Evaluation of a portable, lightweight modular system to deliver high inspired oxygen to trauma casualties without the use of pressurised cylinders.

INTRODUCTION: Administering supplemental oxygen is a standard of care for trauma casualties to minimise the deleterious effects of hypoxaemia. Forward deployment of oxygen using pressurised cylinders is challenging, for example, logistics (weight and finite resource) and environmental risk (fire and explosion). Oxygen concentrators may overcome these challenges. Although previous studies successfully demonstrated fractional inspired oxygen (FiO2) >0.8 using oxygen concentrators and ventilators, the systems did not fulfil the size, weight and power requirements of agile military medical units. This study evaluated whether a modular system of commercially available clinical devices could supply high FiO2 to either ventilated or spontaneously breathing casualties. METHODS: As a proof of principle, we configured an Inogen One G5 oxygen concentrator, Ventway Sparrow ventilator and Wenoll rebreather system to ventilate a simulated lung (tidal volume 500 mL). Casualty oxygen consumption (gas withdrawal inspiratory limb) and carbon dioxide (CO2) production (CO2 added expiratory limb) were simulated (respiratory quotient of 0.7-0.8). Three circuit configurations were evaluated: open (supplementary oxygen introduced into air inlet of ventilator); semiclosed (ventilator replaces rebreather bag of Wenoll, oxygen connected to either ventilator or Wenoll); and semiclosed with reservoir tubing (addition of 'deadspace' tube between ventilator patient circuit and Wenoll). Data presented as mean and 95% reference range. RESULTS: There were modest increases in FiO2 with increasing Inogen settings in 'open' configuration 0.23 (0.23-0.24) and 0.30 (0.28-0.32) (Inogen output 420 and 1260 mL/min, respectively). With the 'semiclosed' configuration and oxygen added directly into rebreather circuit, FiO2 increased to 0.36 (0.36-0.37). The addition of the 'reservoir tubing' elevated FiO2 to 0.78 (0.71-0.85). FiO2 remained stable over a 4-hour evaluation period. Fractional inspired carbon dioxide CO2 increased over time, reaching 0.005 after 170 (157-182) min. CONCLUSION: Combining existing lightweight devices can deliver high (>0.8) FiO2 and offers a potential solution for the forward deployment of oxygen without needing pressurised cylinders.

Breaking barriers in trauma research: A narrative review of opportunities to leverage veterinary trauma for accelerated translation to clinical solutions for pets and people.

Trauma is a common cause of morbidity and mortality in humans and companion animals. Recent efforts in procedural development, training, quality systems, data collection, and research have positively impacted patient outcomes; however, significant unmet need still exists. Coordinated efforts by collaborative, translational, multidisciplinary teams to advance trauma care and improve outcomes have the potential to benefit both human and veterinary patient populations. Strategic use of veterinary clinical trials informed by expertise along the research spectrum (i.e., benchtop discovery, applied science and engineering, large laboratory animal models, clinical veterinary studies, and human randomized trials) can lead to increased therapeutic options for animals while accelerating and enhancing translation by providing early data to reduce the cost and the risk of failed human clinical trials. Active topics of collaboration across the translational continuum include advancements in resuscitation (including austere environments), acute traumatic coagulopathy, trauma-induced coagulopathy, traumatic brain injury, systems biology, and trauma immunology. Mechanisms to improve funding and support innovative team science approaches to current problems in trauma care can accelerate needed, sustainable, and impactful progress in the field. This review article summarizes our current understanding of veterinary and human trauma, thereby identifying knowledge gaps and opportunities for collaborative, translational research to improve multispecies outcomes. This translational trauma group of MDs, PhDs, and DVMs posit that a common understanding of injury patterns and resulting cellular dysregulation in humans and companion animals has the potential to accelerate translation of research findings into clinical solutions.

Resuscitation with whole blood or blood components improves survival and lessens the pathophysiological burden of trauma and haemorrhagic shock in a pre-clinical porcine model.

