Circulation - Shock / Fluid Resuscitation

#### HEMORRHAGIC / HYPOVOLEMIC SHOCK

Anesth Analg. 2018 Oct;127(4):840-849

# Harmful or physiologic: diagnosing fibrinolysis shutdown in a trauma cohort with rotational thromboelastometry.

Gomez-Builes J, Acuna S, Nascimento B, Madotto F, Rizoli S

BACKGROUND: Despite its central role in early trauma coagulopathy, abnormal fibrinolysis continues to be poorly understood. Excessive fibrinolysis is a known contributor to mortality. Recent studies with thromboelastography (TEG) suggest decreased fibrinolysis (or shutdown) may be just as harmful. Considering the broad use of 2 different viscoelastic assays, which are not interchangeable, we proposed for the first time to define and characterize fibrinolysis shutdown using rotational thromboelastometry (ROTEM).

METHODS: Retrospective cohort study of severely injured patients with admission ROTEM. Shutdown was defined by the best Youden index value of the maximum lysis. Fibrinolysis phenotypes were physiologic, hyperfibrinolysis, and shutdown. Multivariable logistic regression evaluated association between Injury Severity Score and the fibrinolysis phenotypes, and the association among shutdown phenotype with mortality, blood transfusion, and thrombotic events.

RESULTS: Five hundred fifty patients were included. Maximum lysis <3.5% was selected to define shutdown. Predominant phenotype was physiologic (70.7%), followed by shutdown (25.6%) and hyperfibrinolysis (3.6%). Shutdown patients had higher Injury Severity Score, lower base excess, and required more transfusions than physiologic group. Shutdown was associated with acidosis (base excess: odds ratio [OR] for a 1 mEq/L increase, 0.93; 95% confidence interval [CI], 0.88-0.98; P = .0094) and the combination of clotting derangements, higher clot firmness (maximum clot formation: OR for a 2 mm increase, 1.8; 95% CI, 1.5-2.27; P <.0001), lower fibrinogen (OR for a 0.5 g/dL decrease, 1.47; 95% CI, 1.18-1.84; P= .0006), and poor clot formation dynamics (clot formation time: OR for a 5 seconds increase, 1.25; 95% CI, 1.15-1.36; P < .0001). Fibrinolysis shutdown was not independently associated with mortality (OR, 0.61; 95% CI, 0.28-1.33; P = .21), massive transfusion (OR, 2.14; 95% CI, 0.79-5.74; P = .1308), or thrombotic events (OR, 1.08; 95% CI, 0.37-3.15; P = .874). Shutdown was associated with increased 24-hour transfusion (OR, 2.24; 95% CI, 1.24-4.04; P = .007).

CONCLUSIONS: Despite higher injury burden, evidence of shock, and greater need for blood transfusions, early fibrinolysis shutdown was not associated with mortality, suggesting that it could represent an adaptive physiologic response to life-threatening trauma.

J Trauma Acute Care Surg. 2017 Sep;83(3):464-468

# Mortality after emergent trauma laparotomy: A multicenter, retrospective study.

Harvin J, Maxim T, Inaba K, Martinez-Aguilar M, King D, Choudhry A, Zielinski M, Akinyeye S, Todd S, Griffin R, Kerby J, Bailey J, Livingston D, Cunningham K, Stein D, Cattin L, Bulger E, Wilson A, Undurraga Perl V, Schreiber M, Cherry-Bukowiec J, Alam H, Holcomb J

BACKGROUND: Two decades ago, hypotensive trauma patients requiring emergent laparotomy had a 40% mortality. In the interim, multiple interventions to decrease hemorrhage-related mortality have been implemented but few have any documented evidence of change in outcomes for patients requiring emergent laparotomy. The purpose of this study was to determine current mortality rates for patients undergoing emergent trauma laparotomy.

METHODS: A retrospective cohort of all adult, emergent trauma laparotomies performed in 2012 to 2013 at 12 Level I trauma centers was reviewed. Emergent trauma laparotomy was defined as emergency department (ED) admission to surgical start time in 90 minutes or less. Hypotension was defined as arrival ED systolic blood pressure (SBP) ≤90 mm Hg. Cause and time to death was also determined. Continuous data are presented as median (interquartile range [IQR]).

RESULTS: One thousand seven hundred six patients underwent emergent trauma laparotomy. The cohort was predominately young (31 years; IQR, 24-45), male (84%), sustained blunt trauma (67%), and with moderate injuries (Injury Severity Score, 19; IQR, 10-33). The time in ED was 24 minutes (IQR, 14-39) and time from ED admission to surgical start was 42 minutes (IQR, 30-61). The most common procedures were enterectomy (23%), hepatorrhaphy (20%), enterorrhaphy (16%), and splenectomy (16%). Damage control laparotomy was used in 38% of all patients and 62% of hypotensive patients. The Injury Severity Score for the entire cohort was 19 (IQR, 10-33) and 29 (IQR, 18-41) for the hypotensive group. Mortality for the entire cohort was 21% with 60% of deaths due to hemorrhage. Mortality in the hypotensive group was 46%, with 65% of deaths due to hemorrhage.

CONCLUSION: Overall mortality rate of a trauma laparotomy is substantial (21%) with hemorrhage accounting for 60% of the deaths. The mortality rate for hypotensive patients (46%) appears unchanged over the last two decades and is even more concerning, with almost half of patients presenting with an SBP of 90 mm Hg or less dying.

