Resuscitation Of Hemorrhagic Shock Research Articles

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation.

Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on tissue oxygenation following hemorrhage and resuscitation in specialized animal models that challenge their resuscitative capabilities. Pre-existing conditions that compromise the vasculature and end organs, such as the liver, may limit the effectiveness of resuscitation and exacerbate the toxicity of these molecules, which is an important but minimally explored therapeutic dimension. In this study, we compared the effective oxygen delivery of intermediate molecular weight PolyhHb (PolyhHb-B3; 500-750 kDa) to high molecular weight PolyhHb (PolyhHb-B4; 750 kDa-0.2 μm) for resuscitative effectiveness in guinea pig models subjected to hemorrhagic shock. We evaluated how the size of PolyhHb impacts hemodynamics and tissue oxygenation in normal guinea pigs and guinea pigs on an atherogenic diet. We observed that while PolyhHb-B3 and -B4 equivalently restore hemodynamic parameters of normal-dieted guinea pigs, high-fat-dieted guinea pigs resuscitated with PolyhHb-B4 have lower mean arterial pressures, impaired tissue oxygenation, and higher plasma lactate levels than those receiving PolyhHb-B3. We characterized the plasma of these animals following resuscitation and found that despite similar oxygen delivery kinetics, circulating PolyhHb-B3 and -B4 demonstrated a size-dependent increase in the plasma viscosity, consistent with impaired perfusion in the PolyhHb-B4 transfusion group. We conclude that intermediate-sized PolyhHbs (such as -B3) are ideal for further research given the effective resuscitation of hemorrhagic shock based on tissue oxygenation in hypercholesterolemic guinea pigs.

Sidestream dark field imaging and biomarker evaluation reveal minimal significant changes to the microcirculation and glycocalyx in a canine hemorrhagic shock model.

To investigate the effects of hemorrhagic shock and fresh whole blood resuscitation on the microcirculation and endothelial glycocalyx using sidestream dark field (SDF) imaging and plasma biomarkers. 8 purpose-bred dogs. Pressure-targeted hemorrhagic shock was induced in anesthetized dogs. SDF measurement of perfused boundary region and microcirculatory variables (RBC flow, total vessel density, and relative and absolute capillary blood volume), biomarker measurement (heparan sulfate, hyaluronan, VE-cadherin, and syndecan-1), mean arterial blood pressure, and cardiac output measurement were performed before anesthesia (TP0), after induction (TP1), after hemorrhagic shock (TP2), and after 50% retransfusion (TP3) and 100% retransfusion (TP4). At TP1, TP2, TP3, and TP4, mean arterial blood pressure was 74.25 ± 7.17 mm Hg, 49.50 ± 13.74 mm Hg, 63.50 ± 13.29 mm Hg, and 71.38 ± 8.77 mm Hg, and cardiac output was 2.57 ± 1.01 L/min, 0.8 ± 0.36 L/min, 1.81 ± 0.57 L/min, and 2.93 ± 1.22 L/min, respectively. Heparan sulfate, hyaluronan, syndecan-1, and VE-cadherin ranges were 24.80 to 77.72 ng/mL, 5.77 to 105.06 ng/mL, below detection to 1,545.69 pg/mL, and 0 to 2.52 ng/mL, respectively. Perfused boundary region, RBC flow, total vessel density, and relative and absolute capillary blood volume ranges were 1.75 to 2.68 µm, 89.6 to 584.5 µm/s, 51.7 to 1,914.3 mm/m2, 0.94 to 1.53 103 μm3, and 1.50 to 94.30 103 μm3, respectively. Heparan sulfate decreased significantly over time (P = .016). No significant differences were found for microcirculatory variables, perfused boundary regions, or other biomarkers. This was the first study to assess microvascular dysfunction and endothelial shedding in a canine hemorrhagic shock model using SDF microscopy (Glycocheck) and plasma biomarkers. Further studies are needed to determine clinical relevance.

Clinical Use of Canine Thawed Refrigerated Plasma: A Historical Case Series.