PURPOSE: In military trauma, disaster medicine, and casualties injured in remote locations, times to advanced medical and surgical treatment are often prolonged, potentially reducing survival and increasing morbidity. Since resuscitation with blood/blood components improves survival over short pre-surgical times, this study aimed to evaluate the quality of resuscitation afforded by blood/blood products or crystalloid resuscitation over extended 'pre-hospital' timelines in a porcine model of militarily relevant traumatic haemorrhagic shock. METHODS: This study underwent local ethical review and was done under the authority of Animals (Scientific Procedures) Act 1986. Forty-five terminally anaesthetised pigs received a soft tissue injury to the right thigh, haemorrhage (30% blood volume and a Grade IV liver injury) and fluid resuscitation initiated 30 min later [Group 1 (no fluid); 2 (0.9% saline); 3 (1:1 packed red blood cells:plasma); 4 (fresh whole blood); or 5 (plasma)]. Fluid (3 ml/kg bolus) was administered during the resuscitation period (maximum duration 450 min) when the systolic blood pressure fell below 80 mmHg. Surviving animals were culled with an overdose of anaesthetic. RESULTS: Survival time was significantly shorter for Group 1 compared to the other groups (P < 0.05). Despite the same triggers for resuscitation when compared to blood/blood components, saline was associated with a shorter survival time (P = 0.145), greater pathophysiological burden and significantly greater resuscitation fluid volume (P < 0.0001). CONCLUSION: When times to advanced medical care are prolonged, resuscitation with blood/blood components is recommended over saline due to the superior quality and stability of resuscitation achieved, which are likely to lead to improved patient outcomes.

Single and Multiplex Immunohistochemistry to Detect Platelets and Neutrophils in Rat and Porcine Tissues.

Platelet-neutrophil complexes (PNCs) occur during the inflammatory response to trauma and infections, and their interactions enable cell activation that can lead to tissue destruction. The ability to identify the accumulation and tissue localisation of PNCs is necessary to further understand their role in the organs associated with blast-induced shock wave trauma. Relevant experimental lung injury models often utilise pigs and rats, species for which immunohistochemistry protocols to detect platelets and neutrophils have yet to be established. Therefore, monoplex and multiplex immunohistochemistry protocols were established to evaluate the application of 22 commercially available antibodies to detect platelet (nine rat and five pig) and/or neutrophil (four rat and six pig) antigens identified as having potential selectivity for porcine or rat tissue, using lung and liver sections taken from models of polytrauma, including blast lung injury. Of the antibodies evaluated, one antibody was able to detect rat neutrophil elastase (on frozen and formalin-fixed paraffin embedded (FFPE) sections), and one antibody was successful in detecting rat CD61 (frozen sections only); whilst one antibody was able to detect porcine MPO (frozen and FFPE sections) and antibodies, targeting CD42b or CD49b antigens, were able to detect porcine platelets (frozen and FFPE and frozen, respectively). Staining procedures for platelet and neutrophil antigens were also successful in detecting the presence of PNCs in both rat and porcine tissue. We have, therefore, established protocols to allow for the detection of PNCs in lung and liver sections from porcine and rat models of trauma, which we anticipate should be of value to others interested in investigating these cell types in these species.

Quantification of stroke volume in a simulated healthy volunteer model of traumatic haemorrhage; a comparison of two non-invasive monitoring devices using error grid analysis alongside traditional measures of agreement.

INTRODUCTION: Haemorrhage is a leading cause of death following traumatic injury and the early detection of hypovolaemia is critical to effective management. However, accurate assessment of circulating blood volume is challenging when using traditional vital signs such as blood pressure. We conducted a study to compare the stroke volume (SV) recorded using two devices, trans-thoracic electrical bioimpedance (TEB) and supra-sternal Doppler (SSD), against a reference standard using trans- thoracic echocardiography (TTE). METHODS: A lower body negative pressure (LBNP) model was used to simulate hypovolaemia and in half of the study sessions lower limb tourniquets were applied as these are common in military practice and can potentially affect some haemodynamic monitoring systems. In order to provide a clinically relevant comparison we constructed an error grid alongside more traditional measures of agreement. RESULTS: 21 healthy volunteers aged 18-40 were enrolled and underwent 2 sessions of LBNP, with and without lower limb tourniquets. With respect to absolute SV values Bland Altman analysis showed significant bias in both non-tourniquet and tourniquet strands for TEB (-42.5 / -49.6 ml), rendering further analysis impossible. For SSD bias was minimal but percentage error was unacceptably high (35% / 48%). Degree of agreement for dynamic change in SV, assessed using 4 quadrant plots showed a seemingly acceptable concordance rate for both TEB (86% / 93%) and SSD (90% / 91%). However, when results were plotted on an error grid, constructed based on expert clinical opinion, a significant minority of measurement errors were identified that had potential to lead to moderate or severe patient harm. CONCLUSION: Thoracic bioimpedance and suprasternal Doppler both demonstrated measurement errors that had the potential to lead to clinical harm and caution should be applied in interpreting the results in the detection of early hypovolaemia following traumatic injury.

