma accounting for more than 90% of injuries in both groups.In contrast, observational studies performed in the civilian setting have evaluated the use of whole blood predominantly for blunt injuries. 17,36,37Additionally, in the initial report on use of LTOWB in the IDF Airborne MedEvac unit by Levin et al., 23 less than 30% of patients had penetrating injury.The in-hospital diagnoses and outcomes in this current case-series further emphasise the severity of injuries in this small cohort.Thus, we expect that based on the initial rollout in ICU ambulances, continued use of LTOWB may yield more reliable measures of the benefits and safety among patient populations with combat injuries.
Time to whole blood administration may play a key role in determining its efficacy and potential effect on mortality. 22The Joint Trauma System consensus statement on whole blood calls for its availability within 30 min of injury. 38In our initial experience, median time to administration was 35 min from injury.Delays in LTOWB administration in our setting may be attributed to several possible causes: complexity of casualty extraction in military circumstances, difficulties in obtaining vascular access and the need to obtain authorization from an on-call physician before proceeding.As noted, five of seven patients described were injured in military scenarios, and extraction from the point-of-injury may have delayed initial assessment by the ICU team.Establishment of peripheral intravenous access may be challenging in patients with shock, 39 as has been mostly demonstrated in the context of septic shock. 40As a result, the use of intraosseous access can be considered an alternative for patients requiring emergent vascular access such as in the case of hypovolemic shock.While intravenous access is often preferred as the initial route, 39 flow rates of whole blood through the intraosseous route have been demonstrated as being sufficient and recommend its use could potentially expedite time to transfusion. 41Accordingly, we plan on evaluating the use of additional intraosseous access devices and techniques for whole blood transfusion.Investigation of the cases presented in this report did not reveal an instance of delay due to on-call physician unavailability.However, when envisioning the potential use of LTOWB in wartime scenarios, "on-call" physician authorization may not be feasible and therefore, establishing strict criteria and indications for administration among unexperienced providers is vital, with other products such as FDP serving as alternatives in certain instances.
The current IDF-MC guidelines for volume resuscitation dictate that hypotension, as determined by a systolic blood pressure ≤90 mmHg is the primary measure indicating volume resuscitation.In four cases, volume resuscitation was indicated due to altered mental status and unmeasurable blood pressure.Considering the potential risk for adverse events upon blood product administration, we believe that indications for volume resuscitation, specifically in the context of inexperienced ALS providers, must rely on objective measures such as systolic blood pressure.However, we recognise that in patients with profound shock, blood pressure measurement may sometimes be challenging or inaccurate, specifically during en-route care. 42Although review of the cases presented here revealed that early volume resuscitation was warranted in all cases, one must consider the possibility of trauma patients who could potentially benefit from LTOWB, who did not fulfil the current criteria.Importantly, administration of whole blood by paramedic-led teams requires policy change, 20 and we thus instituted several stopgaps to ensure proper and indicated administration.Balancing the risks and benefits of whole blood administration could be informed by research evaluating the sensitivity and specificity of prehospital signs dictating hemorrhagic shock, and investigations of additional measures to reliably assess volume status such as point-of-care ultrasound or point of care lactate measurement. 43,44e thresholds for storage time and Anti-A and Anti-B titers utilised in this deployment were stringent, as to reduce the risk of adverse events or potentially diminishing efficacy of LTOWB during this preliminary rollout.Although use of these thresholds was implemented as to reduce the likelihood of adverse transfusion-related reactions or reduced hemostatic activity, 45 the low antibody (<1:100 titer) and storage-time (14-days from receipt by the ICU ambulances) thresholds may be currently unsuitable for larger-scale operational use.First, use of cold-stored whole blood is reliant on the inventory of the National Blood Services, which would presumably be overburdened in times of war, supplying routine hospital requirements as well as the treatment of civilian war-related trauma injuries.Second, maintenance of the cold chain and timely replacement of blood units within the currently determined expiry window may also be hindered by austere operational circumstances.Therefore, further laboratory and clinical data must be collected and analysed to determine if a more permissive approach, with regards to titter and storage, may be possible.Efforts have now been initiated to reduce the duration of the supply-chain with the aim of increasing the expiry window to 21 days in the ICU ambulances.An additional concern underlying the deployment of cold-stored LTOWB to ground units is the waste and discarding of valuable blood units.Levin et al. 23  + transfusions is far inferior to that of RhD-healthy volunteers. 47Ginity et al. 46 expanded on the risk-benefit analysis of RhD+ transfusions, stating that sex differences in injury epidemiology further exemplify the low risks of child-bearing age alloimmunization within whole blood programs.These reservations on the potential risk, joined with the suggested benefits of whole blood for severe traumatic haemorrhage may favour the universal use of more readily available, Rh + units, to reduce mortality and improve availability of LTOWB. 48,49Despite the latter, rollout of RhD+ LTOWB in military organisations, such as the IDF which does not exclude females from any combat role, warrants additional discussion and consideration as the evidence on the topic continues to amount.
The use of LTOWB in the IDF ground units is in its infancy and will continue to evolve in the coming years.Continued experience with treatment of trauma patients with LTOWB in both aeromedical and ground units may prove feasibility, safety and potential efficacy.