Transfus Med Hemother. 2018 Apr;45(2):127-135Nov 15.

# Peripartum haemorrhage: haemostatic aspects of the new German PPH guideline.

Lier H, von Heymann C, Korte W, Schlembach D

Summary Peripartum haemorrhage remains one of the main causes of maternal mortality world-wide. The German, Austrian and Swiss Societies of Gynaecology and Obstetrics have updated the current guidelines for the treatment of peripartum haemorrhage together with the German Society of Anaesthesiology and Intensive Care Medicine and the Society of Thrombosis and Haemostasis Research. The recommendations have been the result of a thorough review of the available scientific literature and a consensus process involving all members of the guideline group. A key element of the anaesthesiological and haemostatic management is the development of a multidisciplinary standard operating procedure combining surgical as well as medical and haemostatic treatments depending on the severity of bleeding. The guideline underscores the value of clinical and laboratory diagnostics of peripartum haemorrhage as early as possible, even pre-emptively. This allows for an early identification of causes of bleeding and a specific treatment. The guideline comprises evidence-based recommendations for the use of uterotonics, tranexamic acid and blood products such as factor concentrates, fresh frozen plasma, platelet concentrates, packed red blood cells, recombinant activated factor VII and desmopressin. In addition, recommendations for blood conservation strategies involving the use of cell salvage, permissive hypotension and transfusion triggers are given.

J Trauma Acute Care Surg. 2018 Sep;85(3):620-625

# Outcomes following trauma laparotomy for hypotensive trauma patients: a UK military and civilian perspective.

Marsden M, Carden R, Navaratne L, Smith I, Penn-Barwell J, Kraven L, Brohi K, Tai N, Bowley D

BACKGROUND: The management of trauma patients has changed radically in the last decade, and studies have shown overall improvements in survival. However, reduction in mortality for the many may obscure a lack of progress in some high-risk patients. We sought to examine the outcomes for hypotensive patients requiring laparotomy in UK military and civilian cohorts.

METHODS: We undertook a review of two prospectively maintained trauma databases: the UK Joint Theatre Trauma Registry for the military cohort (February 4, 2003, to September 21, 2014) and the trauma registry of the Royal London Hospital major trauma center (January 1, 2012, to January 1, 2017) for civilian patients. Adults undergoing trauma laparotomy within 90 minutes of arrival at the emergency department (ED) were included.

RESULTS: Hypotension was present on arrival at the ED in 155 (20.4%) of 761military patients. Mortality was higher in hypotensive casualties (25.8% vs. 9.7% in normotensive casualties; p < 0.001). Hypotension was present on arrival at the ED in 63 (35.7%) of 176 civilian patients. Mortality was higher in hypotensive patients (47.6% vs. 12.4% in normotensive patients; p < 0.001). In both cohorts of hypotensive patients, neither the average injury severity, the prehospital time, the ED arrival systolic blood pressure, nor mortality rate changed significantly during the study period.

CONCLUSIONS: Despite improvements in survival after trauma for patients overall, the mortality for patients undergoing laparotomy who arrive at the ED with hypotension has not changed and appears stubbornly resistant to all efforts. Specific enquiry and research should continue to be directed at this high-risk group of patients.

LEVEL OF EVIDENCE: Prognostic/Epidemiologic, level IV.

J Trauma Acute Care Surg. 2018 Jul;85(1S Suppl 2):S77-S83

# Measurement of compensatory reserve predicts racial differences in tolerance to simulated hemorrhage in women.

Wenner M, Hinds K, Howard J, Nawn C, Stachenfeld N, Convertino V

BACKGROUND: The compensatory reserve measurement (CRM) has been established to accurately measure the body's total integrated capacity to compensate for physiologic states of reduced central blood volume and predict hemodynamic decompensation associated with inadequate tissue oxygenation. We previously demonstrated that African American (AA) women have a higher tolerance to reductions in central blood volume. Therefore, we tested the hypothesis that the CRM would identify racial differences during simulated hemorrhage, before the onset of traditional signs/symptoms.

METHODS: We performed a retrospective analysis during simulated hemorrhage using lower-body negative pressure (LBNP) in 23 AA (22 ± 1 years; 24 ± 1 kg/m) and 31 white women (WW) (20 ± 1 years; 23 ± 1 kg/m). Beat-by-beat blood pressure (BP) and heart rate (HR) were recorded during progressive lower body negative pressure to presyncope. The BP waveforms were analyzed using a machine-learning algorithm to derive the CRM at each lower body negative pressure stage.

RESULTS: Resting mean arterial BP (AA, 78 ± 3 mm Hg vs. WW, 74 ± 2 mm Hg) and HR (AA, 68 ± 2 bpm vs. WW, 65 ± 2 bpm) were similar between groups. The CRM progressively decreased during LBNP in both groups; however, the rate of decline in the CRM was less (p < 0.05) in AA. The CRM was 4% higher in AA at -15 mm Hg LBNP and progressively increased to 21% higher at -50 mm Hg LBNP (p < 0.05). However, changes in BP and HR were not different between groups.

CONCLUSION: These data support the notion that the greater tolerance to simulated hemorrhage induced by LBNP in AA women can be explained by their greater capacity to protect the reserve to compensate for progressive central hypovolemia compared with WW, independent of standard vital signs.

LEVEL OF EVIDENCE: Diagnostic test, level II.