Effect of parachute delivery on red blood cell (RBC) and plasma quality measures of blood for transfusion.

BACKGROUND: Parachute airdrop offers a rapid transfusion supply option for humanitarian aid and military support. However, its impact on longer-term RBC survival is undocumented. This study aimed to determine post-drop quality of RBCs in concentrates (RCC), and both RBCs and plasma in whole blood (WB) during subsequent storage. STUDY DESIGN AND METHODS: Twenty-two units of leucodepleted RCC in saline, adenine, glucose, mannitol (SAGM) and 22 units of nonclinical issue WB were randomly allocated for air transportation, parachute drop, and subsequent storage (parachute), or simply storage under identical conventional conditions (4 ± 2°C) (control). All blood products were 6-8 days post-donation. Parachute units were packed into Credo Cubes, (Series 4, 16 L) inside a PeliCase (Peli 0350) and rigged as parachute delivery packs. Packs underwent a 4-h tactical flight (C130 aircraft), then parachuted from 250 to 400 ft before ground recovery. The units were sampled aseptically before and after airdrop at weekly intervals. A range of assays quantified the RBC storage lesion and coagulation parameters. RESULTS: Blood units were maintained at 2-6°C and recovered intact after recorded ground impacts of 341-1038 m s-2 . All units showed a classical RBC storage lesion and increased RBC microparticles during 42 days of storage. Fibrinogen and clotting factors decreased in WB during storage. Nevertheless, no significant difference was observed between Control and Parachute groups. Air transportation and parachute delivery onto land did not adversely affect, or shorten, the shelf life of fresh RBCs or WB. DISCUSSION: Appropriately packaged aerial delivery by parachute can be successfully used for blood supply.

A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield.

BACKGROUND: Acute trauma coagulopathy (ATC) after military trauma has not been comprehensively studied. ATC is defined as a prolonged prothrombin time ratio (PTr) or reduced clot amplitude (A5) in viscoelastic testing. Compared to civilian trauma, military trauma has more injuries from explosions and gunshot wounds (GSWs), potentially leading to a different pathophysiology for traumatic coagulopathy. This study aimed to characterize military ATC on admission to a military hospital in Afghanistan and to explore any differences due to the mechanism of injury. METHODS: Severely injured military casualties were enrolled in the study. Blood samples were taken on admission and after routine testing, waste plasma was prepared, frozen, and transported to the United Kingdom for in-depth hemostatic analysis. RESULTS: Seventy-seven percent of casualties had ATC defined by a PTr greater than 1.2 and 19% when defined by rotational thromboelastometry (ROTEM) A5 less than 36 mm. Coagulation factor depletion correlated with degree of shock, particularly factor V (p < 0.01), factor X (p < 0.01), and fibrinogen levels (p < 0.01). Thrombin generation was well preserved. Fibrinolytic biomarkers were raised correlating with the degree of shock (p < 0.01), and 8% of casualties had hyperfibrinolysis on ROTEM analysis. Plasmin-antiplasmin complexes (p < 0.01) and d-dimer levels (p = 0.01) were higher and clot firmness lower (p = 0.02) in those injured by explosion compared to GSW's. CONCLUSIONS: ATC was present and correlated with shock, similar to civilian trauma. Thrombin generation remained adequate. Fibrinogen and factor V levels were disproportionately low but still sufficient to allow clot formation. Fibrinolysis is a key feature, probably due to a tissue plasminogen activator surge at the time of injury. Blast injuries are associated with a greater activation of fibrinolysis than GSWs.

Flow Cytometric Analysis of Hematopoietic Populations in Rat Bone Marrow. Impact of Trauma and Hemorrhagic Shock.

