Circulation - Shock / Fluid Resuscitation

Transfusion. 2019 Apr;59(S2):1423-1428

# Outcomes of traumatic hemorrhagic shock and the epidemiology of preventable death from injury.

Eastridge B, Holcomb J, Shackelford S

The majority of potentially preventable deaths after trauma are related to hemorrhage and occur early after injury, with the largest number of deaths occurring before hospital arrival. Approximately one-fourth of trauma deaths may be potentially preventable through early medical and surgical interventions. Interventions dedicated to bleeding control and hemostatic resuscitation have demonstrated merit in decreasing hemorrhagic injury mortality. Advancing these novel strategies to the casualty in the prehospital phase of care, particularly in tactical or austere environments, may prove beneficial for hemorrhage mitigation to temporize the window of survival to definitive care. Future studies of resuscitation and survival after traumatic injury must include analysis of prehospital deaths to fully understand the outcomes of early interventions.

J Trauma Acute Care Surg. 2019 Apr 12; Epub ahead of print

# Pre-hospital adenosine, lidocaine and magnesium has inferior survival compared to tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock.

How R, Glaser J, Schaub L, Fryer D, Ozuna K, Morgan C, Sams V, Cardin S

BACKGROUND: Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized pre-hospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the Golden Hour.

METHODS: Swine were randomized to: 1) TCCC, 2) 2cc/kg vehicle control (VC), 3) 2cc/kg ALM+drip, 4) 4cc/kg ALM+drip, 5) 4cc/kg ALM+delayed drip at 0.5cc/kg/hr, 6) 4cc/kg vehicle control, 7) 4cc/kg ALM for 15 mins + delayed drip at 3cc/kg/hr. Animals underwent pressure controlled hemorrhage to MAP of 30mmHg (S=0). Treatment was administered at T=0. After 120 minutes of simulated pre-hospital care (T=120) blood product resuscitation commenced. Physiologic variables were recorded and labs were drawn at specified time points.

RESULTS: TCCC demonstrated superior survival to all other agents. VC and ALM groups had lower mean arterial pressures (MAPs) and systolic blood pressures (SBPs) compared to TCCC. Except for the vehicle control groups, lactate levels remained similar with correction of base deficit after pre-hospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared to baseline values, TCCC demonstrated significant hypocoagulability.

CONCLUSION: ALM, as administered in this study, is inferior to current Hextend®-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower SBPs and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. ALM does not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.

J Trauma Acute Care Surg. 2019 Mar;86(3):458-463

# The impact of hypothermia on outcomes in massively transfused patients.

Lester E, Fox E, Holcomb J, Brasel K, Bulger E, Cohen M, Cotton B, Fabian T, Kerby J, OʼKeefe T, Rizoli S, Scalea T, Schreiber M, Inaba K; PROPPR study group.

BACKGROUND: Hypothermia is associated with poor outcomes after injury. The relationship between hypothermia during contemporary large volume resuscitation and blood product consumption is unknown. We evaluated this association, and the predictive value of hypothermia on mortality.

METHODS: Patients predicted to receive massive transfusion at 12 level 1 trauma centers were randomized in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial and were grouped into those who were hypothermic (<36°C) or normothermic (36-38.5°C) within the first 6 hours of emergency department arrival. The impact of hypothermia or normothermia on the volume of blood product required during the first 24 hours was determined via negative binomial regression, adjusting for treatment arm, injury severity score, mechanism, demographics, pre-emergency department fluid volume, blood administered before becoming hypothermic, pulse and systolic blood pressure on arrival, and the time exposed to hypothermic or normothermic temperatures.

RESULTS: Of 680 patients, 590 had a temperature measured during the first 6 hours in hospital, and 399 experienced hypothermia. The mean number of red blood cell (RBC) units given to all patients in the first 24 hours of admission was 8.8 (95% confidence interval [CI], 7.9-9.6). In multivariable analysis, every 1°C decrease in temperature below 36.0°C was associated with a 10% increase (incidence rate ratio, 0.90; 95% CI, 0.89-0.92; p < 0.00) in consumption of RBCs during the first 24 hours of admission. There was no association between RBC administration and a temperature above 36°C. Hypothermia on arrival was an independent predictor of mortality, with an adjusted odds ratio of 2.7 (95% CI, 1.7-4.5; p < 0.00) for 24-hour mortality and 1.8 (95% CI, 1.3-2.4; p < 0.00) for 30-day mortality.

CONCLUSION: Hypothermia is associated with increase in blood product consumption and mortality. These findings support the maintenance of normothermia in trauma patients and suggest that further investigation on the impact of cooling or rewarming during massive transfusion is warranted.

LEVEL OF EVIDENCE: Prognostic, level III.

Transfusion. 2019 Mar;59(3):927-930

# Massive transfusion of low-titer cold-stored O-positive whole blood in a civilian trauma setting.

Condron M, Scanlan M, Schreiber M

BACKGROUND: Based on the improved outcomes achieved with fresh whole blood in cases of military trauma as well as with 1:1:1 transfusion strategies for massive traumatic hemorrhage in civilian settings, there has been resurgent interest in using whole blood for civilian trauma patients. There have been reports of giving up to 4 units of low-titer cold-stored O-positive to these patients. This is the first modern report of a massive transfusion with unrestricted low-titer group O whole blood (LTOWB) use in a civilian trauma patient.

STUDY DESIGN AND METHODS: This is a case report describing the resuscitation and massive transfusion of LTOWB of a 69-year-old man struck by an automobile.

RESULTS: While working to achieve hemorrhage control, the patient received 38 units of LTOWB, 13 units of RBCs, 12 units of fresh frozen plasma, 2 packs of platelets, and 2 units of cryoprecipitate. No evidence of hemolytic reaction was observed. The patient was O positive. Monitoring by thrombelastography revealed adequate clot initiation and propagation, but decreased clot strength (49.6 and 50.2) and a drop in fibrinogen (from 207 to 141) during the resuscitation.

CONCLUSION: This is the first report of a massive transfusion for civilian trauma based on cold-stored whole blood in the recent era. While this patient suffered a tremendous burden of traumatic injury and his recovery is not yet complete, his LTOWB resuscitation was successful. Frequent monitoring of coagulation status with thrombelastography during utilization of LTOWB is indicated because the efficacy of its components (particularly platelets) is not yet fully understood.

Transfus Clin Biol. 2018 Nov;25(4):281-286

# Plasma for direct therapeutic use, for today and tomorrow: A short critical overview.

Garraud O, Aubron C, Ozier Y, Coppo P, Tissot J

Plasma for direct therapeutic use is a fast-evolving blood component in terms of its production and presentation. More than a dozen forms are available worldwide, which is often overlooked since most countries apply policies making only one or very few forms available for treating patients in need. It is most often reserved for the same three clinical indications, i.e. overall clotting-factor deficiency, reversal of vitamin K antagonists in the context of active bleeding or prior to urgent surgery, and therapeutic plasma exchange. The level of evidence is often less robust than generally acknowledged for such major indications while novel indications are tending to emerge in medical and trauma settings. This short review explores classical views and new prospects opened up by novel presentations and statuses for therapeutic plasma.

Mil Med. 2018 Nov 5;183(11-12):e721-e729

# Intravenous Hydroxocobalamin Versus Hextend Versus Control for Class III Hemorrhage Resuscitation in a Prehospital Swine Model.

Bebarta V, Garrett N, Boudreau S, Castaneda M.

Background: Hydroxyethyl starch (Hextend) has been used for hemorrhagic shock resuscitation, however, hydroxyethyl starch may be associated with adverse outcomes.

Objective: To compare systolic blood pressure (sBP) in animals that had 30% of their blood volume removed and treated with intravenous hydroxocobalamin, hydroxyethyl starch, or no fluid.

Methods: Twenty-eight swine (45-55 kg) were anesthetized and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged 20 mL/kg over 20 minutes and then administered 150 mg/kg IV hydroxocobalamin in 180 mL saline, 500 mL hydroxyethyl starch, or no fluid and monitored for 60 minutes. Data were modeled using repeated measures multivariate analysis of variance.

Results: There were no significant differences before treatment. At 20 minutes after hemorrhage, there was no significant difference in mean sBP between treated groups, however, control animals displayed significantly lower mean sBP (p < 0.001). Mean arterial pressure and heart rate improved in the treated groups but not in the control group (p < 0.02). Prothrombin time was longer and platelet counts were lower in the Hextend group (p < 0.05). Moreover, thromboelastography analysis showed longer clotting (K) times (p < 0.05) for the hydroxyethyl starch-treated group.

Conclusion: Hydroxocobalamin restored blood pressure more effectively than no treatment and as effectively as hydroxyethyl starch but did not adversely affect coagulation.

Transfusion. 2019 Feb;59(2):707-713

# Single-donor spray-dried plasma.

Liu Q, Carney R, Sohn J, Sundaram S, Fell M

BACKGROUND: Dried plasma is logistically superior for hemostasis management because it can be transported and stored under nonfrozen conditions and quickly reconstituted at the point of care, enabling prehospital administration. Velico Medical has developed a spray-drying system to be integrated into routine blood center work streams for spray drying single donor plasma units. This study compared the quality of the spray-dried plasma (on-demand plasma [ODP]) with fresh frozen plasma (FFP).

STUDY DESIGN AND METHODS: ODP units (n = 60) were manufactured from never frozen fresh plasma, which was pretreated with glycine-hydrochloric acid and stored at 1to 6°C. Paired aliquots were frozen and stored at -18°C or less. After 31 to 33 days, ODP samples were reconstituted with water for injection and comprehensively characterized in parallel with paired FFP. The quantities of plasma dried and rehydration fluid were predetermined, ensuring comparable total protein concentration in ODP and paired FFP.

RESULTS: ODP is comparable to FFP in global coagulation function as assessed by activated partial thromboplastin time and prothrombin time and in clot formation evaluated by thrombelastography. Compared to FFP, ODP had greater than 80% levels of functional coagulation factors and related proteins and chemistry analytes except for Factor XIII (74%). Pretreatment mitigated cleavage of high-molecular-weight von Willebrand factor multimers by spray drying and resulted in 60% vWF:ristocetin cofactor activity in ODP compared to FFP.

CONCLUSIONS: ODP demonstrates coagulation function comparable to that of FFP. The spray drying system can be implemented in blood centers and is capable of producing units of ODP.

Eur J Emerg Med. 2018 Dec 7; Epub ahead of print

# Feasibility of prehospital freeze-dried plasma administration in a UK Helicopter Emergency Medical Service.

Oakeshott J, Griggs J, Wareham G, Lyon R; Kent Surrey Sussex Air Ambulance Trust.

BACKGROUND: Early transfusion of patients with major traumatic haemorrhage may improve survival. This study aims to establish the feasibility of freeze-dried plasma transfusion in a Helicopter Emergency Medical Service in the UK.

PATIENTS AND METHODS: A retrospective observational study of major trauma patients attended by Kent, Surrey and Sussex Helicopter Emergency Medical Service and transfused freeze-dried plasma since it was introduced in April 2014.