The initial experience with ground deployment and treatment of predominantly military-related injuries as presented here, could contribute to the end goal of bringing whole blood resuscitation far-forward, to austere, remote combat environments, as well as to civilian prehospital national emergency medical services.This experience will enable further refinement of guidelines and techniques for whole blood transfusion among prehospital providers.Future studies are required to better characterise the indications, safety, and benefits of whole blood in resuscitating severely injured trauma patients in the prehospital setting.

3 | RESULTS 3 . 1 |
Patient demographics and injury setting Overall, 10 cases of ground ambulance LTOWB administration were identified in the IDF-TR between January and December 2022.During this time-period, 23 patients treated by other IDF-MC ALS teams, not equipped with whole blood, were administered freeze-dried plasma, and 11 patients were administered LTOWB by the IDF Airborne MedEvac Unit.In three instances of LTOWB administration by ground teams, the indication was traumatic cardiac arrest prior to ALS team arrival, and these were excluded from the analysis.Of the seven patients administered LTOWB for profound shock, six were males with a median age of 28 (IQR 19.5-42) years.Five of the patients

35 (
IQR 28.5-40) minutes, and median time from injury to hospital arrival 53 (IQR 41.5-63) minutes.In only one case, a second unit of volume resuscitation (With the highest priority blood product available to the team) was indicated following reassessment and prior to hospital arrival.In this case, a unit of freeze-dried plasma was administered, as the team had only one unit of non-expired whole blood on hand.Additionally, 1 g of IV tranexamic acid was administered in 6/7 cases.No adverse events were recorded after whole blood administration.
Laboratory measures upon admission of patients treated with LTOWB by Israel Defense Forces ICU ambulances.Data ascertained from review of cases in the IDF-TR and hospital records of patients receiving whole blood.Abbreviations: BPM, beats per minute; DBP, diastolic blood pressure; ED, emergency department; Hb, haemoglobin; HR, heart rate; INR, international normalised ratio; PLT, platelets; SBP, systolic blood pressure.
documented a utilisation rate of 2% in the IDF Airborne MedEvac whole blood deployment, indicative of large amounts of discarded products.As such, novel approaches, such as the rotation of whole blood units as pioneered by the Southwest Texas Regional Advisory Council,21 may warrant adoption to the military and national settings, aiming to maximise usage of products.An additional topic which warrants discussion in the context of our patient population is the use of Rhesus D positive (RhD+) LTOWB on a universal basis.In this current case-series, 35-year-old woman received a unit of Rh + LTOWB during prehospital treatment, following severe blunt trauma in a motor vehicle accident.Given her hospital presentation in severe hemorrhagic shock (Blood pressure 60/30, rushed for damage control laparotomy), the single unit of LTOWB administered during prehospital transport may have contributed greatly to her survival.As has been thoroughly discussed by McGinity and colleagues, 46 the primary concern with uncrossmatched use of RhD+ blood is anti-D alloimmunization and subsequent hemolytic disease of the fetus and newborn among women of childbearing age.Selleng et al. 47 demonstrated that the risk of alloimmunization among RhD-trauma patients receiving Rh Description and characteristics of patients treated with LTOWB by Israel Defense Forces ICU ambulances.
(Continues) T A B L E 1 (Continued) T A B L E 1 (Continued) Note: Data ascertained from review of cases in the IDF-TR and hospital records of patients receiving whole blood.Abbreviations: AW, airway; BPM, beats per minute; CT, computed tomography; GCS, Glasgow coma scale; ICU, intensive care unit; IV, intravenous; PRBC, packed red blood cells; SaO intraosseous routes.Administration of 1 g of tranexamic acid (TXA) is also indicated for patients with profound shock (If presenting within 3 h from injury).Following the completion of each unit, patients are reassessed for signs of profound shock.If signs of profound shock remain, an additional unit of the best available fluid is indicated.The hierarchy of products currently available to IDF-MC teams includes LTOWB, followed by FDP, packed red blood cells and crystalloids if established in 1997 to document point-of-injury and en-route care of trauma patients treated by IDF advanced life support (ALS) teams. 28Data recorded in the registry is based on casualty cards filled during treatment and additional data entered by ALS providers as part of the after-action report for each incident.Data entry undergoes quality assurance review by a team at the IDF-MC Trauma and Combat Medicine Branch, which maintains the database.For select cases of interest (i.e., severely wounded patients, novel treatment administered etc.), data regarding the in-hospital diagnoses, treatment and outcomes are provided by civilian hospital trauma coordinators and integrated into the registry.In this study, cases identified in the IDF-TR of ground ambulance LTOWB administration were extracted for manual review of both categorised and free-text case data by two of the authors (T.T, M. M).Variables of interest documented in the registry were recorded in dedicated Excel spreadsheets (i.e., patient age, sex, trauma mechanism, vital signs etc.) for further statistical analyses.Continuous variables are presented as medians and interquartile ranges (IQR) and categorical variables as n (%).Statistical analyses and were performed using R (version 4.0.3;R Foundation, Vienna, Austria).