#### BLOOD / BLOOD PRODUCTS

J Trauma Acute Care Surg. 2018 May;84(5):786-794

# Fresh whole blood resuscitation does not exacerbate skeletal muscle edema and long-term functional deficit after ischemic injury and hemorrhagic shock.

Aurora A, Roe J, Umoh N, Dubick M, Wenke J, Walters TJ

BACKGROUND: Hemorrhagic shock caused by extremity vascular injuries is common in combat injuries. Fluid resuscitation is the standard treatment for severe hemorrhage (HEM). Tourniquets (TKs) used for HEM control cause ischemia-reperfusion (I/R) injury that induces edema formation in the injured muscle. Resuscitation fluids affect edema formation; however, its effect on long-term functional response remains unknown. The objectives of this study are to (1) compare acute muscle damage; (2) determine long-term functional recovery of ischemic muscle; and (3) compare local and systemic inflammatory response including the expression of junctional proteins following early resuscitation with Hextend and fresh whole blood using a rodent model of combined HEM and TK-induced limb I/R.

METHODS: Anesthetized Sprague-Dawley rats underwent 42.5% arterial HEM, followed by 3 hours of TK application. Animals were either not resuscitated or resuscitated with Hextend or fresh whole blood. Two time points were evaluated, 2 and 28 days. Plasma cytokine concentrations were determined at baseline and end resuscitation. At 2 days, edema formation, expression of junctional proteins, and tissue level cytokines concentrations were evaluated. At 28 days, in vivo muscle contractile properties were determined. At both time points, routine histology was performed and graded using a semiquantitative grading system.

RESULTS: All animals developed hemorrhagic hypovolemia; the mortality rate was 100% in nonresuscitated rats. Hextend resuscitation exacerbated muscle edema (~11%) and muscle strength deficit (~20%). Fresh whole blood resuscitation presented edema and muscle strength akin to TK only. Fresh whole blood resuscitation upregulated expression of junctional proteins including proangiogenic factors and dampened the inflammatory response.

CONCLUSION: Fresh whole blood resuscitation does not exacerbate either TK-induced edema or muscle strength deficit. Fresh whole blood resuscitation may reduce both acute and long-term morbidity associated with extremity trauma. To our knowledge, this is the first study to demonstrate the nature of the resuscitation fluid administered following HEM impacts short- and long-term indices of I/R in skeletal muscle.

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S69-S76

# The evolution of pediatric transfusion practice during combat operations 2001-2013.

Cannon J, Neff L, Pidcoke H, Aden J, Spinella P, Johnson M, Cap A, Borgman M

BACKGROUND: Hemostatic resuscitation principles have significantly changed adult trauma resuscitation over the past decade. Practice patterns in pediatric resuscitation likely have changed as well; however, this evolution has not been quantified. We evaluated pediatric resuscitation practices over time within a combat trauma system.

METHODS: The Department of Defense Trauma Registry was queried from 2001 to 2013 for pediatric patients (<18 years). Patients with burns, drowning, and missing injury severity score were excluded. Volumes of crystalloid, packed red blood cells (PRBC), whole blood, plasma, and platelets (PLT) given in the first 24 hours were calculated per kilogram body weight. Tranexamic acid use was also determined. Patients were divided into Early (2001-2005) and Late (2006-2013) cohorts, and subgroups of transfused (TX+) and massively transfused (MT+) patients were created. Intensive care unit and hospital length of stay and 24-hour and in-hospital mortality rates were compared.

RESULTS: A total of 4,358 patients met inclusion criteria. Comparing Early versus Late, injuries from explosions, isolated or predominant head injuries, and injury severity score all increased. The proportion of TX+ patients also increased significantly (13.6% vs 37.4%, p < 0.001) as did the number of MT+ patients (2.1% vs 15.5%, p < 0.001). Transfusion of high plasma:RBC and PLT:RBC ratios increased in both the TX+ and MT+ subgroups, although overall, PLT and whole blood use was low. After adjusting for differences between groups, the odds of death was no different Early versus Late but decreased significantly in the MT+ patients with time as a continuous variable.

CONCLUSION: Transfusion practice in pediatric combat casualty care shifted toward a more hemostatic approach over time. All-cause mortality was low and remained stable overall and even decreased in MT+ patients despite more injuries due to explosions, more head injuries, and greater injury severity. However, further study is required to determine the optimal resuscitation practices in critically injured children.

LEVEL OF EVIDENCE: Epidemiologic study, level IV.

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S125-S131

# Immediate effects of blood donation on physical and cognitive performance-A randomized controlled double-blinded trial.

Eliassen H, Hervig T, Backlund S, Sivertsen J, Iversen V, Kristoffersen M, Wengaard E, Gramstad A, Fosse T, Bjerkvig CK, Apelseth T, Doughty H, Strandenes G.

BACKGROUND: The success of implementing damage control resuscitation principles pre-hospital has been at the expense of several logistic burdens including the requirements for resupply, and the question of donor safety during the development of whole blood programs. Previous studies have reported effects on physical performance after blood donation; however, none have investigated the effects of blood donation on cognitive performance.

METHOD: We describe a prospective double-blinded, randomized, controlled study comprised of a battery of tests: three cognitive tests, and VO2max testing on a cycle ergometer. Testing was performed 7 days before blinded donation (baseline day), immediately after donation (Day 0), and 7 days (Day 7) after donation. The inclusion criteria included being active blood donors at the Haukeland University Hospital blood bank, where eligibility requirements were met on the testing days, and providing informed consent. Participants were randomized to either the experimental (n = 26) or control group (n = 31). Control group participants underwent a 'mock donation" in which a phlebotomy needle was placed but blood was not withdrawn.