RESULTS: Of the 1873 patients attended over a 12-month period before its introduction, 79 patients received packed red blood cells (4.2%) with a total of 193 units transfused. Of 1881 patients after the introduction of freeze-dried plasma, 10 patients received packed red blood cells only and 66 received both packed red blood cells and freeze-dried plasma, with a total of 158 units of packed red blood cells transfused, representing an 18% reduction between the two 12-month periods. In the 20 months since its introduction, of 216 patients transfused with at least one unit of freeze-dried plasma, 116 (54.0%) patients received both freeze-dried plasma and packed red blood cells in a 1 : 1 ratio. Earlier transfusion was feasible, transferring the patient to the hospital before transfusion would have incurred a delay of 71 min (interquartile range: 59-90 min).

CONCLUSION: Prehospital freeze-dried plasma and packed red blood cell transfusion is feasible in a 1 : 1 ratio in patients with suspected traumatic haemorrhage. The use of freeze-dried plasma as a first-line fluid bolus reduced the number of prehospital packed red blood cell units required and reduced the time to transfusion.

Curr Opin Anaesthesiol. 2019 Apr;32(2):200-205

# The use of new procoagulants in blunt and penetrating trauma.

Peralta M, Chowdary P.

PURPOSE OF REVIEW: Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes the current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use.

RECENT FINDINGS: Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy.

SUMMARY: There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies.

Trauma Surg Acute Care Open. 2019 Jan 24;4(1):e000207

# The focused assessment with sonography in trauma (FAST) in hypotensive injured patients frequently fails to identify the need for laparotomy: a multi-institutional pragmatic study.

Rowell S, Barbosa R, Holcomb J, Fox E, Barton C, Schreiber M

Background: The ability of focused assessment with sonography for trauma (FAST) to detect clinically significant hemorrhage in hypotensive injured patients remains unclear. We sought to describe the sensitivity and specificity of FAST using findings at laparotomy as the confirmatory test.

Methods: Patients from the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study that had a systolic blood pressure < 90mm Hg and underwent FAST were analysed. Results were compared with findings at laparotomy. A therapeutic laparotomy (T-LAP) was defined as an abdominal operation within 6 hours in which a definitive procedure was performed. The sensitivity and specificity of FAST were calculated.

Results: The cohort included 317 patients that underwent FAST (108 positive, 209 negative). T-LAP was performed in 69% (n=75) of FAST(+) patients and 22% (n=48) of FAST(-) patients. FAST had a sensitivity of 62% and specificity of 83%.

Conclusions: In our multicenter cohort, 22% of FAST(-) patients underwent T-LAP within 6 hours of admission. In hypotensive patients with a negative FAST, clinicians should still maintain a high index of suspicion for significant abdominal hemorrhage.

Level of evidence: Level IV.

Injury. 2019 Feb;50:226-234

# What is the impact of prehospital blood product administration for patients with catastrophic haemorrhage: an integrative review.

Shand S, Curtis K, Dinh M, Burns B

INTRODUCTION: Catastrophic haemorrhage is recognised as the leading cause of preventable death in trauma and is also prevalent in medical and other surgical aetiology. Prehospital blood product transfusion is increasingly available for both military and civilian emergency teams. Hospitals have well-established massive transfusion protocols for the resuscitation of this patient group, however the use and impact in the prehospital field is less understood.

AIM: To identify and evaluate the current knowledge surrounding prehospital blood product administration for patients with catastrophic haemorrhage.

METHODS: The integrative review method included systematic searching of online databases Medline, EMBASE, SCOPUS and CINAHL alongside hand-searching for primary research articles published prior to 19 November 2018. Papers were included if the population studied patients with catastrophic haemorrhage who received prehospital transfusion of blood products. The level of evidence and quality was evaluated using the NHMRC hierarchy of evidence. All identified full text articles were reviewed by all authors.

RESULTS: Twenty-two papers were included in the final analysis, including both civilian (16) and military (6) practice. The earliest publication for prehospital transfusion was 1999, with increasing prevalence in recent years. Findings were extracted and into two main categories; (1) transfusion processes included team staffing, product selection, and criteria for transfusion and (2) transfusion outcomes; transfusion safety, haemoglobin, hospital intervention and mortality.

DISCUSSION: The level of evidence specific to prehospital blood product transfusion is low, with predominantly retrospective methods and rarely sufficient sample sizes to reach statistical significance. Prehospital research is challenged by clinical and logistical variability preventing accurate cohortmatching, sample sizes and inconsistent data collection. Evaluation of prehospital transfusion in isolation is also particularly problematic as multiple factors and developments in clinical practice affect patient outcomes and all samples were subject to survival bias. Conclusion The volume and strength of the available evidence prevents accurate evaluation of the intervention and definitive practice recommendations however prehospital transfusion is shown to be logistically achievable and without serious incident. The reviewed evidence broadly supports the translation of recent in-hospital studies, such as PROMTT and PROPPR. Further research specific to prehospital practice is required to guide the development of evidence-based protocols.

J Trauma Acute Care Surg. 2018 Dec;85(6):1055-1062

# Whole blood mitigates the acute coagulopathy of trauma and avoids the coagulopathy of crystalloid resuscitation.

Sheppard F, Schaub L, Cap A, Macko A, Moore H, Moore E, Glaser C

INTRODUCTION: The contributions of type and timing of fluid resuscitation to coagulopathy in trauma remain controversial. As part of a multifunctional resuscitation fluid research effort, we sought to further characterize the coagulation responses to resuscitation, specifically as compared to whole blood. We hypothesized that early whole blood administration mitigates the acute coagulopathy of trauma by avoiding the coagulopathy of CR resuscitation.

METHODS: Anesthetized rhesus macaques underwent polytraumatic, hemorrhagic shock, then a crossover study design resuscitation (n = 6 each) with either whole blood first (WB-1st) followed by crystalloid (CR); or CR-1st followed by WB. Resuscitation strategies were the following: WB-1st received 50% shed blood in 30minutes, followed by twice the shed blood volume (SBV) of CR over 30minutes and one times the SBV CR over 60minutes, where CR-1st received twice the SBV of CR over 30minutes, followed by 50% of shed blood in 30minutes, and one times the SBV CR over 60minutes. Blood samples were collected at baseline, end-of-shock, end-of-first and end-of-second resuscitation stages, and end-of-resuscitation for assessment (thromboelastometry, platelet aggregation, and plasmatic coagulation factors). Statistical analyses were conducted using two-way analysis of variance ANOVA with Bonferroni correction and t-tests; significance was at p < 0.05.

RESULTS: Survival, blood loss, hemodynamics, and shock duration were equivalent between the groups. Compared to baseline, parameters measured at first and second resuscitation stage time points directly following CR infusion revealed abnormalities in thromboelastometry (clot formation time, α angle, and maximumclot firmness), platelet aggregation response (to collagen, arachidonic acid, and adenosine diphosphate), and plasmatic coagulation (prothrombin time, anti-thrombin 3, and fibrinogen), while whole blood infusion resulted in stabilization or correction of these parameters following its administration.

CONCLUSIONS: These data suggest that in the setting of trauma and hemorrhagic shock, the coagulation alterations begin before intervention/resuscitation; however, these are significantly aggravated by CR resuscitation and could perhaps be best termed acute coagulopathy of resuscitation.

STUDY TYPE: Translational animal model.

J Trauma Acute Care Surg. 2019 Jan;86(1):108-115

# The impact of prehospital administration of freeze-dried plasma on casualty outcome.

Shlaifer A, Siman-Tov M, Radomislensky I, Peleg K, Klein Y, Glassberg E, Yitzhak A.

BACKGROUND: Hemorrhage is the most common preventable cause of death in both civilian and military trauma. There is no consensus regarding the appropriate fluid resuscitation protocol. Plasma, as a resuscitative fluid, has substantial benefits as a volume expander, owing to its relatively high oncotic pressure and its positive effect on trauma-induced coagulopathy by replenishing the lostcoagulation factors, rather than diluting the casualty's remaining factors. The Israel Defense Force Medical Corps decided to use freeze-dried plasma (FDP) as the fluid of choice for casualties in hemorrhagic shock in the prehospital setting. The aim of our study is to compare the differences of coagulation, perfusion measurements, resource utilization, and outcome between casualties receiving FDP to casualties who did not receive FDP in the prehospital setting.

METHODS: This is a retrospective matched cohort study based on two groups of casualties (those treated with FDP vs. those without FDP treatment). The control group was compiled in three steps of precision for age, sex, mechanism of injury and maximum level of severity for each nine injured body regions. Data were collected from the IDF Trauma Registry and The National Israel Trauma Registry.

RESULTS: The study group comprised 48 casualties receiving FDP and 48 controls with no differences in demographic, evacuation time, and injury characteristics. The FDP group demonstrated a lower level of hemoglobin (12.7 gr/dzl) (odds ratio [OR], 3.11; 95% confidence interval [CI], 1.10-8.80), lower level of international normalized ratio (1.1) (OR, 3.09; 95% CI, 1.04-9.14), and lower level of platelets (230 × 109/L) (OR, 3.06; 95% CI, 1.16-8.06). No other differences were found between the two groups.

CONCLUSION: The use of FDP in the prehospital setting has logistic benefits and a positive effect on coagulation profile, with no other significant effects. Future studies need to be performed on larger groups to verify trends or nullify our hypotheses.

Transfusion. 2019 Feb 5; [Epub ahead of print]

# International assessment of massive transfusion protocol contents and indications for activation.

Thomasson R, Yazer M, Gorham J, Dunbar N MTP Use Study Investigators, on behalf of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative.

BACKGROUND: Massive transfusion protocols (MTPs) provide blood products rapidly and in fixed amounts. MTPs are commonly used in trauma but may also be used in other clinical settings, although evidence to support fixed-ratio resuscitation in nontraumatic hemorrhage is lacking. The goals of this study were to describe the types and contents of available MTPs and the clinical indications for MTP activation.

METHODS: A survey was distributed to 353 transfusion medicine specialists to assess the types and contents of available MTPs. Survey participants were invited to provide the clinical indications for consecutive adult and pediatric MTP activations for at least 6 months during 2015 to 2017.

RESULTS: There were 125 completed surveys (35% response rate) including three from children's specialty hospitals. Most hospitals that treated adult patients (90/122, 74%) utilized only one MTP for all adult bleeding emergencies, while one hospital had no MTP. Of the 31 hospitals that provided more than one adult MTP, 20 provided MTPs specific for obstetric bleeding cases. Of these, 50% (10/20) included at least one pool of cryoprecipitate or fibrinogen concentrate in the first MTP round, compared with 14% (13/90) of the hospitals with one MTP (p = 0.0012). Fifty-seven hospitals provided the clinical indication for 4176 adult and 155 pediatric MTP activations. Although trauma was the single most common indication, the majority of adult (58%) and pediatric (65%) activations were for nontrauma indications.

CONCLUSIONS: The majority of hospitals use a single MTP to manage massive hemorrhage. The majority of MTP activations were for nontrauma indications.

Transfusion. 2019 Mar;59:965-970

# Transfusion. 2019 Mar;59(3):965-970The use of whole blood in US military operations in Iraq, Syria, and Afghanistan since the introduction of low-titer Type O whole blood: feasibility, acceptability, challenges.