Severe injury and hemorrhagic shock (HS) result in multiple changes to hematopoietic differentiation, which contribute to the development of immunosuppression and multiple organ failure (MOF). Understanding the changes that take place during the acute injury phase may help predict which patients will develop MOF and provide potential targets for therapy. Obtaining bone marrow from humans during the acute injury phase is difficult so published data are largely derived from peripheral blood samples, which infer bone marrow changes that reflect the sustained inflammatory response. This preliminary and opportunistic study investigated leucopoietic changes in rat bone marrow 6 h following traumatic injury and HS. Terminally anesthetized male Porton Wistar rats were allocated randomly to receive a sham operation (cannulation with no injury) or femoral fracture and HS. Bone marrow cells were flushed from rat femurs and immunophenotypically stained with specific antibody panels for lymphoid (CD45R, CD127, CD90, and IgM) or myeloid (CD11b, CD45, and RP-1) lineages. Subsequently, cell populations were fluorescence-activated cell sorted for morphological assessment. Stage-specific cell populations were identified using a limited number of antibodies, and leucopoietic changes were determined 6 h following trauma and HS. Myeloid subpopulations could be identified by varying levels CD11b expression, CD45, and RP-1. Trauma and HS resulted in a significant reduction in total CD11b + myeloid cells including both immature (RP-1(-)) and mature (RP-1+) granulocytes. Multiple B-cell lymphoid subsets were identified. The total percentage of CD90+ subsets remained unchanged following trauma and HS, but there was a reduction in the numbers of maturing CD90(-) cells suggesting movement into the periphery. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Haemostatic Changes in Five Patients Infected with Ebola Virus.

Knowledge on haemostatic changes in humans infected with Ebola virus is limited due to safety concerns and access to patient samples. Ethical approval was obtained to collect plasma samples from patients in Sierra Leone infected with Ebola virus over time and samples were analysed for clotting time, fibrinogen, and D-dimer levels. Plasma from healthy volunteers was also collected by two methods to determine effect of centrifugation on test results as blood collected in Sierra Leone was not centrifuged. Collecting plasma without centrifugation only affected D-dimer values. Patients with Ebola virus disease had higher PT and APTT and D-dimer values than healthy humans with plasma collected in the same manner. Fibrinogen levels in patients with Ebola virus disease were normal or lower than values measured in healthy people. Clotting times and D-dimer levels were elevated during infection with Ebola virus but return to normal over time in patients that survived and therefore could be considered prognostic. Informative data can be obtained from plasma collected without centrifugation which could improve patient monitoring in hazardous environments.

Closed chest compressions reduce survival in an animal model of haemorrhage-induced traumatic cardiac arrest.

Closed chest compressions (CCC) are recommended for medical cardiac arrest, but there is little evidence to support their inclusion for traumatic cardiac arrest (TCA). This laboratory study evaluated CCC following haemorrhage-induced TCA and whether resuscitation with blood improved survival compared to saline. The study was conducted with the authority of UK Animals (Scientific Procedures) Act 1986 (received institutional ethical approval and a Home Office Licence) using 39 terminally anesthetised, instrumented, juvenile Large White pigs. Following baseline measurements, animals underwent captive bolt injury to the right thigh and controlled haemorrhage (30% blood volume). Sixty minutes later there was a further haemorrhage to a MAP of 20 mmHg. The randomised resuscitation protocol was initiated within 5 min: CCC (Group 1); IV whole blood (Group 2); IV 0.9% saline (Group 3); IV whole blood + CCC (Group 4); and IV saline + CCC (Group 5). Fluid was administered as 3 × 10 ml/kg boluses using the Belmont® Rapid Infuser. The LUCAS™ II Chest Compression System delivered CCC. Primary Outcome was attainment of return of spontaneous circulation (ROSC MAP ≥ 50 mmHg) at Study End (fifteen minutes post-resuscitation) and secondary outcomes included haemodynamics. Mortality (MAP≤10 mmHg) was significantly higher in Group 1 compared to Groups 2 and 3 (P < 0.0001). Resuscitation with whole blood was significantly better than saline (P = 0.0069), no animals in Group 3 attained ROSC. The addition of chest compressions to fluid resuscitation resulted in a significantly worse outcome with saline resuscitation (P = 0.0023) but not with whole blood (P = 0.4411). Cardiovascular variables at the end of the Resuscitation Phase and Study End were significantly worse for Group 5 compared to Group 3. Some significant differences were present at the end of the Resuscitation Phase for Group 4 versus Group 2 but these differences were no longer present by Study End. CCC were associated with increased mortality and compromised haemodynamics compared to intravenous fluid resuscitation. Whole blood resuscitation was better than saline.