Thawed plasma (TP) refers to defrosted fresh frozen plasma stored refrigerated. TP is used in human medicine for the rapid provision of coagulation factors and resuscitation of haemorrhagic shock, but its use in dogs is poorly described. The objectives of this historical case series were to describe the reasons for TP transfusion, treatment outcomes, and adverse events associated with canine TP transfusions in a veterinary teaching hospital. We hypothesised that TP would be used most commonly for the treatment of haemorrhage secondary to anticoagulant rodenticide intoxication and trauma. Blood bank plasma transfusion logs were searched to identify dogs that received at least one unit of TP between December 2015 and June 2021. Briefly, 166 dogs received a total of 262 units of TP. Anticoagulant rodenticide intoxication (37/166, 22.3%) was the most common reason for transfusion, followed by traumatic haemorrhage (23, 13.9%) and spontaneous haemoperitoneum (22, 13.2%). The majority of dogs received one unit of TP (111/166, 67.1%) and pRBCs were commonly simultaneously transfused with TP (65, 39.2%). Severe prolongations of prothrombin time and activated partial thromboplastin time were reduced following TP transfusions. Allergic reactions were the most common transfusion reaction (19/166, 11.4%). Most dogs survived to discharge (101/166, 60.8%).

Polyoxazoline-conjugated porcine serum albumin as an artificial plasma expander for dogs

Veterinary medicine has made tremendous progress for domestic dogs, which are irreplaceable family members enriching human life. Nevertheless, no adequate supply system exists for their blood products. This study examined the synthesis, structure, safety, and efficacy of poly(2-ethyl-2-oxazoline)-conjugated porcine serum albumin (POx-PSA) as an artificial plasma expander for dogs. The aqueous POx-PSA solution showed moderately high colloid osmotic pressure and good blood cell compatibility. Actually, lyophilized powder stored for 1 year can regenerate into a homogeneous solution. The circulation half-life of POx-PSA in rats was 2.1-fold longer than that of naked PSA. Rats produced neither anti-PSA IgG antibody nor anti-POx IgG antibody, which suggests excellent immunological stealth properties of POx-PSA. Complete resuscitation of hemorrhagic shock in rats was achieved soon after injection of POx-PSA solution. Serum biochemistry tests and histopathological observations indicated no abnormality in the related organs. When POx-PSA was administered to dogs intravenously, (i) no serum biochemical or hematological alteration was observed, also (ii) no overt deterioration of animal health was observed. These results indicate that POx-PSA has potential as an artificial plasma expander for dogs.

Microcirculatory effects of rewarming in experimental hemorrhagic shock.

Rewarming is a recommended therapy during the resuscitation of hypothermic patients with hemorrhagic shock. In experimental models, however, it increases inflammatory response and mortality. Although microcirculation is potential target of inflammation, the microvascular effects of rewarming during the resuscitation of hemorrhagic shock have not been studied. Our goal was to assess the systemic and microcirculatory effects of an increase in core temperature (T°) during the retransfusion of hemorrhagic shock in sheep. Our hypothesis was that rewarming could hamper microcirculation. In anesthetized and mechanically ventilated sheep, we measured systemic, intestinal, and renal hemodynamics and oxygen transport. O2 consumption (VO2) and respiratory quotient were measured by indirect calorimetry. Cortical renal, intestinal villi and sublingual microcirculation were assessed by IDF-videomicroscopy. After basal measurements, hemorrhagic shock was induced and T° was reduced to ~33°C. After 1h of shock and hypothermia, blood was retransfused and Ringer lactate solution was administered to prevent arterial hypotension. In the control group (n=12), T° was not modified, while in the intervention (rewarming) group, it was elevated ~3°C. Measurements were repeated after 1h. During shock, both groups showed similar systemic and microvascular derangements. After retransfusion, VO2 remained decreased compared to baseline in both groups, but was lower in the control compared to the rewarming group. Perfused vascular density has a similar behavior in both groups. Compared to baseline, it remained reduced in peritubular (control vs. rewarming group, 13.8 [8.7-17.5] vs. 15.7 [10.1-17.9] mm/mm2, PNS) and villi capillaries (14.7 [13.6-16.8] vs. 16.3 [14.2-16.9] mm/mm2, PNS), and normalized in sublingual mucosa (19.1 [16.0-20.3] vs. 16.6 [14.7-17.2] mm/mm2, PNS). This is the first experimental study assessing the effect of rewarming on systemic, regional, and microcirculatory perfusion in hypothermic hemorrhagic shock. We found that a 3°C increase in T° neither improved nor impaired the microvascular alterations that persisted after retransfusion. In addition, sublingual mucosa was less susceptible to reperfusion injury than villi and renal microcirculation.