Vanderspurt C, Spinella P, Cap A, Hill R, Matthews S, Corley J, Gurney J

BACKGROUND: Hemorrhage is the leading cause of preventable death in military and civilian traumatic injury. Blood product resuscitation improves survival. Low-titer Type O Whole Blood (LTOWB) was recently re-introduced to the combat theater as a universal resuscitation product for hemorrhagic shock. This study assessed the utilization patterns of LTOWB compared to warm fresh whole blood (WFWB) and blood component therapy (CT) in US Military Operations in Iraq/Syria and Afghanistan known as Operation Inherent Resolve (OIR) and Operation Freedom's Sentinel (OFS) respectively. We hypothesized LTOWB utilization would increase over time given its advantages.

STUDY DESIGN AND METHODS: Using the Theater Medical Data Store, patients receiving blood products between January 2016 and December 2017 were identified. Product utilization ratios (PUR) for LTOWB, WFWB, and CT were compared across Area of Operations (AORs), medical treatment facilities (Role 2 vs. Role 3), and time. PUR was defined as number of blood products transfused/(number of blood products transfused + number of blood products wasted).

RESULTS: The overall PUR for all blood products was 17.4%; the LTOWB PUR was 14.3%. Over the study period, the total number of blood products transfused increased 133%. Although the total whole blood (WB) increased from 2.1% to 6.6% of all products transfused, WFWB use remained at 2% while LTOWB transfusions increased from 0.5% to 4%. Transfusion of LTOWB occurred more in austere Role 2 facilities compared to Role 3 hospitals.

CONCLUSIONS: LTOWB transfusion is feasible in austere, far-forward environments. Further investigation is needed regarding the safety, clinical outcomes, and drivers of LTOWB transfusions.

Transfusion. 2019 Apr;59(S2):1499-1506

# Changes in donor antibody titer levels over time in a military group O low-titer whole blood program.

Bailey J, Fisher A, Yazer M, Howard J, Corley J, Miles E, Cap A

BACKGROUND: The ability to rapidly administer whole blood (WB) at the point of injury is an important intervention to save lives. This can be accomplished using low titer group O WB donors. Titers of immunoglobulin M anti-A and anti-B might change over time. This study describes titer testing in a large series of donors.

STUDY DESIGN AND METHODS: Data were collected retrospectively from the Armed Services Blood Program and the Theater Medical Data Store. Soldiers assigned to the 75th Ranger Regiment were screened and titered upon completion of training or before deployment or during periodic unit readiness activities. A Ranger group O low-titer (ROLO) donor was defined as having titers of both anti-A and -B of less than 256 by immediate spin testing.

RESULTS: Between May 2015 and January 2017, of a total of 2237 participating soldiers, 1892 (84.5%) soldiers underwent antibody titering once, while 266 (11.9%) were titered twice, 62 (2.8%) were titered three times, and 17 (0.8%) were titered at least four times. The mean age was 26.5 ± 6.5, and 2197 (98.2%) were male. A total of 69.5% of donors met ROLO donor criteria on the first test. The percentage of donors meeting universal-donor criteria increased to 83.5% on the second test, 91.1% on the third test, and 100% on the fourth and fifth tests.

CONCLUSIONS: With successive titer testing, it appears that individuals display a tendency toward lower titers. This may indicate that titer testing may not be required after the second test if donors have been identified initially as low titer.

World J Emerg Surg. 2019 Feb 15;14:6

# Pre-hospital plasma in haemorrhagic shock management: current opinion and meta-analysis of randomized trials.

Coccolini F, Pizzilli G, Corbella D, Sartelli M, Agnoletti V, Agostini V, Baiocchi G, Ansaloni L, Catena F

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 I Study type: Systematic review with Meta-analysis.

Transfus Apher Sci. 2019 Apr;58(2):212-215

Implementation of a protocol for prehospital transfusion of low-titer, leukocyte-depleted whole blood for civilian bleeding patients.

Espinosa A, Dybvik B, Medby C, Vangberg G

Blood component therapy is considered the gold standard for the treatment of the massively bleeding patient, but it can be challenging to perform outside the hospital environment. The successful experience from the military shows that whole blood can efficiently provide treatment for massively bleeding patients. Whole blood transfusion has been in use in Norway to some extent in paediatric cardiac surgery, but no major interest has been paid from the blood centres to implement the use of whole blood as an alternative or a supplement to traditional blood component therapy. On the other hand, the increasing number of reports showing a potential benefit of whole blood and the availability of the last generation whole blood leukocyte filters, allowing the platelets to remain in the blood product, has led to the first experiences with prehospital use of whole blood in Norway. Our institution is completing the planning of a program for the use of prehospital whole blood transfusion in the civilian setting, following the same trend at two other hospitals in Norway.

J Trauma Acute Care Surg. 2019 Apr 23; Epub ahead of print

# Conducting Fresh Whole Blood Transfusion Training.

Fisher A, Carius B, Corley J, Dodge P, Miles E, Taylor A

Fresh whole blood is the optimal resuscitation fluid for casualties in hemorrhagic shock according to the Committee on Tactical Combat Casualty Care and has demonstrated to improve outcomes in severely wounded patients. Like all medical interventions, fresh whole blood transfusions are not without risks, but similarly can be mitigated through increased training to develop provider knowledge and proficiency. To date, no literature has been published regarding the proper technique to conduct fresh whole blood transfusion training. This article provides a structured foundation to establish a standardized fresh whole blood transfusion training program in order to increase skill and preparedness for fresh whole blood protocol implementation. Using these techniques in a training environment, providers will be able to provide optimal resuscitation in hemorrhagic shock in austere environments.

Ann Surg. 2019;Epub ahead of print

# Prehospital Blood Product and Crystalloid Resuscitation in the Severely Injured Patient: A Secondary Analysis of the Prehospital Air Medical Plasma Trial.

Guyette F, Sperry J, Peitzman A, Billiar T, Daley B, Miller R, Harbrecht B, Claridge J, Putnam T, Duane T, Phelan H, Brown J

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 increasedmortality 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.

J Trauma Acute Care Surg. 2019 Jan;86(1):128-133

# The Las Vegas mass shooting: An analysis of blood component administration and blood bank donations.

Lozada M, Cai S, Li M, Davidson S, Nix J, Ramsey G.

BACKGROUND: The deadliest mass shooting in modern United States history occurred on October 1, 2017, in Las Vegas, killing 58 and overwhelming hospitals with more than 600 injured. The scope of the tragedy offers insight into medical demands, which may help guide preparedness for future mass shooting incidents.

METHODS: Retrospective, deidentified, health care institution-provided data from all hospitals and blood banks providing care to Las Vegas shooting victims were gathered. Study authors independently reviewed all data and cross-referenced it for verification. Main outcomes and measures include the number of victims requiring hospital and intensive care admission, the amount and types of blood components transfused during the first 24 hours, and the amount of blood donated to local blood banks following the Las Vegas mass shooting.

RESULTS: Two hundred twenty patients required hospital admission, 68 of them to critical care. Nearly 500 blood components were transfused during the first 24 hours in a red blood cell-to-plasma-to-platelet ratio of 1:0.54:0.81. Public citizens donated almost 800 units of blood immediately after the shooting; greater than 17% of this donated blood went unused.

CONCLUSIONS: The amount of blood components transfused per patient admitted was similar in magnitude to other mass casualty events, and available blood supply met patient demand. The public call for blood donors was not necessary to meet immediate demand and led to resource waste. Preparation for future mass shooting incidents should include training the community in hemorrhage control, encouraging routine blood donation, and avoiding public calls for blood donation unless approved by local blood suppliers.

LEVEL OF EVIDENCE: Therapeutic study, level V.

J Emerg Med. 2019 Apr;56(4):431-436

# Safety of Peripheral Line Administration of 3% Hypertonic Saline and Mannitol in the Emergency Department.

Mesghali E, Fitter S, Bahjri K, Moussavi K

BACKGROUND: Hypertonic saline (HTS) and mannitol are frequently utilized in the emergency department (ED) to manage elevations in intracranial pressure (ICP).

OBJECTIVE: The objective of this study was to compare the incidence of extravasation injury when HTS or mannitol was administered via peripheral i.v. line (PIV).

METHODS: This retrospective cohort study evaluated adult and pediatric patients given either 3% HTS or mannitol via PIV while in the ED. The primary outcome was extravasation incidence.

RESULTS: One hundred and ninety-two patients were included, of which 85 (44%) received HTS and 107 (56%) received mannitol. Patients who received HTS were younger (27.5 ± 24.3 years vs. 53.9 ± 22.3 years; p < 0.001); 55.3% of patients given HTS received it for traumatic brain injury (TBI) versus 38.3% of patients given mannitol (p = 0.021); and 44.9% of patients given mannitol received it for intracerebral hemorrhage versus 21.2% of patients given HTS (p = 0.001). There was no incidence of extravasation in either group. Patients who received HTS had lower ICP measurement 24 h post admission (2.107 ± 5.5 mm Hg vs. 4.236 ± 8.1 mm Hg; p = 0.047) and higher Glasgow Coma Scale (GCS) score upon discharge (GCS 14; interquartile range [IQR] 3-15 vs. GCS 3; IQR 3-14.2; p = 0.004). In-hospital mortality was higher in the mannitol group (54.7% vs. 32.9%; p = 0.003). Duration of mechanical ventilation was shorter in those patients who received HTS (1 day; IQR 0-56 days vs. 2 days; IQR 0-56 days; p = 0.023).

CONCLUSIONS: There were no incidences of extravasation among patients given 3% HTS or mannitol. Clinicians should reconsider recommendations to restrict HTS or mannitol to central lines.

Transfusion. 2019 Apr;59(S2):1587-1592

# The need for dried plasma - a national issue.

Pusateri A, Butler F, Shackelford S, Sperry J, Moore E, Cap A, Taylor A, Homer M, Hoots W, Weiskopf R, Davis M

Recent studies have demonstrated that early transfusion of plasma or RBCs improves survival in patients with severe trauma and hemorrhagic shock. Time to initiate transfusion is the critical factor. It is essential that transfusion begin in the prehospital environment when transport times are longer than approximately 15 to 20 minutes. Unfortunately, logistic constraints severely limit the use of blood products in the prehospital setting, especially in military, remote civilian, and mass disaster circumstances, where the need can be most acute. US military requirements for logistically supportable blood products are projected to increase dramatically in future conflicts. Although dried plasma products have been available and safely used in a number of countries for over 20 years, there is no dried plasma product commercially available in the United States. A US Food and Drug Administration-approved dried plasma is urgently needed. Considering the US military, disaster preparedness, and remote civilian trauma perspectives, this is an urgent national health care issue.

Injury. 2019 May;50(5):1017-1027

# Is prehospital blood transfusion effective and safe in haemorrhagic trauma patients? A systematic review and meta-analysis.

Rijnhout T, Wever K, Marinus R, Hoogerwerf N, Geeraedts L, Tan E

BACKGROUND: Life-threatening haemorrhage accounts for 40% mortality in trauma patients worldwide. After bleeding control is achieved, circulating volume must be restored. Early in-hospital transfusion of blood components is already proven effective, but the scientific proof for the effectiveness of prehospital blood-component transfusion (PHBT) in trauma patients is still unclear.