RESULTS: In the experimental group, mean ± SEM VO2max declined 6% from 41.35 ± 1.7 mLO2/(min·kg) at baseline to 39.0 ± 1.6 mLO2/(min·kg) on Day 0 and increased to 40.51 ± 1.5 mLO2/(min·kg) on Day 7. Comparable values in the control group were 42.1 ± 1.8 mLO2/(min·kg) at baseline, 41.6 ± 1.8 mLO2/(min·kg)) on Day 1 (1% decline from baseline), and 41.8 ± 1.8 mLO2/(min·kg) on Day 7.Comparing scores of all three cognitive tests on Day 0 and Day 7 showed no significant differences (p > 0.05).

CONCLUSION: Our main findings are that executive cognitive and physical performances were well maintained after whole blood donation in healthy blood donors. The findings inform postdonation guidance on when donors may be required to return to duty.

LEVEL OF EVIDENCE: Randomized, controlled, double-blinded prospective trial study, level 1.

Transfusion. 2018 Aug;58(8):1821-1823

# Get ready: whole blood is back and it’s good for patients.

Holcomb J, Jenkins D

The ongoing war has convinced a new generation of clinicians that whole blood (WB) benefits bleeding patients. As with many changes in civilian trauma care, the use of WB has transitioned from a wartime practice to the civilian world, becoming routine at many centers.

At last count, 19 leading trauma centers are using this approved product as their first line transfusion, with some starting prehospital (both ground and air ambulance) and continuing into the Emergency Department (ED) and Operating Room. Seheult and colleagues have been leaders in this civilian effort, along with a multinational group of collaborators.

The ongoing war has convinced a new generation of clinicians that whole blood (WB) benefits bleeding patients. As with many changes in civilian trauma care, the use of WB has transitioned from a wartime practice to the civilian world, becoming routine at many centers.5 At last count, 19 leading trauma centers are using this approved product as their first line transfusion, with some starting prehospital (both ground and air ambulance) and continuing into the Emergency Department (ED) and Operating Room.

Trauma Surg Acute Care Open. 2018 Jan 8;3(1):e000140. doi: 10.1136/tsaco-2017-000140. eCollection 2018.

# Is thromboelastography (TEG)- based resuscitation better than empirical 1:1 transfusion?

Howley I, Haut E, Jacobs L, Morrison J, Scalea T

Thomboelastography (TEG) is a whole blood measure of coagulation which was originally described in the 1950s. However, it has only been in the last few decades that assays have become accessible and viable as a point-of-care test. Following the observation that hemorrhagic shock is associated with an intrinsic coagulopathy, TEG has been used as a method of diagnosing specific coagulation defects in order to direct individualized blood products resuscitation. An alternative transfusion strategy is the administration of fixed ratio products, a paradigm borne out of military experience. It is unknown which strategy is superior and this topic was debated at the 36th Annual Point/Counterpoint Acute Care Surgery Conference. The following article summarizes the discussants points of view along with a summary of the evidence.Level of evidence: Level III.

JAMA Pediatr. 2018 May 1;172(5):491-492. doi: 10.1001/jamapediatrics.2017.5238.

# Use of uncrossmatched cold-stored whole blood in injured children with hemorrhagic shock.

Leeper CM, Yazer M, Cladis F, Saladino R, Triulzi D, Gaines B

Hemorrhagic shock is the most common cause of preventable death in pediatric civilian trauma. Balanced resuscitation with blood components has become the standard of care for initial hemostatic resuscitation in adults and children to mitigate the deleterious effects of trauma-induced coagulopathy. Whole blood (WB) contains plasma, red blood cells (RBCs), and platelets and requires less processing and dilution compared with reconstituting WB using components, making it an ideal resuscitative fluid. However, in non–group O recipients, there is a theoretical risk for hemolysis from anti-A and anti-B antibodies in group O WB units. Recently, the transfusion of WB in bleeding adult male trauma patients has been instituted in a large adult trauma center. Whole blood has never been transfused in a pediatric civilian trauma population; the novel use of transfusion of WB in injured children is herein described.

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S115-S119

# Prehospital low-titer cold-stored whole blood: Philosophy for ubiquitous utilization of O-positive product for emergency use in hemorrhage due to injury.

McGinity A, Zhu C, Greebon L, Xenakis E, Waltman E, Epley E, Cobb D, Jonas R, Nicholson S, Eastridge B, Stewart R, Jenkins D

The mortality from hemorrhage in trauma patients remains high. Early balanced resuscitation improves survival. These truths, balanced with the availability of local resources and our goals for positive regional impact, were the foundation for the development of our prehospital whole blood initiative-using low-titer cold-stored O RhD-positive whole blood. The main concern with use of RhD-positive blood is the potential development of isoimmunization in RhD-negative patients. We used our retrospective massive transfusion protocol (MTP) data to analyze the anticipated risk of this change in practice. In 30 months, of 124 total MTP patients, only one female of childbearing age that received an MTP was RhD-negative. With the risk of isoimmunization very low and the benefit of increased resources for the early administration of balanced resuscitation high, we determined that the utilization of low-titer cold-stored O RhD-positive whole blood would be safe and best serve our community.