Trauma Hemostasis and Oxygenation Research Network position paper on the role of hypotensive resuscitation as part of remote damage control resuscitation.

The Trauma Hemostasis and Oxygenation Research (THOR) Network has developed a consensus statement on the role of permissive hypotension in remote damage control resuscitation (RDCR). A summary of the evidence on permissive hypotension follows the THOR Network position on the topic. In RDCR, the burden of time in the care of the patients suffering from noncompressible hemorrhage affects outcomes. Despite the lack of published evidence, and based on clinical experience and expertise, it is the THOR Network's opinion that the increase in prehospital time leads to an increased burden of shock, which poses a greater risk to the patient than the risk of rebleeding due to slightly increased blood pressure, especially when blood products are available as part of prehospital resuscitation.The THOR Network's consensus statement is, "In a casualty with life-threatening hemorrhage, shock should be reversed as soon as possible using a blood-based HR fluid. Whole blood is preferred to blood components. As a part of this HR, the initial systolic blood pressure target should be 100 mm Hg. In RDCR, it is vital for higher echelon care providers to receive a casualty with sufficient physiologic reserve to survive definitive surgical hemostasis and aggressive resuscitation. The combined use of blood-based resuscitation and limiting systolic blood pressure is believed to be effective in promoting hemostasis and reversing shock".

Microcirculatory perfusion shows wide inter-individual variation and is important in determining shock reversal during resuscitation in a porcine experimental model of complex traumatic hemorrhagic shock.

BACKGROUND: Traumatic hemorrhagic shock (THS) is a leading cause of preventable death following severe traumatic injury. Resuscitation of THS is typically targeted at blood pressure, but the effects of such a strategy on systemic and microcirculatory flow remains unclear. Failure to restore microcirculatory perfusion has been shown to lead to poor outcomes in experimental and clinical studies. Systemic and microcirculatory variables were examined in a porcine model of complex THS, in order to investigate inter-individual variations in flow and the effect of microcirculatory perfusion on reversal of the shock state. METHODS: Baseline standard microcirculatory variables were obtained for 22 large white pigs using sublingual incident dark field (IDF) video-microscopy. All animals were subjected to a standardised hind-limb injury followed by a controlled haemorrhage of approximately 35 % of blood volume (shock phase). This was followed by 60 min of fluid resuscitation with either 0.9 % saline or component blood products and a target SBP of 80 mmHg (early resuscitation phase). All animals were then given blood products to a target SBP of 110 mmHg for 120 min (mid-resuscitation phase), and a further 100 min (late resuscitation phase). IDF readings were obtained at the midpoint of each of these phases. Cardiac output was measured using a pulmonary artery catheter. Animals were divided into above average (A) and below average (B) perfused vessel density (PVD) groups based on the lowest recorded PVD measurement taken during the shock and early resuscitation phases. RESULTS: There was minimal inter-individual variation in blood pressure but wide variation of both systemic and microcirculatory flow variables during resuscitation. During shock and early resuscitation, group A (n = 10) had a mean PVD of 10.5 (SD ± 2.5) mm/mm(2) and group B (n = 12) 5.5 (SD ± 4.1) mm/mm(2). During the later resuscitation phases, group A maintained a significantly higher PVD than group B. Group A initially had a higher cardiac output, but the difference between the groups narrowed as resuscitation progressed. At the end of resuscitation, group A had significantly lower plasma lactate, higher lactate clearance, lower standard base deficit and smaller mixed venous-arterial CO2 gradient. There was no significant difference in blood pressure between the two groups at any stage. CONCLUSION: There was a wide variation in both macro- and microcirculatory flow variables in this pressure-targeted experimental model of THS resuscitation. Early changes in microvascular perfusion appear to be key determinants in the reversal of the shock state during resuscitation. Microcirculatory flow parameters may be more reliable markers of physiological insult than pressure-based parameters and are potential targets for goal-directed resuscitation.

The Cytocam video microscope. A new method for visualising the microcirculation using Incident Dark Field technology.