OBJECTIVE: To systematically review the evidence for effectiveness and safety of PHBT to haemorrhagic trauma patients.

METHODS: CINAHL, Cochrane, EMBASE, and Pubmed were searched in the period from 1988 until August 1, 2018. Meta-analysis was performed for matched trauma patients receiving PHBT with the primary outcomes 24-hour mortality and long-term mortality. Secondary outcome measure was adverse events as a result of PHBT.

RESULTS: Trauma patients who received PHBT with simultaneous use of packed red blood cells (pRBCs) and plasma showed a statistically significant reduction in long-term mortality (OR = 0.51; 95% CI, 0.36-0.71; P < 0.0001) but no difference in 24-hour mortality (OR = 0.47, 95% CI, 0.17-1.34; P = 0.16). PHBT with individual use of pRBCs showed no difference in long-term mortality (OR = 1.18; 95% CI, 0.93-1.49; P =  0.17) or 24-hour mortality (OR = 0.92; 95% CI, 0.46-1.85; P =  0.82). In a total of 1341 patients who received PHBT, 14 adverse events were reported 1.04%, 95% CI 0.57-1.75%.

CONCLUSIONS: PHBT with simultaneous use of both pRBCs and plasma resulted in a significant reduction in the odds for long-term mortality. However, based on mainly poor quality evidence no hard conclusion can be drawn about a possible survival benefit for haemorrhagic trauma patients receiving PHBT. Overall, PHBT is safe but results of currently ongoing randomised controlled trials have to be awaited to demonstrate a survival benefit.

STUDY TYPE: Systematic review and meta-analysis.

Transfusion. 2019 Jan;59(1):146-158

# In silico model of the dilutional effects of conventional component therapy versus whole blood in the management of massively bleeding adult trauma patients.

Seheult J, Stram M, Sperry J, Spinella P, Triulzi D, Yazer M

BACKGROUND: There are multiple approaches to the blood product and fluid resuscitation of a bleeding trauma patient. An in silico model of different trauma resuscitation strategies was constructed to predict their effects on the volumes of the different body fluid compartments and on several important hemostatic factors.

STUDY DESIGN AND METHODS: This multicompartment dynamic deterministic model comprised four interconnected modules (hemostatic, resuscitation, body fluid compartment, and dilutional coagulopathy). The model was divided into five resuscitation phases with simulations using six different resuscitation strategies: whole blood (WB) only, conventional component therapy (CCT) only or 10 units of WB followed by CCT, with either 1 L of crystalloid or 1.5 units of WB or red blood cells in the prehospital phase.

RESULTS: At the end of the simulations using 1 L of crystalloid fluids in the prehospital resuscitation phase, the use of WB led to a 1.4 g/dL higher hemoglobin concentration, 32 mg/dL higher fibrinogen concentration, and 0.9 L lower total extracellular fluid volume compared to CCT. Prehospital blood product transfusion in place of crystalloid resulted in higher hemoglobin and fibrinogen concentrations and a lower international normalized ratio throughout the resuscitation regardless of the resuscitation strategy used. Throughout both the prehospital crystalloid and prehospital blood product transfusion simulations, the hemoglobin and fibrinogen concentrations and platelet counts were higher, and the international normalized ratio was lower, when WB was used compared to CCT.

CONCLUSIONS: This model predicted improved hemostatic factor levels and a smaller total extracellular fluid volume volume when WB was transfused instead of CCT to bleeding trauma patients.

Emerg Med Australas. 2019 Apr 9. doi: 10.1111/1742-6723.13290.

# Heterogeneous emergency department management of published recommendation defined hypotension in patients with acute traumatic spinal cord injury: A multi-centre overview.

Sharwood L, Joseph A, Guo C, Flower O, Ball J, Middleton J

OBJECTIVE: Evidence-based management for patients with acute traumatic spinal cord injury (TSCI) in the ED has a critical impact on long-term outcomes. Acute hypotension post-injury may compromise spinal cord perfusion and extend neurological damage. Published guidelines recommend mean arterial blood pressure (BP) maintenance between 85 and 90 mmHg for 7 days post-injury; the extent to which this is followed in Australia is unknown.

METHODS: Prospective observational study of patients ≥16 years with TSCI, treated at 48 hospitals across two Australian states. Mean arterial BPs were recorded in the Ambulance, and ED arrival and discharge. Patients' medical records documented treatment provided (intravenous fluids, vasopressors or both) for BP augmentation. Hypotension was defined as mean arterial BP <85 mmHg, per the American Association of Neurological Surgeons guidelines.

RESULTS: The 208 patients with TSCI in the present study were more likely to receive BP augmentation if they experienced direct transport to a Spinal Cord Service hospital (OR 5.57, 95% CI 2.32-10.11), had a cervical level injury (OR 2.32, 95% CI 1.01-5.5) or were hypotensive on ED arrival (OR 2.42, 95% CI 1.34-4.39). Of the 112 patients who were hypotensive, 71 (63.4%) received treatment for this; however, the majority (76%) remained hypotensive on discharge.

CONCLUSION: Hypotensive patients' post-TSCI experienced heterogeneous ED care discordant with published guidelines; varying by hospital type. Specialist care and more severe injury increased likelihood of guideline adherence. Lack of adherence may influence patient outcomes. Level 1 evidence is needed along with consistent guideline implementation and clinician training to likely improve TSCI management and outcomes.

Transfusion. 2019 Apr 3;Epub ahead of print

# Prehospital whole blood resuscitation prevents coagulopathy and improves acid-base status at hospital arrival in a nonhuman primate hemorrhagic shock model.

Sheppard F, Mitchell T, Cap A, Schaub L, Macko A, Glaser J

BACKGROUND: Hemorrhage remains the primary cause of preventable death in civilian and military trauma. The Committee on Tactical Combat Casualty Care recommends prehospital (PH) resuscitation with whole blood (WB). However, 6% hetastarch in lactated electrolyte (HEX) and crystalloids are more commonly available and used for PH resuscitation in military and civilian environments, respectively. The mechanistic benefits of PH WB resuscitation have not been well studied and remain to be elucidated.

STUDY DESIGN AND METHODS: The aim of this study was to evaluate the differences in simulated PH WB and HEX resuscitation, specifically with regards to coagulation, physiologic, and metabolic outcomes to better elucidate the mechanistic benefits of WB. In a randomized study, the physiologic, coagulation, and metabolic responses to simulated PH WB (n = 12) or HEX (n = 12) were evaluated in a nonhuman primate model of severe polytraumatic hemorrhagic shock.

RESULTS: Notable findings included 1) equivalence of shock reversal between simulated PH WB and HEX treatment groups as determined by hemodynamics and base deficit and 2) prevention of coagulopathy at simulated hospital arrival with initial WB resuscitation as determined by viscoelastic and plasmatic coagulation assays.

CONCLUSION: The major benefit of WB, as compared to HEX, in simulated PH resuscitation appears to be prevention of coagulopathy at hospital arrival. Both fluids effectively reversed shock in this model, implying that efficacious provision preload (cardiac output support and hence oxygen delivery) and coagulation proteins (prevention of coagulopathy) are mechanisms underlying WB's effectiveness in early resuscitation of hemorrhagic shock.

J Emerg Med. 2019 May;56(5):491-498

# Whole Blood in Trauma: A Review for Emergency Clinicians.

Weymouth W, Long B, Koyfman A, Winckler C

BACKGROUND: Blood products are a cornerstone of trauma resuscitation. From the historically distant battlefields of World War II through present-day conflict around the globe, whole blood (WB) has been a potent tool in the treatment of massive hemorrhagic shock. Component therapy with a targeted ratio of packed red blood cells, platelets, and plasma has previously been utilized.

OBJECTIVES: This narrative review describes modern-day WB transfusion, its benefits, potential drawbacks, and implementation.

DISCUSSION: The current form of stored low-titer O WB seems to be the safest and most effective solution. There are many advantages to WB, including the maintenance of coagulation factors, the lack of subsequent thrombocytopenia, and the reduction of infused anticoagulant. Several studies suggest its utility in trauma. Most of the disadvantages of WB stem from a lack of prospective data on the topic, which are likely forthcoming. Logistical issues likely present the greatest barrier to this therapy, but an advanced prehospital protocol developed in San Antonio, Texas, has successfully overcome several of these challenges.

CONCLUSIONS: Although stored WB holds promise, it is not without its distinct challenges, including logistical issues, which this article addresses. There are programs underway currently that demonstrate its feasibility in metropolitan areas. As demonstrated in military settings, WB is likely the ideal resuscitation fluid for civilian trauma in the prehospital and emergency department settings.

J Trauma Acute Care Surg. 2019 Mar 15;Epub ahead of print

# 4-Factor Prothrombin Complex Concentrate is associated with Improved Survival in Trauma Related Hemorrhage: A Nationwide Propensity Matched Analysis.

Zeeshan M, Hamidi M, Feinstein A, Gries L, Jehan F, Sakran J, Northcutt A, OʼKeeffe T, Kulvatunyou N, Joseph B

INTRODUCTION: Post-traumatic hemorrhage is the most common preventable cause of death in trauma. Numerous small single-center studies have shown the superiority of 4-factor prothrombin complex concentrate (4-PCC) along with fresh frozen plasma (FFP) over FFP-alone in resuscitation of trauma patients. The aim of our study was to evaluate outcomes of severely injured trauma patients who received 4-PCC+FFP compared to FPP-alone.

METHODS: 2-year (2015-2016) analysis of the American College of Surgeons-Trauma Quality Improvement Program database. All adult (age≥18years) trauma patients who received 4-PCC+FFP or FFP-alone were included. We excluded patients who were on preinjury anticoagulants. Patients were stratified into two groups: 4-PCC+FFP vs. FFP-alone and were matched in a 1:1 ratio using propensity-score-matching for demographics, vitals, injury parameters, comorbidities and level of trauma centers. Outcome measures were packed red blood cells (pRBC), plasma & platelets transfused, complications, and mortality.

RESULTS: A total of 468 patients (4-PCC+FFP: 234, FFP-alone: 234) were matched. Mean age was 50±21years; 70% were males, median injury severity score was 27[20-36], and 86% had blunt injuries. 4-PCC+FFP was associated with a decreased requirement for pRBC (6 units vs. 10 units; p=0.02) and FFP (3 units vs. 6 units; p=0.01) transfusion compared to FFP-alone. Patients who received 4-PCC+FFP had a lower mortality (17.5% vs 27.7%, p=0.01) and lower rates of acute respiratory distress syndrome (1.3% vs 4.7%, p=0.04) & acute kidney injury (2.1% vs 7.3%, p=0.01). There was no difference in the rates of deep venous thrombosis (p=0.11) & pulmonary embolism (p=0.33), adverse discharge disposition (p=0.21) and platelets transfusion (p=0.72) between the two groups.

CONCLUSIONS: Our study demonstrates that the use of 4-factor PCC as an adjunct to FFP is associated with improved survival and reduction in transfusion requirements compared to FFP alone in resuscitation of severely injured trauma patients. Further studies are required to evaluate the role of addition of PCC to the massive transfusion protocol.

LEVEL OF EVIDENCE: Level III, Therapeutic studies.