Lancet. 2018 Jul 28;392(10144):283-291

# Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial.

Moore H, Moore E, Chapman M, McVaney K, Bryskiewicz G, Blechar R, Chin T, Burlew C, Pieracci F, West F, Fleming C, Ghasabyan A, Chandler J, Silliman C, Banerjee A, Sauaia A

BACKGROUND: Plasma is integral to haemostatic resuscitation after injury, but the timing of administration remains controversial. Anticipating approval of lyophilised plasma by the US Food and Drug Administration, the US Department of Defense funded trials of prehospital plasma resuscitation. We investigated use of prehospital plasma during rapid ground rescue of patients with haemorrhagic shock before arrival at an urban level 1 trauma centre.

METHODS: The Control of Major Bleeding After Trauma Trial was a pragmatic, randomised, single-centre trial done at the Denver Health Medical Center (DHMC), which houses the paramedic division for Denver city. Consecutive trauma patients in haemorrhagic shock (defined as systolic blood pressure [SBP] ≤70 mm Hg or 71-90 mm Hg plus heart rate ≥108 beats per min) were assessed for eligibility at the scene of the injury by trained paramedics. Eligible patients were randomly assigned to receive plasma or normal saline (control). Randomisation was achieved by preloading all ambulances with sealed coolers at the start of each shift. Coolers were randomly assigned to groups 1:1 in blocks of 20 according to a schedule generated by the research coordinators. If the coolers contained two units of frozen plasma, they were defrosted in the ambulance and the infusion started. If the coolers contained a dummy load of frozen water, this indicated allocation to the control group and saline was infused. The primary endpoint was mortality within 28 days of injury. Analyses were done in the as-treated population and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01838863.

FINDINGS: From April 1, 2014, to March 31, 2017, paramedics randomly assigned 144 patients to study groups. The as-treated analysis included 125 eligible patients, 65 received plasma and 60 received saline. Median age was 33 years (IQR 25-47) and median New Injury Severity Score was 27 (10-38). 70 (56%) patients required blood transfusions within 6 h of injury. The groups were similar at baseline and had similar transport times (plasma group median 19 min [IQR 16-23] vs control 16 min [14-22]). The groups did not differ in mortality at 28 days (15% in the plasma group vs 10% in the control group, p=0·37). In the intention-to-treat analysis, we saw no significant differences between the groups in safety outcomes and adverse events. Due to the consistent lack of differences in the analyses, the study was stopped for futility after 144 of 150 planned enrolments.

INTERPRETATION: During rapid ground rescue to an urban level 1 trauma centre, use of prehospital plasma was not associated with survival benefit. Blood products might be beneficial in settings with longer transport times, but the financial burden would not be justified in an urban environment with short distances to mature trauma centres.

FUNDING: US Department of Defense.

PLoS One. 2018 Feb 2;13(2):e0192363. doi: 10.1371/journal.pone.0192363. eCollection 2018.

# Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock.

Pati S, Peng Z, Wataha K, Miyazawa B, Potter D, Kozar R

In severe trauma and hemorrhage the early and empiric use of fresh frozen plasma (FFP) is associated with decreased morbidity and mortality. However, utilization of FFP comes with the significant burden of shipping and storage of frozen blood products. Dried or lyophilized plasma (LP) can be stored at room temperature, transported easily, reconstituted rapidly with ready availability in remote and austere environments. We have previously demonstrated that FFP mitigates the endothelial injury that ensues after hemorrhagic shock (HS). In the current study, we sought to determine whether LP has similar properties to FFP in its ability to modulate endothelial dysfunction in vitro and in vivo. Single donor LP was compared to single donor FFP using the following measures of endothelial cell (EC) function in vitro: permeability and transendothelial monolayer resistance; adherens junction preservation; and leukocyte-EC adhesion. In vivo, using a model of murine HS, LP and FFP were compared in measures of HS- induced pulmonaryvascular inflammation and edema. Both in vitro and in vivo in all measures of EC function, LP demonstrated similar effects to FFP. Both FFP and LP similarly reduced EC permeability, increased transendothelial resistance, decreased leukocyte-EC binding and persevered adherens junctions. In vivo, LP and FFP both comparably reduced pulmonary injury, inflammation and vascular leak. Both FFP and LP have similar potent protective effects on the vascular endothelium in vitro and in lung function in vivo following hemorrhagic shock. These data support the further development of LP as an effective plasma product for human use after trauma and hemorrhagic shock.

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S104-S114

# Effects of platelet-sparing leukocyte reduction and agitation methods on in vitro measures of hemostatic function in cold-stored whole blood.

Remy K, Yazer M, Saini A, Mehanovic-Varmaz A, Rogers S, Cap A, Spinella P

BACKGROUND: Agitation of platelet units stored at room temperature is performed routinely to maintain platelet function, and leukoreduction of blood products is the standard of care in many countries to reduce immune consequences of transfusion. The effect of agitation and leukoreduction on whole blood stored at 4°C requires investigation, as reductions in hemostatic capacity of whole blood may reduce its efficacy in treating trauma-induced coagulopathy and platelet dysfunction. We hypothesize that agitation of whole blood will not affect hemostatic function and that leukoreduction will reduce hemostatic function of whole blood.