UNLABELLED: We report a new microcirculatory assessment device, the Braedius Cytocam, an Incident Dark Field (IDF) video microscope, and compare it with a precursor device utilising side stream dark field (SDF) imaging. METHODS: Time matched measurements were made with both devices from the sublingual microcirculation of pigs subjected to traumatic injury and hemorrhagic shock at baseline and during a shock phase. Images were analysed for vessel density, microcirculatory flow and image quality. RESULTS: There were no differences in density or flow data recorded from the two devices at baseline [TVD IDF 14.2 ± 2.4/TVD SDF 13.2 ± 2.0, p 0.17] [MFI IDF 3 (2.8-3.0)/MFI SDF 3 (2.9-3.0), p 0.36] or during the shock state [TVD IDF 11.64 ± 3.3/TVD SDF 11.4 ± 4.0 p = 0.98] [MFI IDF 1.9 (0.6-2.7)/MFI SDF 1.7 (0.3-2.6) p 0.55]. Bland and Altman analysis showed no evidence of significant bias. Vessel contrast was significantly better with the IDF device for both capillaries [17.1 ± 3.9 (IDF) v 3.4 ± 3.6 (SDF), p = 0.0006] and venules [36.1 ± 11.4 (IDF) v 26.4 ± 7.1 (SDF) p 0.014] CONCLUSION: The Braedius Cytocam showed comparable vessel detection to a precursor device during both baseline and low flow (shock) states.

Blast Wave Exposure to the Extremities Causes Endothelial Activation and Damage.

Extremity injury is a significant burden to those injured in explosive incidents and local ischaemia can result in poor functionality in salvaged limbs. This study examined whether blast injury to a limb resulted in a change in endothelial phenotype leading to changes to the surrounding tissue.The hind limbs of terminally anaesthetized rabbits were subjected to one of four blast exposures (high, medium, low, or no blast). Blood samples were analyzed for circulating endothelial cells pre-injury and at 1, 6, and 11 h postinjury as well as analysis for endothelial activation pre-injury and at 1, 6, and 12  h postinjury. Post-mortem tissue (12  h post-injury) was analysed for both protein and mRNA expression and also for histopathology. The high blast group had significantly elevated levels of circulating endothelial cells 6  h postinjury. This group also had significantly elevated tissue mRNA expression of IL-6, E-selection, TNF-α, HIF-1, thrombomodulin, and PDGF. There was a significant correlation between blast dose and the degree of tissue pathology (hemorrhage, neutrophil infiltrate, and oedema) with the worst scores in the high blast group. This study has demonstrated that blast injury can activate the endothelium and in some cases cause damage that in turn leads to pathological changes in the surrounding tissue. For the casualty injured by an explosion the damaging effects of hemorrhage and shock could be exacerbated by blast injury and vice versa so that even low levels of blast become damaging, all of which could affect tissue functionality and long-term outcomes.

Evaluation of Prehospital Blood Products to Attenuate Acute Coagulopathy of Trauma in a Model of Severe Injury and Shock in Anesthetized Pigs.

Acute trauma coagulopathy (ATC) is seen in 30% to 40% of severely injured casualties. Early use of blood products attenuates ATC, but the timing for optimal effect is unknown. Emergent clinical practice has started prehospital deployment of blood products (combined packed red blood cells and fresh frozen plasma [PRBCs:FFP], and alternatively PRBCs alone), but this is associated with significant logistical burden and some clinical risk. It is therefore imperative to establish whether prehospital use of blood products is likely to confer benefit. This study compared the potential impact of prehospital resuscitation with (PRBCs:FFP 1:1 ratio) versus PRBCs alone versus 0.9% saline (standard of care) in a model of severe injury. Twenty-four terminally anesthetised Large White pigs received controlled soft tissue injury and controlled hemorrhage (35% blood volume) followed by a 30-min shock phase. The animals were allocated randomly to one of three treatment groups during a 60-min prehospital evacuation phase: hypotensive resuscitation (target systolic arterial pressure 80 mmHg) using either 0.9% saline (group 1, n = 9), PRBCs:FFP (group 2, n = 9), or PRBCs alone (group 3, n = 6). Following this phase, an in-hospital phase involving resuscitation to a normotensive target (110 mmHg systolic arterial blood pressure) using PRBCs:FFP was performed in all groups. There was no mortality in any group. A coagulopathy developed in group 1 (significant increase in clot initiation and dynamics shown by TEG [thromboelastography] R and K times) that persisted for 60 to 90 min into the in-hospital phase. The coagulopathy was significantly attenuated in groups 2 and 3 (P = 0.025 R time and P = 0.035 K time), which were not significantly different from each other. Finally, the volumes of resuscitation fluid required was significantly greater in group 1 compared with groups 2 and 3 (P = 0.0067) (2.8 ± 0.3 vs. 1.9 ± 0.2 and 1.8 ± 0.3 L, respectively). This difference was principally due to a greater volume of saline used in group 1 (P = 0.001). Prehospital PRBCs:FFP or PRBCs alone may therefore attenuate ATC. Furthermore, the amount of crystalloid may be reduced with potential benefit of reducing the extravasation effect and later tissue edema.