J Trauma Acute Care Surg. 2019 Epub ahead of print

# Implementation of a Prehospital Air Medical Thawed Plasma Program: Is It Even Feasible?

Adams P, Warren K, Guyette F, Yazer M, Brown J, Daily B, Miller R, Harbrecht B, Claridge J, Phelan H, Witham W, Putnam A, Zuckerbraun B, Neal M, Sperry J; PAMPer study group.

INTRODUCTION: The PAMPer trial demonstrated a 30-day survival benefit among hypotensive trauma patients treated with prehospital plasma during air medical transport. We characterized resources, costs and feasibility of air medical prehospital plasma program implementation.

METHODS: We performed a secondary analysis using data derived from the recent PAMPer trial. Intervention patients received thawed plasma (5-day shelf-life). Unused plasma units were recycled back to blood bank affiliates, when possible. Distribution method and capability of recycling varied across sites. We determined the status of plasma units deployed, utilized, wasted, and returned. We inventoried thawed plasma use and annualized costs for distribution and recovery.

RESULTS: The PAMPer trial screened 7,275 patients and 5,103 plasma units were deployed across 22 air medical bases over a 42-month time period. Only 368 units (7.2%) of this total thawed plasma pool were provided to plasma randomized PAMPer patients. Of the total plasma pool, 3,716 (72.8%) units of plasma were returned to the blood bank with the potential for transfusion prior to expiration and 1,019 (20.0%) thawed plasma units were deemed wasted for this analysis. The estimated average annual cost of implementation of a thawed plasma program per air medical base at an average courier distance would be between $24,343 and $30,077 depending on the ability to recycle plasma and distance of courier delivery required.

CONCLUSION: A prehospital plasma program utilizing thawed plasma is resource intensive. Plasma waste can be minimized depending on trauma center and blood bank specific logistics. Implementation of a thawed plasma program can occur with financial cost. Products with a longer shelf-life such as liquid plasma or freeze-dried plasma may provide a more cost-effective prehospital product relative to thawed plasma.

STUDY TYPE: Secondary Analysis of Clinical Trial

LEVEL OF EVIDENCE: III.

J Trauma Acute Care Surg. 2019 Aug;87(2):342-349

# Earlier time to hemostasis is associated with decreased mortality and rate of complications: Results from the Pragmatic Randomized Optimal Platelet and Plasma Ratio trial.

Chang R, Kerby J, Kalkwarf K, Van Belle G, Fox E, Cotton B, Cohen M, Schreiber M, Brasel K, Bulger E, Inaba K, Rizoli S, Podbielski J, Wade C, Holcomb J; PROPPR Study Group.

BACKDROP: Clinicians intuitively recognize that faster time to hemostasis is important in bleeding trauma patients, but these times are rarely reported.

METHODS: Prospectively collected data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial were analyzed. Hemostasis was predefined as no intraoperative bleeding requiring intervention in the surgical field or resolution of contrast blush on interventional radiology (IR). Patients who underwent an emergent (within 90 minutes) operating room (OR) or IR procedure were included. Mixed-effects Poisson regression with robust error variance (controlling for age, Injury Severity Score, treatment arm, injury mechanism, base excess on admission [missing values estimated by multiple imputation], and time to OR/IR as fixed effects and study site as a random effect) with modified Bonferroni corrections tested the hypothesis that decreased time to hemostasis was associated with decreased mortality and decreased incidence of acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF), sepsis, and venous thromboembolism.

RESULTS: Of 680 enrolled patients, 468 (69%) underwent an emergent procedure. Patients with decreased time to hemostasis were less severely injured, had less deranged base excess on admission, and lower incidence of blunt trauma (all p < 0.05). In 408 (87%) patients in whom hemostasis was achieved, every 15-minute decrease in time to hemostasis was associated with decreased 30-day mortality (RR, 0.97; 95% confidence interval [CI], 0.94-0.99), AKI (RR, 0.97; 95% CI, 0.96-0.98), ARDS (RR, 0.98; 95% CI, 0.97-0.99), MOF (RR, 0.94; 95% CI, 0.91-0.97), and sepsis (RR, 0.98; 95% CI, 0.96-0.99), but not venous thromboembolism (RR, 0.99; 95% CI, 0.96-1.03).

CONCLUSION: Earlier time to hemostasis was independently associated with decreased incidence of 30-day mortality, AKI, ARDS, MOF, and sepsis in bleeding trauma patients. Time to hemostasis should be considered as an endpoint in trauma studies and as a potential quality indicator.

LEVEL OF EVIDENCE: Therapeutic/care management, level III.

J Trauma Acute Care Surg. 2019 Apr 25;Epub ahead of print

# Progress on combat damage control resuscitation/ surgery and its application in the Chinese People's Liberation Army.

Chen S, Yang J, Zhang L, Yang L, Qin H, Liu D, Ye Z, Du W, Zhong X, Zong Z

Damage control resuscitation and damage control surgery (DCR/DCS) has now been developed as a well-established standard of care for severely injured civilian patients worldwide. On the other hand, the application of combat DCR/DCS has saved the lives of thousands of severely injured casualty in several wars during the last two decades. This article describes the great progress on DCR/DCS in the last two decades and its application in the Chinese People's Liberation Army (PLA). The main development of the advanced theories of combat DCR/DCS including the global integration of DCR/DCS, application of remote battlefield DCR, balanced hemostatic resuscitation in combat hospitals and enhancement of en route DCR. There are two key factors that determine the feasibility of combat DCR: one is the availability of resources and supplies to implement the advanced theories of combat DCR/DCS, the other is the availability of qualified personnel who master the skills needed for the implementation of DCR/DCS. In the PLA, the advanced theories of combat DCR/DCS have now been widely accepted, and some of related advanced products such as fresh-frozen plasma, packed red blood cells and platelets have been available in level III medical facilities. In conclusion, great progress in combat DCR/DCS has been achieved in recent years, and the Chinese PLA is keeping good pace with this development, although there is still room for improvement. Study type Review article evel of evidence This is a general review article, does not require a level of evidence.

Asian J Transfus Sci. 2019 Jan-Jun;13(1):23-29

# A study on factors influencing the hemostatic potential of fresh frozen plasma.

Dhantole L, Dubey A, Sonker A

BACKGROUND: Fresh frozen plasma (FFP) is administered to correct deficiencies of various coagulation factors. The level of these factors in FFP varies with donor demographics and ex-vivo processing of plasma. In this study we have compared the quality control parameters of FFP collected from donors of different genders, age groups, ABO blood groups, smoking and alcohol intake habits.

MATERIALS AND METHODS: Four ABO group matched plasma units were pooled, split and further processed by four different freeze-thaw algorithms: frozen by contact shock freezer; thawed at 37°C, frozen by contact shock freezer; thawed at 45°C, frozen by mechanical freezer; thawed at 37°C, frozen by mechanical freezer; thawed at 45°C. The coagulation factor levels in plasma units were compared.

RESULTS: There were no significant differences in the quality parameters with donor age, gender and alcohol intake. Factor VIII levels were significantly lower in O group FFP (P < 0.05). Smokers had significantly higher levels of fibrinogen (P < 0.05). There were no significant differences in PT, fibrinogen and factor VII levels of FFP processed through various algorithms. Plasma frozen rapidly through contact shock freezer had significantly lower aPTT and higher levels of factor V and VIII compared to mechanical freezing. There were no significant differences between PT, aPTT, fibrinogen, factor V, factor VII and factor VIII levels of FFP thawed at 37°C and 45°C. Mean thawing time was 28 minutes at 37°C and 17 minutes at 45°C.

CONCLUSION: Rapid freezing is recommended for optimum preservation of coagulation factors. Thawing may be done at 45°C in cases of emergency, without compromising hemostatic potential.

J Trauma Acute Care Surg. 2019 Jul;87(1S Suppl 1):S184-S190

# Conducting fresh whole blood transfusion training.

Fisher A, Carius B, Corley J, Dodge P, Miles E, Taylor A

Fresh whole blood is the optimal resuscitation fluid for casualties in hemorrhagic shock according to the Committee on Tactical Combat Casualty Care and has demonstrated to improve outcomes in severely wounded patients. Like all medical interventions, fresh whole blood transfusions are not without risks, but similarly can be mitigated through increased training to develop provider knowledge and proficiency. To date, no literature has been published regarding the proper technique to conduct fresh whole blood transfusion training. This article provides a structured foundation to establish a standardized fresh whole blood transfusion training program to increase skill and preparedness for fresh whole blood protocol implementation. Using these techniques in a training environment, providers will be able to provide optimal resuscitation in hemorrhagic shock in austere environments.

J Trauma Acute Care Surg. 2019 Aug;87(2):263-273

# Selective aortic arch perfusion with fresh whole blood or HBOC-201 reverses hemorrhage-induced traumatic cardiac arrest in a lethal model of noncompressible torso hemorrhage.

Hoops H, Manning J, Graham T, McCully B, McCurdy S, Ross J

BACKGROUND: Hemorrhage-induced traumatic cardiac arrest (HiTCA) has a dismal survival rate. Previous studies demonstrated selective aortic arch perfusion (SAAP) with fresh whole blood (FWB) improved the rate of return of spontaneous circulation (ROSC) after HiTCA, compared with resuscitative endovascular balloon occlusion of the aorta and cardiopulmonary resuscitation (CPR). Hemoglobin-based oxygen carriers, such as hemoglobin-based oxygen carrier (HBOC)-201, may alleviate the logistical constraints of using FWB in a prehospital setting. It is unknown whether SAAP with HBOC-201 is equivalent in efficacy to FWB, whether conversion from SAAP to extracorporeal life support (ECLS) is feasible, and whether physiologic derangement post-SAAP therapy is reversible.

METHODS: Twenty-six swine (79 ± 4 kg) were anesthetized and underwent HiTCA which was induced via liver injury and controlled hemorrhage. Following arrest, swine were randomly allocated to resuscitation using SAAP with FWB (n = 12) or HBOC-201 (n = 14). After SAAP was initiated, animals were monitored for a 20-minute prehospital period prior to a 40-minute damage control surgery and resuscitation phase, followed by 260 minutes of critical care. Primary outcomes included rate of ROSC, survival, conversion to ECLS, and correction of physiology.

RESULTS: Baseline physiologic measurements were similar between groups. ROSC was achieved in 100% of the FWB animals and 86% of the HBOC-201 animals (p = 0.483). Survival (t = 320 minutes) was 92% (11/12) in the FWB group and 67% (8/12) in the HBOC-201 group (p = 0.120). Conversion to ECLS was successful in 100% of both groups. Lactate peaked at 80 minutes in both groups, and significantly improved by the end of the experiment in the HBOC-201 group (p = 0.001) but not in the FWB group (p = 0.104). There was no significant difference in peak or end lactate between groups.

CONCLUSION: Selective aortic arch perfusion is effective in eliciting ROSC after HiTCA in a swine model, using either FWB or HBOC-201. Transition from SAAP to ECLS after definitive hemorrhage control is feasible, resulting in high overall survival and improvement in lactic acidosis over the study period.