METHODS: In this in vitro randomized controlled study, 21 units of leukoreduced and 20 nonleukoreduced whole blood units were each randomly assigned into four agitation groups. Hemostatic parameters were measured using viscoelastic assays (rotational thromboelastometry-Extrinsic Screening Test (ROTEM-EXTEM) and thromboelastography (TEG) platelet mapping), impedance aggregometry (agonists-adenosine phosphate, arachidonic acid, thrombin receptor activating peptide, and collagen), and a thrombin generation assay from these whole blood units before and after filtration and on 0, 5, 10, and 15 days of storage at 4°C.

RESULTS: Leukoreduction compared to nonleukoreduction reduced platelet concentration on Day 0. Viscoelastic measures and thrombin generation parameters revealed significant reduction in hemostatic function between the leukoreduced units and the nonleukoreduced units at a few time points. Leukoreduced units consistently demonstrated reduced platelet aggregation compared to the nonleukoreduced units. Agitation methods did not significantly affect any of the hemostatic parameters examined.

CONCLUSIONS: Leukoreduction of whole blood with a platelet-sparing filter caused a moderate but significant reduction in some measures of whole blood hemostatic function most evident early in storage. The benefits of leukoreduction should be weighed against the potential reduced hemostatic function of leukoreduced units. Agitation of whole blood is not required to maintain hemostatic function.

LEVEL OF EVIDENCE: In vitro randomized controlled trial, level 1.

J Trauma Acute Care Surg. 2018 Jul;85(1S Suppl 2):S33-S38

# Whole blood and Hextend: Bookends of modern tactical combat casualty care field resuscitation and starting point for multifunctional resuscitation fluid development.

Sheppard F, Mitchell T, Macko A, Fryer D, Schaub L, Ozuna K, Glaser J

BACKGROUND: Hemorrhage is the leading cause of preventable death in traumatically injured civilian and military populations. Prehospital resuscitation largely relies on crystalloid and colloid intravascular expansion, as whole blood and component blood therapy are logistically arduous. In this experiment, we evaluated the bookends of Tactical Combat Casualty Care Guidelines recommendations of prehospital resuscitation with Hextend and whole blood in a controlled hemorrhagic shock model within non-human primates, as means of a multifunctional resuscitative fluid development.

METHODS: In the nonhuman primate, a multiple injuries model was used, consisting of a musculoskeletal injury (femur fracture), soft tissue injury (15-cm laparotomy), and controlled hemorrhage to a mean arterial pressure of 20 mm Hg, demarcating the beginning of the shock period. Animals were randomized to prehospital interventions of whole blood or Hextend at T = 0 minutes, and at T = 90 minutes definitive surgical interventions and balanced sanguineous damage control resuscitation could be implemented. All animals were euthanized at T = 480 minutes. Data are expressed as mean ± SEM; significance, p < 0.05.

RESULTS: No significant differences in survival (83% vs. 100%; p = 0.3), tissue perfusion (EtCO2 and StO2) or endpoints of resuscitation (base deficit, lactate, pH) between Hextend and whole blood were identified. Second, whole blood compared with Hextend demonstrated significantly earlier normalization of clot formation time, maximal clot firmness, and α angle.

CONCLUSION: A future multifunctional resuscitative fluid including an asanguineous, oncotic, non-oxygen-carrying component to facilitate intravascular volume expansion, and a component with synthetic coagulation factors and fibrinogen to deter coagulopathy may show equivalence to whole blood.

LEVEL OF EVIDENCE: N/A: Study type: translational animal model.

N Engl J Med. 2018 Jul 26;379(4):315-326. doi: 10.1056/NEJMoa1802345.

# Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock.

Sperry J, Guyette F, Brown J, Yazer M, Triulzi D Early-Young B, Adams P, Daley B, Miller R, Harbrecht B, Claridge J,Phelan H, Witham W, Putnam A, Duane T, Alarcon L, Callaway C, Zuckerbraun B, Neal M, Rosengart M, Forsythe R, Billiar T, Yealy D, Peitzman A, Zenati M; PAMPer Study Group.

Collaborators: Buck M, Ryman A, Gimbel E, Gilchrist E, Buhay M, Chang C, Talisa V, Xu T, Kalloway K, Yates A, Rawn S, Jenkins J, Trachtenberg L, Eden R, Fraifogl J, Bates C, Howard C, Stebbins C, McNeill C, Snyder A, Ropp J, Caliman C, Beamon M.

BACKGROUND: After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting.

METHODS: To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport. The primary outcome was mortality at 30 days.

RESULTS: A total of 501 patients were evaluated: 230 patients received plasma (plasma group) and 271 received standard-care resuscitation (standard-care group). Mortality at 30 days was significantly lower in the plasma group than in the standard-care group (23.2% vs. 33.0%; difference, -9.8 percentage points; 95% confidence interval, -18.6 to -1.0%; P=0.03). A similar treatment effect was observed across nine prespecified subgroups (heterogeneity chi-square test, 12.21; P=0.79). Kaplan-Meier curves showed an early separation of the two treatment groups that began 3 hours after randomization and persisted until 30 days after randomization (log-rank chi-square test, 5.70; P=0.02). The median prothrombin-time ratio was lower in the plasma group than in the standard-care group (1.2 [interquartile range, 1.1 to 1.4] vs. 1.3 [interquartile range, 1.1 to 1.6], P<0.001) after the patients' arrival at the trauma center. No significant differences between the two groups were noted with respect to multiorgan failure, acute lung injury-acute respiratory distress syndrome, nosocomial infections, or allergic or transfusion-related reactions.