Endothelial activation and chemoattractant expression are early processes in isolated blast brain injury.

Blast injuries are an increasing problem in military conflicts and terrorist incidents. Blast-induced traumatic brain injury has risen to prominence and represents a specific form of primary brain injury, with sufficiently different physical attributes (and possibly biological consequences) to be classified separately. There is increasing interest in the role of blast in initiating inflammatory responses, which may be linked to the pathological processes seen clinically. Terminally anaesthetised rats were exposed to a blast wave directed at the cranium, using a bench-top blast wave generator. Control animals were not exposed to blast. Animals were killed after 8 h, and the brains examined for evidence of an inflammatory response. Compared to controls, erythropoietin, endothelial integrins, ICAM and sVCAM, and the pro-inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1) were significantly elevated. Other pro-inflammatory cytokines, including MIP-1α, were also detectable, but levels did not permit accurate quantification. Six inflammatory genes examined by qRT-PCR exhibited a biologically significant increase in activity in the blast-exposed animals. These included genes supporting chemokines responsible for monocyte recruitment, including MCP-1, and chemokines influencing T cell movement. Brain injury is usually accompanied by pathological neuro-inflammation. This study shows that blast brain injury is no exception, and the data provide important mechanistic clues regarding the drivers of such inflammation. Whilst this effect alone is unlikely to be responsible for the totality of consequences of blast brain injury, it suggests a mechanism that may be priming the cerebral inflammatory response and rendering cerebral tissue more susceptible to the deleterious effects of systemic inflammatory reactions.

Combat Casualty Care research programme.

The Combat Casualty Care research programme is an integrated suite of projects designed to address Defence Medical Services' research needs for casualty care. The programme covers a broad spectrum of topics ranging from the pathophysiological and immunological impact of military relevant injuries to the effects of these disturbances on the response to early treatment. Dstl Porton Down has a long history of studying military injuries and has developed models, both in vivo and physical, to address the research needs. The work is conducted in close collaboration with clinical colleagues at the Royal Centre for Defence Medicine who have direct experience of the clinical issues faced by combat casualties and insights into the potential clinical implications of emerging strategies. This article reviews progress in research areas spanning forward resuscitation, with a particular focus on blast-related injuries, trauma coagulopathy, effects of drugs on the response to haemorrhage and deployed research. A significant 'value added' component has been the underpinning of higher degrees for seconded military clinicians at Dstl Porton Down who have made a valuable contribution to the overall programme.

The development of an experimental model of contaminated muscle injury in rabbits.

Extent of tissue trauma and contamination determine outcome in extremity injury. In contrast to fracture, osteomyelitis, and closed muscle injury studies, there are limited small animal models of extremity muscle trauma and contamination. To address this we developed a model of contaminated muscle injury in rabbits. Twenty-eight anesthetized New Zealand White rabbits underwent open controlled injury of the flexor carpi ulnaris (FCU). Twenty-two animals had subsequent contamination of the injured muscle with Staphylococcus aureus. All animals were sacrificed at 48 hours and the level of muscle injury and contamination determined by quantitative histological and microbiological analysis. A 1-kg mass dropped 300 mm onto the mobilized FCU resulted in localized necrosis of the muscle belly. Delivery of a mean challenge of 3.71 × 10(6) cfu/100 µL S aureus by droplet spread onto the injured muscle produced a muscle contamination of 8.79 × 10(6) cfu/g at 48 hours. Ipsilateral axillary lymph nodes demonstrated clinically significant activation. All animals had normal body temperature and hematological parameters throughout and blood and urinalysis culture at autopsy were negative for organisms. This model allows reproducible muscle injury and contamination with the organism ubiquitous to extremity wound infection at a level sufficient to allow quantitative assessment of subsequent wound care interventions without incurring systemic involvement.