J Trauma Acute Care Surg. 2019 Jul;87(1):68-75

# Prehospital adenosine, lidocaine, and magnesium has inferior survival compared with tactical combat casualty care resuscitation in a porcine model of prolonged hemorrhagic shock.

How R, Glaser J, Schaub L, Fryer D, Ozuna K, Morgan C, Sams V, Cardin S

BACKGROUND: Adenosine, lidocaine, and magnesium (ALM) is a cardioplegic agent shown to improve survival by improving cardiac function, tissue perfusion, and coagulopathy in animal models of shock. We hypothesized prehospital ALM treatment in hemorrhagic shock would improve survival compared to current Tactical Combat Casualty Care (TCCC) resuscitation beyond the golden hour.

METHODS: Swine were randomized to: (1) TCCC, (2) 2 mL·kg vehicle control (VC), (3) 2 mL·kg ALM + drip, (4) 4 mL·kg ALM + drip, 5) 4 mL·kg ALM + delayed drip at 0.5 mL·kg·h, 6) 4 mL/kg VC, 7) 4 mL·kg ALM for 15 minutes + delayed drip at 3 mL·kg·h. Animals underwent pressure controlled hemorrhage to mean arterial pressure (MAP) of 30 mm Hg (S = 0). Treatment was administered at T = 0. After 120 minutes of simulated prehospital care (T = 120) blood product resuscitation commenced. Physiologic variables were recorded and laboratories were drawn at specified time points.

RESULTS: Tactical Combat Casualty Care demonstrated superior survival to all other agents. The VC and ALM groups had lower MAPs and systolic blood pressures compared with TCCC. Except for the VC groups, lactate levels remained similar with correction of base deficit after prehospital resuscitation in all groups. Kidney function and liver function remained comparable across all groups. Compared with baseline values, TCCC demonstrated significant hypocoagulability.

CONCLUSION: Adenosine, lidocaine, and magnesium, as administered in this study, are inferior to current Hextend-based resuscitation for survival from prolonged hemorrhagic shock in this model. In survivors, ALM groups had lower systolic blood pressures and MAPs, but provided a protective effect on coagulopathy as compared to TCCC. Adenosine, lidocaine, and magnesium do not appear to be a suitable low volume replacement to current TCCC resuscitation. The reduced coagulopathy compared to TCCC warrants future studies of ALM, perhaps as a therapeutic adjunct.

J Trauma Acute Care Surg. 2019 Aug;87(2):420-429

# Essentials of emergency transfusion-The complement to stop the bleed.

Lewis M, Shulman I, Hudgins J, Moore EE, Inaba K.

Over the past decade, the shift toward damage control surgery for bleeding trauma patients has come with an increased emphasis on optimal resuscitation. Two lifesaving priorities predominate: to quickly stop the bleed and effectively resuscitate the hemorrhagic shock. Blood is separated into components for efficient storage and distribution; however, bleeding patients require all components in a balanced ratio. A variety of blood products are available to surgeons, and these products have evolved over time. This review article describes the current standards for resuscitation of bleeding patients, including characteristics of all available products. The relevant details of blood donation and collection, blood banking, blood components, and future therapies are discussed, with the goal of guiding surgeons in their emergency transfusion practice.

J Trauma Acute Care Surg. 2019 Jul;87(1S Suppl 1):S83-S90

# Freeze-dried plasma mitigates the dilution effects of a hemoglobin-based oxygen carrier (HBOC-201) in a model of resuscitation for hemorrhage and hemodilution.

Meledeo M, Peltier G, McIntosh C, Taylor A, Bynum J, Pusateri A, Cap A

BACKGROUND: Hemoglobin-based oxygen carriers (HBOCs) have proven useful for supplementing oxygen delivery when red cells are unavailable; however, HBOCs do not promote hemostasis. The need for prehospital bridges to blood transfusion informed this study which sought to determine the impact of HBOCs on coagulation, with or without cotransfusion of freeze-dried plasma (FDP).

METHODS: Treatment was simulated in vitro by replacing whole blood volume (or whole blood prediluted with 25% plasmalyte A as a hemodilution model) with HBOC-201, FDP, or both at ratios of 10% to 50% of original volume. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, complete blood count, viscosity, thromboelastography (TEG), and platelet adhesion to collagen under flow were evaluated. Subsequently, tissue plasminogen activator was added to model hemorrhagic shock effects on fibrinolysis.

RESULTS: Substituting blood with HBOC resulted in dose-dependent decreases in fibrinogen and cells, which lengthened PT (+61% at highest dose) and aPTT (+40% at highest dose) and produced TEG parameters consistent with dilutional coagulopathy. While substituting blood with FDP decreased cell counts accordingly, fibrinogen, PT, aPTT, and TEG parameters were not statistically changed. When HBOC and FDP were combined 1:1 for volume replacement, observed HBOC-only detriments were mitigated: PT and aPTT were increased by 17% and 11%, respectively, at the highest doses. In prediluted samples, similar trends were seen with exacerbated differences. Platelet adhesion to collagen was directly affected by hematocrit. Samples containing both HBOC and tissue plasminogen activator were highly susceptible to fibrinolysis.

CONCLUSION: A dose equivalent to 1 unit to 2 units each of HBOC-201 and FDP had a modest impact on functional coagulation measures and is reasonable to consider for clinical study as a part of early transfusion intervention. Higher doses may impart hemodilution risks similar to resuscitation with crystalloid or other colloids in coagulation-compromised patients. Further study of HBOC effects on fibrinolysis is also indicated.

STUDY TYPE: In vitro laboratory study.

Burns Trauma. 2019 Jul 18;7:22. doi: 10.1186/s41038-019-0160-5

# Timely completion of multiple life-saving interventions for traumatic haemorrhagic shock: a retrospective cohort study.

Mitra B, Bade-Boon J, Fitzgerald M, Beck B, Cameron P

Background: Early control of haemorrhage and optimisation of physiology are guiding principles of resuscitation after injury. Improved outcomes have been previously associated with single, timely interventions. The aim of this study was to assess the association between multiple timely life-saving interventions (LSIs) and outcomes of traumatic haemorrhagic shock patients.

Methods: A retrospective cohort study was undertaken of injured patients with haemorrhagic shock who presented to Alfered Emergency & Trauma Centre between July 01, 2010 and July 31, 2014. LSIs studied included chest decompression, control of external haemorrhage, pelvic binder application, transfusion of red cells and coagulation products and surgical control of bleeding through angio-embolisation or operative intervention. The primary exposure variable was timely initiation of ≥ 50% of the indicated interventions. The association between the primary exposure variable and outcome of death at hospital discharge was adjusted for potential confounders using multivariable logistic regression analysis. The association between total pre-hospital times and pre-hospital care times (time from ambulance at scene to trauma centre), in-hospital mortality and timely initiation of ≥ 50% of the indicated interventions were assessed.

Results: Of the 168 patients, 54 (32.1%) patients had ≥ 50% of indicated LSI completed within the specified time period. Timely delivery of LSI was independently associated with improved survival to hospital discharge (adjusted odds ratio (OR) for in-hospital death 0.17; 95% confidence interval (CI) 0.03-0.83; p = 0.028). This association was independent of patient age, pre-hospital care time, injury severity score, initial serum lactate levels and coagulopathy. Among patients with pre-hospital time of ≥ 2 h, 2 (3.6%) received timely LSIs. Pre-hospital care times of ≥ 2 h were associated with delayed LSIs and with in-hospital death (unadjusted OR 4.3; 95% CI 1.4-13.0).

Conclusions: Timely completion of LSI when indicated was completed in a small proportion of patients and reflects previous research demonstrating delayed processes and errors even in advanced trauma systems. Timely delivery of a high proportion of LSIs was associated with improved outcomes among patients presenting with haemorrhagic shock after injury. Provision of LSIs in the pre-hospital phase of trauma care has the potential to improve outcomes.

Transfusion. 2019 Jul;59(7):2177-2179

# Low titer group O whole blood for prehospital hemorrhagic shock: It is an offer we cannot refuse.

Spinella P, Gurney J, Yazer M

Traumatic hemorrhagic shock carries very high morbidity and mortality. In adult trauma the 30‐day mortality rate ranges between 20% and 25%, whereas in children it is approximately 50%. Trauma is not only the most common cause of death in patients 1 to 46 years of age, it is also the most common cause of years of life lost for all patients less than 75 years of age. Traumatic hemorrhagic shock is the most common cause of preventable death after injury, accounting for approximately 30,000 deaths per year in the US. The vast majority of these deaths, 25,000 per year in the US, occur in the prehospital phase of resuscitation. The time from injury to death from traumatic hemorrhage is short, ranging from 1 to 3 hours from injury, with the average time to death being 1.6 hours. The most severely injured succumb in less than 30 minutes. Therefore when severe traumatic hemorrhage occurs, it must be recognized and addressed expeditiously: minutes matter.

Damage control resuscitation has been developed as a bundle of care intended to reduce morbidity and mortality from traumatic hemorrhagic shock. In both military and civilian trauma and transfusion communities, the debate continues whether cold‐stored LTOWB is optimal compared to individual blood components for in‐hospital resuscitation of patients with traumatic hemorrhagic shock. In the prehospital phase of resuscitation, there is less debate about the benefits of LTOWB over conventional components for traumatic shock. Shock and coagulopathy occur quickly after injury; survival improves the earlier we treat shock and coagulopathy.

US military trauma systems in collaboration with the Armed Services Blood Procurement Office have dramatically changed prehospital resuscitation in the past decade from exclusively using crystalloid/colloids to now where blood products are very commonly available prehospital. Trauma systems in the US are also working together with blood suppliers to coordinate donor recruitment and inventory management at all hospitals and emergency medical systems. Emergency medical systems in the US are increasingly starting to incorporate LTOWB for prehospital resuscitation. This is a big change in transfusion medicine. Trauma and transfusion medicine communities need to work together to improve outcomes for patients with severe bleeding in the prehospital setting. Moving forward, we should leave the clear fluids and take the whole blood. It is an offer we cannot refuse our patients.

J Trauma Acute Care Surg. 2019 Aug;87(2):393-401

# Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

Williams A, Bhatti U, Biesterveld B, Graham N, Chtraklin K, Zhou J, Dennahy I, Kathawate R, Vercruysse C, Russo R, Li Y, Alam H

BACKGROUND: Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes.

METHODS: Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes.

RESULTS: This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels.

CONCLUSION: VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.

J Trauma Acute Care Surg. 2019 Nov;87(5):1077-1081

# Implementation of a prehospital air medical thawed plasma program: Is it even feasible?

Adams P, Warren K, Guyette F, Yazer M, Brown J, Daily B, Miller R, Harbrecht B, Claridge J, Phelan HA, Witham WR, Putnam AT, Zuckerbraun BS, Neal M, Sperry J; PAMPer study group.

BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) trial demonstrated a 30-day survival benefit among hypotensive trauma patients treated with prehospital plasma during air medical transport. We characterized resources, costs and feasibility of air medical prehospital plasma program implementation.

METHODS: We performed a secondary analysis using data derived from the recent PAMPer trial. Intervention patients received thawed plasma (5-day shelf life). Unused plasma units were recycled back to blood bank affiliates, when possible. Distribution method and capability of recycling varied across sites. We determined the status of plasma units deployed, utilized, wasted, and returned. We inventoried thawed plasma use and annualized costs for distribution and recovery.