CONCLUSIONS: In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation.

(Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).

J Trauma Acute Care Surg. 2018 Jun;84(6S Suppl 1):S89-S92

# Staff officers as blood suppliers: effects of repeated donations and autologous reinfusion of untransfused units.

Strandenes G, Sivertsen J, Eliassen H, Braathen H, Hervig T

BACKGROUND: Limited blood inventory and resupply chains in combat settings can result in preventable deaths from traumatic hemorrhage. One way of mitigating this could be to establish donor pools where blood is collected in advance of high-risk missions and then reinfused back to the donor if not needed to treat casualties.

METHODS: Four hundred fifty milliliters plus 56 mL of blood was collected, rested for 2 hours in room temperature, and stored at 4°C. The blood was reinfused 22 to 24 hours after donation and the donor observed for adverse reactions. Samples were collected before and 20 minutes after each donation for hematology, immunoglobulin G, ferritin, C-reactive protein, total protein, lactate dehydrogenase, bilirubin, haptoglobin, and activated partial thromboplastin time.

RESULTS: Nine participants went through a total of 36 donation and reinfusion procedures. Four donors participated in five rounds, two in four rounds, two in three rounds, and one in two rounds. A significant drop was seen in hemoglobin (14.6 ± 0.9 to 13.9 ± 0.9) and ferritin (179 ± 70 to 149 ± 78) from before the first donation to after the last reinfusion (p < 0.05). Other parameters were unaffected.

CONCLUSION: This small pilot study suggests that repeated donations and reinfusions may be both feasible and safe. Blood collected in this way should be labeled with the donor's full name and social security number (or similar) and the identity visually verified by the donor immediately before both donation and reinfusion. To further reduce risk, this form of donation should be restricted to scenarios where there is no other option for making blood available.

LEVEL OF EVIDENCE: Therapeutic/Care management study, level V.

Injury. 2018 May;49(5):903-910

# Early transfusion on battlefield before admission to role 2: a preliminary observational study during “Barkhane” operations in Sahel.

Vitalis V, Carfantan C, Montcriol A, Peyrefitte S, Luft A, Pouget T, Sailliol A, Ausset S, Meaudre E, Bordes J

INTRODUCTION: Haemorrage is the leading cause of death after combat related injuries and bleeding management is the cornerstone of management of these casualties. French armed forces are deployed in Barkhane operation in the Sahel-Saharan Strip who represents an immense area. Since this constraint implies evacuation times beyond doctrinal timelines, an institutional decision has been made to deploy blood products on the battlefield and transfuse casualties before role 2 admission if indicated. The purpose of this study was to evaluate the transfusion practices on battlefield during the first year following the implementation of this policy.

MATERIALS AND METHODS: Prospective collection of data about combat related casualties categorized alpha evacuated to a role 2. Battlefield transfusion was defined as any transfusion of blood product (red blood cells, plasma, whole blood) performed by role 1 or Medevac team before admission at a role 2. Patients' characteristics, battlefield transfusions' characteristics and complications were analysed.

RESULTS: During the one year study, a total of 29 alpha casualties were included during the period study. Twenty-eight could be analysed, 7/28 (25%) being transfused on battlefield, representing a total of 22 transfusion episodes. The most frequently blood product transfused was French lyophilized plasma (FLYP). Most of transfusion episodes occurred during medevac. Compared to non-battlefield transfused casualties, battlefield transfused casualties suffered more wounded anatomical regions (median number of 3 versus 2, p = 0.04), had a higher injury severity score (median ISS of 45 versus 25, p = 0,01) and were more often transfused at role 2, received more plasma units and whole blood units. There was no difference in evacuation time to role 2 between patients transfused on battlefield and non-transfused patients. There was no complication related to battlefield transfusions. Blood products transfusion onset on battlefield ranged from 75 min to 192 min after injury.

CONCLUSION: Battlefield transfusion for combat-related casualties is a logistical challenge. Our study showed that such a program is feasible even in an extended area as Sahel-Saharan Strip operation theatre and reduces time to first blood product transfusion for alpha casualties. FLYP is the first line blood product on the battlefield.

#### FLUID RESUSCITATION

Sci Rep. 2018 Aug 1;8(1):11567

# Synthetic colloid resuscitation in severely injured patients: analysis of a nationwide trauma registry (TraumaRegister DGU).

Hilbert-Carius P, Schwarzkopf D, Reinhart K, Hartog C, Lefering R, Bernhard M, Struck M

The purpose of this study was to investigate the efficacy and safety of synthetic colloid resuscitation among severely injured patients. Fluid resuscitation of trauma patients of a nationwide trauma registry was analysed between 2002 and 2015. Effects of synthetic colloid resuscitation in the pre-hospital setting and emergency department on renal failure, renal replacement therapy and multiple organ failure were analysed among patients with ≥2 days intensive care unit stay, and in-hospital mortality was analysed among all patients. 48,484 patients with mean age of 49 years and mean injury severity score of 23 points were included; 72.3% were male and 95.5% had blunt trauma. Risk-adjusted analyses revealed that patients receiving >1,000 ml synthetic colloids experienced an increase of renal failure and renal replacement therapy rates (OR 1.42 and 1.32, respectively, both p ≤ 0.006). Any synthetic colloid use was associated with an increased risk of multiple organ failure (p < 0.001), but there was no effect on hospital mortality (p = 0.594). Between 2002 and 2015 usage of synthetic colloids dropped, likewise did total fluid intake and usage of blood products. The data from this analysis suggests that synthetic colloid resuscitation provides no beneficial effects and might be harmful in patients with severe trauma.