Targeted resuscitation improves coagulation and outcome.

BACKGROUND: Acute trauma coagulopathy in seriously injured casualties may be initiated by tissue hypoperfusion. A targeted (or novel hybrid [NH]) resuscitation strategy was developed to overcome poor tissue oxygen delivery associated with prolonged hypotension. METHODS: Under the Animals (Scientific Procedures) Act 1986, terminally anesthetized large white pigs were divided into four groups (n = 6). Groups 1 and 2 received blast injury and 3 and 4 no blast (sham). All were given a controlled hemorrhage (35% blood volume) and an uncompressed grade IV liver injury. Five minutes later, all were resuscitated with 0.9% saline to a systolic arterial pressure (SAP) of 80 mm Hg. After 60 minutes, the NH groups (1 and 3) were resuscitated to a SAP (110 mm Hg), whereas hypotensive groups (2 and 4) continued with SAP 80 mm Hg for up to 8 hours from onset of resuscitation. RESULTS: Mean survival time was shorter in group 2 (258 minutes) compared with groups 1, 3, and 4 (452 minutes, 448 minutes, and 369 minutes). By the end of the study, hypotension was associated with a significantly greater prothrombin time (1.73 ± 0.10 and 1.87 ± 0.15 times presurgery, groups 2 and 4) compared with NH (1.44 ± 0.09 and 1.36 ± 0.06, groups 1 and 3, p = 0.001). Blast versus sham had no significant effect on prothrombin time (p = 0.56). Peak levels of interleukin 6 were significantly lower in NH groups. Arterial base excess was significantly lower with hypotension (-18.4 mmol/L ± 2.7 mmol/L and -12.1 mmol/L ± 3.2 mmol/L) versus NH (-3.7 mmol/L ± 2.8 mmol/L and -1.8 mmol/L ± 1.8 mmol/L, p = 0.0001). Hematocrit was not significantly different between groups (p = 0.16). CONCLUSION: Targeted resuscitation (NH) attenuates the development of acute trauma coagulopathy and systemic inflammation with improved tissue perfusion and reduced metabolic acidosis in a model of complex injury. This emphasizes the challenge of choosing a resuscitation strategy for trauma patients where the needs of tissue perfusion must be balanced against the risk of rebleeding during resuscitation.

Effect of acute traumatic brain injury on baroreflex function.

The integrity of the arterial baroreflex is central to cardiovascular homeostasis. There is evidence of altered cardiovascular regulation after acute traumatic brain injury (TBI). We hypothesized that arterial baroreflex is modified by acute TBI. An experimental study using 18 terminally anesthetized male Wistar rats weighing 240 to 260 g was undertaken at a university laboratory setting. Brain injury was induced using the lateral fluid percussion brain injury model. The fluid percussion device delivered an applied cortical pressure of 1.2 atm and 1.8 atm, producing mild and moderate TBI, respectively. Control animals underwent identical surgical procedures but no applied cortical pressure. Arterial baroreflex was assessed by determining the relationship between heart period (R - R interval) and systolic blood pressure using the modified phenylephrine pressor test adapted for the rat. The arterial baroreflex was tested before (Tcon), post-TBI, at 10 min (T10), and 30 min (T30). Analysis of baroreflex function after moderate TBI using repeated-measures analysis of variance revealed significant differences in baroreflex sensitivity (BRS) at T10 and T30 (F2,15 = 10.18; P = 0.005) compared with pre-TBI (weighted mean ± SD; Tcon, 0.39 ± 0.00 ms mmHg; T10, 0.85 ± 0.01 ms mmHg; T30, 0.81 ± 0.01 ms mmHg). The changes in BRS were not significant after mild TBI (P = 0.152). Repeated-measures analysis of variance comparing trends between the three groups indicated significant differences between the control and moderate TBI groups only (F2,15 = 6.26; P = 0.01). Acute TBI of moderate severity is associated with an early significant modification in arterial BRS. This is a key component of cardiovascular homeostasis. The clinical implications of this observation require further investigation.