RESULTS: The PAMPer trial screened 7,275 patients and 5,103 plasma units were deployed across 22 air medical bases during a 42-month period. Only 368 (7.2%) units of this total thawed plasma pool were provided to plasma randomized PAMPer patients. Of the total plasma pool, 3,716 (72.8%) units of plasma were returned to the blood bank with the potential for transfusion prior to expiration and 1,019 (20.0%) thawed plasma units were deemed wasted for this analysis. The estimated average annual cost of implementation of a thawed plasma program per air medical base at an average courier distance would be between US $24,343 and US $30,077, depending on the ability to recycle plasma and distance of courier delivery required.

CONCLUSION: A prehospital plasma program utilizing thawed plasma is resource intensive. Plasma waste can be minimized depending on trauma center and blood bank specific logistics. Implementation of a thawed plasma program can occur with financial cost. Products with a longer shelf life, such as liquid plasma or freeze-dried plasma, may provide a more cost-effective prehospital product relative to thawed plasma.

LEVEL OF EVIDENCE: Therapeutic, level III.

J Surg Res. 2019 Oct 7;246:190-199

# Safety of Pressurized Intraosseous Blood Infusion Strategies in a Swine Model of Hemorrhagic Shock.

Auten J, McEvoy C, Roszko P, Polk T, Kachur R, Kemp J, Natarajan R, Zarow G

BACKGROUND: Current guidelines support intraosseous access for trauma resuscitation when intravenous access is not readily available. However, safety of intraosseous blood transfusions with varying degrees of infusion pressure has not been previously characterized.

MATERIALS AND METHODS: Adult female Yorkshire swine (Sus scrofa; n = 36; mean (M): 80 kg, 95% CI: 78-82 kg) were cannulated and then bled approximately 30% total blood volume. Swine were randomly assigned to proximal humerus intraosseous blood infusion with either Rapid Infuser, or Pressure Bag, or Push-Pull methods (n = 12 each). Flow rates, infusion pressures, vitals, biochemical variables, and pulmonary and renal tissue pathology were contrasted between groups.

RESULTS: Flow rates were greater for the Push-Pull strategy than Pressure Bag (96.5 mL/min versus 72.6 mL/min, P = 0.02) or Rapid Infuser (96.5 mL/min versus 60 mL/min, P = 0.002) strategies. The pressures generated during the Push-Pull transfusion (3058 mmHg) were greater than the other strategies (≤360 mmHg). After the observation period, plasma-free hemoglobin levels were higher in the Push-Pull strategy than in the Rapid Infuser (40 mg/dL versus 12 mg/dL, P = 0.02) or Pressure Bag (40 mg/dL versus 12 mg/dL, P = 0.01). Groups did not significantly differ in vitals, biochemical variables, or tissue pathology.

CONCLUSIONS: Push-Pull conferred the highest flow rates, but with higher infusion pressures and evidence of intravascular hemolysis. Rapid Infuser and Pressure Bag infusions had no increase from baseline in plasma-free hemoglobin. Pressure Bag infusion was noted to confer an advantage in flow rates over Rapid Infuser. Intraosseous blood transfusion with pressure bags can safely bridge toward central access in the early phases of trauma resuscitation.

J Trauma Acute Care Surg. 2019 Oct;87(4):954-960

# Progress on combat damage control resuscitation/surgery and its application in the Chinese People's Liberation Army.

Chen S, Yang J, Zhang L, Yang L, Qin H, Liu D, Ye Z, Du W, Zhong X, Zong Z.

Damage control resuscitation (DCR) and damage control surgery (DCS) has now been developed as a well-established standard of care for severely injured civilian patients worldwide. On the other hand, the application of combat DCR/DCS has saved the lives of thousands of severely injured casualties in several wars during the last two decades. This article describes the great progress on DCR/DCS in the last two decades and its application in the Chinese People's Liberation Army (PLA). The main development of the advanced theories of combat DCR/DCS including the global integration of DCR/DCS, application of remote battlefield DCR, balanced hemostatic resuscitation in combat hospitals and enhancement of en route DCR. There are two key factors that determine the feasibility of combat DCR: one is the availability of resources and supplies to implement the advanced theories of combat DCR/DCS, the other is the availability of qualified personnel who master the skills needed for the implementation of DCR/DCS. In the PLA, the advanced theories of combat DCR/DCS have now been widely accepted, and some of related advanced products, such as fresh-frozen plasma, packed red blood cells, and platelets, have been available in Level III medical facilities. In conclusion, great progress in combat DCR/DCS has been achieved in recent years, and the Chinese PLA is keeping good pace with this development, although there is still room for improvement.

Ann Surg. 2019 Oct 22;Epub ahead of print

# A Decade of Damage Control Resuscitation: New Transfusion Practice, New Survivors, New Directions.

Cole E, Weaver A, Gall L, West A, Nevin D, Tallach R, O'Neill B, Lahiri S, Allard S, Tai N, Davenport R, Green L, Brohi K

OBJECTIVE: The aim of this study was to identify the effects of recent innovations in trauma major hemorrhage management on outcome and transfusion practice, and to determine the contemporary timings and patterns of death.

BACKGROUND: The last 10 years have seen a research-led change in hemorrhage management to damage control resuscitation (DCR), focused on the prevention and treatment of trauma-induced coagulopathy.

METHODS: A 10-year retrospective analysis of prospectively collected data of trauma patients who activated the Major Trauma Centre's major hemorrhage protocol (MHP) and received at least 1 unit of red blood cell transfusions (RBC).

RESULTS: A total of 1169 trauma patients activated the MHP and received at least 1 unit of RBC, with similar injury and admission physiology characteristics over the decade. Overall mortality declined from 45% in 2008 to 27% in 2017, whereas median RBC transfusion rates dropped from 12 to 4 units (massive transfusion rates from 68% to 24%). The proportion of deaths within 24 hours halved (33%-16%), principally with a fall in mortality between 3 and 24 hours (30%-6%). Survivors are now more likely to be discharged to their own home (57%-73%). Exsanguination is still the principal cause of early deaths, and the mortality associated with massive transfusion remains high (48%). Late deaths are now split between those due to traumatic brain injury (52%) and multiple organ dysfunction (45%).

CONCLUSIONS: There have been remarkable reductions in mortality after major trauma hemorrhage in recent years. Mortality rates continue to be high and there remain important opportunities for further improvements in these patients.

J Spec Oper Med. 2019 Fall;19(3):24-25.

# Risk Associated With Autologous Fresh Whole Blood Training.

Donham B, Barbee GA, Deaton TG, Kerr W, Wier RP, Fisher AD.

Fresh whole blood (FWB) is increasingly being recognized as the ideal resuscitative fluid for hemorrhagic shock. Because of this, military units are working to establish the capability to give FWB from a walking blood bank donor in environments that are unsupported by conventional blood bank services. Therefore, many military units are performing autologous blood transfusion training. In this training, a volunteer has a unit of blood collected and then transfused back into the same donor. The authors report their experience performing an estimated 3408 autologous transfusions in training and report no instances of hemolytic transfusion reactions or other major complications. With appropriate control measures in place, autologous FWB training is low-risk training.

J Trauma Acute Care Surg. 2019 Aug 5;Epub ahead of print

# A Novel Protocol to Maintain Continuous Access to Thawed Plasma at a Rural Trauma Center.

Hannigan C, Ologun G, Trecartin A, Colom L, Bloomdahl R, Seyer A, LaRock L, Tubby B, Cagir B, Granet J, Behm R.

BACKGROUND: Early administration of plasma improves mortality in massively transfused patients, but the thawing process causes delay. Small rural centers have been reluctant to maintain thawed plasma due to waste concerns. Our 254-bed rural level II trauma center initiated a protocol allowing continuous access to thawed plasma and we hypothesized its implementation would not increase waste or cost.

METHODS: Two units of thawed plasma are continuously maintained in the trauma bay blood refrigerator. After 3 days these units are replaced with freshly thawed plasma and returned to the blood bank for utilization prior to their 5-day expiration date. The blood bank monitors and rotates the plasma. Only trauma surgeons can use the plasma stored in the trauma bay. Wasted units and cost were measured over a 12-month period and compared to the previous 2 years.

RESULTS: The blood bank thawed 1127 units of plasma during the study period assigning 274 to the trauma bay. When compared to previous years, we found a significant increase in waste (p<0.001) and cost (p=0.020) after implementing our protocol. It cost approximately $125/month extra to maintain continuous access to thawed plasma during the study period.A protocol to maintain thawed plasma in the trauma bay at a rural level II trauma center resulted in a miniscule increase in waste and cost when considering the scope of maintaining a trauma center. We feel this cost is also minimal when compared to the value of having immediate access to thawed plasma. Constant availability of thawed plasma can be offered at smaller rural centers without a meaningful impact on cost.Level III; Economic & Value-based Evaluations.

Shock. 2019 Oct;52:4-6

# Hemoglobin-based Oxygen Carriers (HBOC)-What the Next Generation Holds: When Red Blood Cells are not an Option.

Hill-Pryor C, Pusateri A, Weiskopf R

NO ABSTRACT AVAILABLE

Transfusion. 2019 Oct;59(10):3077-3083

# Blood transfusion for deep space exploration.

Nowak E, Reyes D, Bryant B, Cap A, Kerstman E, Antonsen E

BACKGROUND: Astronauts on exploration missions may be at risk for traumatic injury and medical conditions that lead to life threatening hemorrhage. Resuscitation protocols are limited by the austere conditions of spaceflight. Solutions may be found in low-resource terrestrial settings. The existing literature on alternative blood product administration and walking blood banks was evaluated for applicability to spaceflight.

STUDY DESIGN AND METHODS: A literature review was done using PubMed and Google Scholar. References were crosschecked for additional publications not identified using the initial search terms. Twenty-seven articles were identified, including three controlled trials, six retrospective cohort analyses, 15 reviews, one case report, and two experimental studies.

RESULTS: Solutions to blood transfusion in austere settings include lyophilized blood products, hemoglobin-based oxygen carriers (HBOCs), and fresh whole blood. Many of these products are investigational. Protocols for walking blood banks include methods for screening and activating donors, transfusion, and monitoring for adverse reactions. Microgravity and mission limitations create additional challenges for transfusion, including baseline physiologic changes, difficulty reconstituting lyophilized products, risk of air emboli during transfusion, equipment constraints, and limited evacuation and surgical options.

CONCLUSION: Medical planning for space exploration should consider the possibility of acute blood loss. A model for "floating" blood banks based on terrestrial walking blood bank protocols from austere environments is presented, with suggestions for future development. Constraints on volume, mass, storage, and crew, present challenges to blood transfusion in space and must be weighed against the benefits of expanding medical capabilities.

Curr Opin Crit Care. 2019 Dec;25(6):668-674

# Coagulopathy in the surgical patient: trauma-induced and drug-induced coagulopathies.

Peralta R, Thani H, Rizoli S

PURPOSE OF REVIEW: Coagulopathy is the derangement of hemostasis that in surgical patients may result in excessive bleeding, clotting or no measurable effect. The purpose of this review is to provide an overview of the most current evidence and practical approach to trauma- and drug-induced coagulopathy in surgical patients.