J Emerg Trauma Shock. 2018 Jan-Mar;11(1):15-24

# 7.5% NaCI resuscitation leads to abnormal clot fibrinolysis after severe hemorrhagic shock and its correction with 7.5% NaCI adenosine, lidocaine, and Mg².

Letson H, Dobson G

Background: Hyperfibrinolysis is a common complication of hemorrhagic shock. Our aim was to examine the effect of small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ (ALM) on fibrinolysis in the rat model of hemorrhagic shock.

Methods: Rats were anesthetized and randomly assigned to one of four groups: (1) baseline, (2) shock, (3) 7.5% NaCl controls, and (4) 7.5% NaCl ALM. Animals were bled for 20 min (42% blood loss) and left in shock for 60 min before resuscitation with 0.3 ml intravenous bolus 7.5% NaCl ± ALM. Rats were sacrificed at 5, 10, 15, 30, and 60 min for rotation thromboelastometry and 15 and 60 min for ELISA analyses.

Results: After hemorrhagic shock, 7.5% NaCl failed to resuscitate and exacerbated coagulopathy and fibrinolysis. At 15 and 60 min, the activation as extrinsically-activated test using tissue factor (EXTEM) with aprotinin to inhibit fibrinolysis (APTEM) test showed little or no correction of fibrinolysis, indicating a plasmin-independent fibrinolysis. Clots also had ~ 60% lower fibrinogen (fibrin-based EXTEM activated test with platelet inhibitor cytochalasin D A10) and 36%-50% reduced fibrinogen-to-platelet ratio (11%-14% vs. 22% baseline). In contrast, 7.5% NaCl ALM resuscitated mean arterial pressure and attenuated hyperfibrinolysis and coagulopathy by 15 min. Correction was associated with lower plasma tissue factor, higher plasminogen activator inhibitor-1, and lower D-dimers (5% of controls at 60 min). Platelet selectin fell to undetectable levels in ALM animals, which may imply improved endothelial and platelet function during resuscitation.

Conclusions: Small-volume 7.5% NaCl resuscitation exacerbated coagulopathy and fibrinolysis that was not corrected by APTEM test. Fibrinolysis appears to be associated with altered fibrin structure during early clot formation and elongation. In contrast, 7.5% NaCl ALM rapidly corrected both coagulopathy and hyperfibrinolysis.

BMJ Open. 2018 Jan 23;8(1):e019627. doi: 10.1136/bmjopen-2017-019627.

# What fluids are given during air ambulance treatment of patients with trauma in the UK, and what might this mean for the future? Results from the RESCUER observational cohort study.

Naumann D, Hancox J, Raitt J, Smith I, Crombie N, Doughty H, Perkins G, Midwinter M; RESCUER Collaborators.

Collaborators: Evans D, Conway J, Leech C, Lewis S, Church N, Mickwitz C, Pountney A, Bell F, Shewan J, Hyde P, Eddie M, Walker M, Hindson R, Wilson A, Elms S, Hood C, Blackham J, Grier S, Brown V, Irwin R, Clarke N, Corfield A, Cadman A, Evans D, Conway J, Leech C, Lewis S, Church N, Mickwitz C, Pountney A, Bell F, Shewan J, Hyde P, Eddie M, Walker M, Hindson R, Wilson A, Elms S, Hood C, Blackham J, Grier S, Brown V, Irwin R, Clarke N, Corfield A, Cadman A.

OBJECTIVES: We investigated how often intravenous fluids have been delivered during physician-led prehospital treatment of patients with hypotensive trauma in the UK and which fluids were given. These data were used to estimate the potential national requirement for prehospital blood products (PHBP) if evidence from ongoing trials were to report clinical superiority.

SETTING: The Regional Exploration of Standard Care during Evacuation Resuscitation (RESCUER) retrospective observational study was a collaboration between 11 UK air ambulance services. Each was invited to provide up to 5 years of data and total number of taskings during the same period.

PARTICIPANTS: Patients with hypotensive trauma (systolic blood pressure <90 mm Hg or absent radial pulse) attended by a doctor.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the number of patients with hypotensive trauma given prehospital fluids. Secondary outcomes were types and volumes of fluids. These data were combined with published data to estimate potential national eligibility for PHBP.

RESULTS: Of 29 037 taskings, 729 (2.5%) were for patients with hypotensive trauma attended by a physician. Half were aged 21-50 years; 73.4% were male. A total of 537 out of 729 (73.7%) were given fluids. Five hundred and ten patients were given a single type of fluid; 27 received >1 type. The most common fluid was 0.9% saline, given to 486/537 (90.5%) of patients who received fluids, at a median volume of 750 (IQR 300-1500) mL. Three per cent of patients received PHBP. Estimated projections for patients eligible for PHBP at these 11 services and in the whole UK were 313 and 794 patients per year, respectively.

CONCLUSIONS: One in 40 air ambulance taskings were manned by physicians to retrievepatients with hypotensive trauma. The most common fluid delivered was 0.9% saline. If evidence justifies universal provision of PHBP, approximately 800 patients/year would be eligible in the UK, based on our data combined with others published. Prospective investigations are required to confirm or adjust these estimations.