RECENT FINDINGS: Early identification and timely correction of coagulopathy in surgical patients with significant bleeding is paramount to prevent death and other consequences of hemorrhage. Trauma-induced coagulopathy is managed by protocols recommending fibrinogen replacement, FFP, platelets, TXA and frequent lab monitorization including viscoelastic tests. For warfarin- or DOAC-induced coagulopathy, the management follows similar principles plus drug reversal. Warfarin is diagnosed by prolonged international normalized ratio and reversed by PCC or FFP. DOACs are inconsistently diagnosed by routine coagulation tests, and reversed by a combination of TXA, PCC and specific antidotes (if available).

SUMMARY: Despite different understandings of the pathophysiology, trauma- and drug-induced coagulopathies are managed following similar protocols. In most of cases of significant surgical bleeding, timely and protocolized approach to correct the coagulopathy is likely to improve patients' outcome.

J Trauma Acute Care Surg. 2019 Sep 12;Epub ahead of print

# PREHOSPITAL PLASMA IN INJURED PATIENTS IS ASSOCIATED WITH SURVIVAL PRINCIPALLY IN BLUNT INJURY: RESULTS FROM TWO RANDOMIZED PREHOSPITAL PLASMA TRIALS.

Reitz K, Moore H, Guyette F, Sauaia A, Pusateri A, Moore E, Hassoune A, Chapman M, Daley B, Miller R, Harbrecht B, Claridge J, Phelan H, Brown J, Zuckerbraun B, Neal M, Yazer M, Sperry J

INTRODUCTION: Recent evidence demonstrated that prehospital plasma in patients at risk of hemorrhagic shock was safe for ground transport and resulted in a 28-day survival benefit for air medical transport patients. Whether any beneficial effect of prehospital plasma varies across injury mechanism remains unknown.

METHODS: We performed a secondary analysis using a harmonized dataset derived from two recent prehospital plasma randomized trials. Identical inclusion/exclusion criteria and primary/secondary outcomes were employed for the trials. Prehospital time, arrival shock parameters and 24-hour transfusion requirements were compared across plasma and control groups stratified by mechanism of injury. Stratified survival analysis and Cox hazard regression were performed to determine the independent survival benefits of plasma across blunt and penetrating injury.

RESULTS: Blunt patients had higher injury severity, were older and had a lower GCS. Arrival indices of shock and coagulation parameters were similar across blunt and penetrating injury. The percentage of patients with a prehospital time less than 20 mins was significantly higher for penetrating patients relative to blunt injured patients (28.0% vs 11.6%, p<0.01). Stratified Kaplan-Meier curves demonstrated a significant separation for blunt injured patients (n=465, p=0.01) with no separation demonstrated for penetrating injured patients (n=161, p=0.60) Stratified Cox hazard regression verified, after controlling for all important confounders, that prehospital plasma was associated with a 32% lower independent hazard for 28 day mortality in blunt injured patients (HR 0.68, 95% CI 0.47-0.96, p= 0.03) with no independent survival benefit found in penetrating patients (HR 1.16, 95%CI 0.4-3.1, p=0.78).

CONCLUSION: A survival benefit associated with prehospital plasma at 24 hours and 28 days exists primarily in blunt injured patients with no benefit shown in penetrating trauma patients. No detrimental effects attributable to plasma are demonstrated in penetrating injury. These results have important relevance to military and civilian trauma systems.Original ArticleSecondary Analysis LEVEL OF EVIDENCE: I.

JAMA Netw Open. 2019 Sep 4;2(9):e1912076

# Association of Early, High Plasma-to-Red Blood Cell Transfusion Ratio With Mortality in Adults With Severe Bleeding After Trauma.

Roquet F, Neuschwander A, Hamada S, Favé G, Follin A, Marrache D, Cholley B, Pirracchio R); Traumabase Group.

Importance: Optimal transfusion management is crucial when treating patients with trauma. However, the association of an early, high transfusion ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBC) with survival remains uncertain.

Objective: To study the association of an early, high FFP-to-PRBC ratio with all-cause 30-day mortality in patients with severe bleeding after trauma.

Design, Setting, and Participants: This cohort study analyzes the data included in a multicenter national French trauma registry, Traumabase, from January 2012 to July 2017. Traumabase is a prospective, active, multicenter adult trauma registry that includes all consecutive patients with trauma treated at 15 trauma centers in France. Overall, 897 patients with severe bleeding after trauma were identified using the following criteria: (1) received 4 or more units of PRBC during the first 6 hours or (2) died from hemorrhagic shock before receiving 4 units of PRBC.

Exposures: Eligible patients were divided into a high-ratio group, defined as an FFP-to-PRBC ratio more than 1:1.5, and a low-ratio group, defined as an FFP-to-PRBC ratio of 1:1.5 or less. The ratio was calculated using the cumulative units of FFP and PRBC received during the first 6 hours of management.

Main Outcomes and Measures: A Cox regression model was used to analyze 30-day survival with the transfusion ratio as a time-dependent variable to account for survivorship bias.

Results: Of the 12 217 patients included in the registry, 897 (7.3%) were analyzed (median [interquartile range] age, 38 (29-54) years; 639 [71.2%] men). The median (interquartile range) injury severity score was 34 (22-48), and the overall 30-day mortality rate was 33.6% (301 patients). A total of 506 patients (56.4%) underwent transfusion with a high ratio and 391 (43.6%) with a low ratio. A high transfusion ratio was associated with a significant reduction in 30-day mortality (hazard ratio, 0.74; 95% CI, 0.58-0.94; P = .01). When only analyzing patients who had complete data, a high transfusion ratio continued to be associated with a reduction in 30-day mortality (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04).

Conclusions and Relevance: In this analysis of the Traumabase registry, an early FFP-to-PRBC ratio of more than 1:1.5 was associated with increased 30-day survival among patients with severe bleeding after trauma. This result supports the use of early, high FFP-to-PRBC transfusion ratios in patients with severe trauma.

Blood Rev. 2019 Nov;38:100593

# Review of current transfusion therapy and blood banking practices.

Storch E, Custer B, Jacobs M, Menitove J, Mintz P

Transfusion Medicine is a dynamically evolving field. Recent high-quality research has reshaped the paradigms guiding blood transfusion. As increasing evidence supports the benefit of limiting transfusion, guidelines have been developed and disseminated into clinical practice governing optimal transfusion of red cells, platelets, plasma and cryoprecipitate. Concepts ranging from transfusion thresholds to prophylactic use to maximal storage time are addressed in guidelines. Patient blood management programs have developed to implement principles of patient safety through limiting transfusion in clinical practice. Data from National Hemovigilance Surveys showing dramatic declines in blood utilization over the past decade demonstrate the practical uptake of current principles guiding patient safety. In parallel with decreasing use of traditional blood products, the development of new technologies for blood transfusion such as freeze drying and cold storage has accelerated. Approaches to policy decision making to augment blood safety have also changed. Drivers of these changes include a deeper understanding of emerging threats and adverse events based on hemovigilance, and an increasing healthcare system expectation to align blood safety decision making with approaches used in other healthcare disciplines.

J Trauma Acute Care Surg. 2019 Aug 28;Epub ahead of print

# SAFETY PROFILE AND IMPACT OF LOW-TITER GROUP O WHOLE BLOOD FOR EMERGENCY USE IN TRAUMA.

Williams J, Merutka N, Meyer D, Bai Y, Prater S, Cabrera R, Holcomb J, Wade C, Love J, Cotton B

PURPOSE: Following US military implementation of a cold-stored whole blood program, several US trauma centers have begun incorporating uncrossmatched, group O cold-stored whole blood into civilian trauma resuscitation. We set out to evaluate the safety profile, transfusion reactions events, and impact of low-titer group O whole blood (LTO-WB) at our center.

METHODS: In November 2017, we added LTO-WB to each of our helicopters and to our emergency department (ED) refrigerator, alongside that of existing RBCs and plasma. We collected information on all trauma patients receiving prehospital or ED transfusion of uncrossed, emergency release blood products between 11/17 and 06/18. Patients were divided into those receiving any LTO-WB and those receiving only RBC and or plasma (COMP). Serial hemolysis panels were obtained at 3-hrs, 24-hrs, and 48-hrs. All data was run using STATA 12.1. Statistical significance was set at p<0.05.

RESULTS: 198 patients received LTO-WB and 152 patients received COMP. There were no differences in age, sex, or mechanism. LTO-WB patients had higher chest AIS scores (median 3 vs. 2; p=0.027), as well as worse arrival base excess (median -7 vs. -5; p=0.014) and lactate (5.1 vs. 3.5; p<0.001). LTO-WB patients received less post-ED blood products than the COMP patients (median 0 vs. 3; p=0.001). There was no difference in survival (LTO-WB 73%, COMP 74%; p=0.805). There were only two suspected transfusion reactions, both in the COMP group (p=0.061). There was no difference in hemolysis panel values. Controlling for age, severity of injury and prehospital physiology, LTO-WB was associated with a 53% reduction in post-ED blood product transfusion (OR 0.47; 0.23-0.94; p=0.033) and two-fold increase in likelihood of survival (OR 2.19, 1.01-4.76, p=0.047).

CONCLUSIONS: LTO-WB has similar evidence of laboratory hemolysis, similar transfusion reaction rates, and is associated with a reduction in post-ED transfusions and increase likelihood of survival.Level of evidence Level II, Prospective comparator study without negative effect.

Transfusion. 2019 Nov;59(11):3485-3490

# Freeze-dried plasma stability under prehospital field conditions.

Zur M, Glassberg E, Gorenbein P, Epstein E, Eisenkraft A, Misgav M, Avramovich E

BACKGROUND: This study evaluated the effect of routine, uncontrolled, Israeli field storage conditions on the stability and efficacy of Lyo-Plas N freeze-dried plasma (FDP). We evaluated clotting factors V, VIII, and XI; proteins S and C; fibrinogen; partial thromboplastin time (PTT); antithrombin III (ATIII); von Willebrand factor (VWF); and international normalized ratio (INR) in FDP stored at 4°C, 25°C, and 40°C for 6 and 12 months, as well as FDP returned from field units after uncontrolled storage for 15 months (manufacturer's shelf life).

METHODS AND MATERIALS: After reconstitution, clotting factor levels were compared to those of freshly supplied FDP doses.

RESULTS: At 4°C for 12 months, factor V decreased slightly. At 25°C, average fibrinogen and factor V content were significantly lower at both periods, and INR was higher after 12 months. At 40°C, all samples were out of normal range in at least one clotting factor after 6 or 12 months. After field storage for 15 months, fibrinogen, factors V and XI, PTT, and protein S were significantly decreased, and INR increased. However, these levels were still within laboratory norms. Statistically significant difference in clotting factors compared to laboratory normal range was found in INR (higher) and factor V (lower).

CONCLUSIONS: Our data show minimal decreases in clotting factors in FDP after storage under field conditions, when compared to laboratory normal ranges. Along with the many advantages of FDP, this supports its use at the point of injury under battlefield conditions, despite uncontrolled storage environments. Under controlled storage conditions at 4°C, shelf life could possibly be extended, although further study is required.