Adaptive closed-loop resuscitation controllers for hemorrhagic shock resuscitation.

After hemorrhage control, fluid resuscitation is the most important intervention for hemorrhage. Even skilled providers can find resuscitation challenging to manage, especially when multiple patients require care. In the future, attention-demanding medical tasks like fluid resuscitation for hemorrhage patients may be reassigned to autonomous medical systems when availability of skilled human providers is limited, such as in austere military settings and mass casualty incidents. Central to this endeavor is the development and optimization of control architectures for physiological closed-loop control systems (PCLCs). PCLCs can take many forms, from simple table look-up methods to widely used proportional-integral-derivative or fuzzy-logic control theory. Here, we describe the design and optimization of multiple adaptive resuscitation controllers (ARCs) that we have purpose-built for the resuscitation of hemorrhaging patients. Three ARC designs were evaluated that measured pressure-volume responsiveness using different methodologies during resuscitation from which adapted infusion rates were calculated. These controllers were adaptive in that they estimated required infusion flow rates based on measured volume responsiveness. A previously developed hardware-in-loop test platform was used to evaluate the ARCs implementations across several hemorrhage scenarios. After optimization, we found that our purpose-built controllers outperformed traditional control system architecture as embodied in our previously developed dual-input fuzzy-logic controller. Future efforts will focus on engineering our purpose-built control systems to be robust to noise in the physiological signal coming to the controller from the patient as well as testing controller performance across a range of test scenarios and in vivo.

Dexmedetomidine improves acute lung injury by activating autophagy in a rat hemorrhagic shock and resuscitation model

Dexmedetomidine (DEX) can reduce lung injury in a hemorrhagic shock (HS) resuscitation (HSR) model in rats by inhibiting inflammation. Here, we aimed to investigate if these effects of DEX are due to autophagy activation. Therefore, we established HSR rat models and divided them into four groups. HS was induced using a blood draw. The rats were then resuscitated by reinjecting the drawn blood and saline. The rats were sacrificed 24 h after resuscitation. Lung tissues were harvested for histopathological examination, determination of wet/dry lung weight ratio, and detection of the levels of autophagy-related marker proteins LC3, P62, Beclin-1, and the ATG12-ATG5 conjugate. The morphological findings of hematoxylin and eosin staining in lung tissues and the pulmonary wet/dry weight ratio showed that lung injury improved in HSR + DEX rats. However, chloroquine (CQ), an autophagy inhibitor, abolished this effect. Detecting the concentration of autophagy-related proteins showed that DEX administration increased LC3, ATG12-ATG5, and Beclin-1 expression and decreased P62 expression. The expression levels of these proteins were similar to those in the HSR group after CQ + DEX administration. In summary, DEX induced autophagic activation in an HSR model. These findings suggest that DEX administration partially ameliorates HSR-induced lung injury via autophagic activation.

The Whole Story: A Comprehensive Review of Whole Blood Resuscitation for Hemorrhagic Shock

The Whole Story: A Comprehensive Review of Whole Blood Resuscitation for Hemorrhagic Shock

SULFORAPHANE ADMINISTRATION AFTER HEMORRHAGIC SHOCK/RESUSCITATION IN MICE REDUCES THE SECRETION OF INFLAMMATORY CYTOKINES AND INCREASES THE IMMUNOCOMPETENCE OF SPLENIC MACROPHAGES.

Objective : The purpose of this study was to investigate the immunomodulatory effects of sulforaphane (SFN), a nuclear factor erythroid 2-related factor (Nrf2) pathway activator, on splenic macrophages' immunocompetence after hemorrhagic shock/resuscitation (HS/R). Methods : Male C57/BL6 wild-type mice (n = 6 per group) were subjected to either pressure-controlled HS (MAP, 35-45 mm Hg) or a sham procedure surgery (without HS). After 90 minutes of HS, fluid resuscitation with withdrawn blood and 0.9% NaCl was performed. Sulforaphane (50 mg/kg of body weight) was applied intraperitoneally immediately after the resuscitation phase as well as 24 and 48 h thereafter, depending on group allocation. The mice were killed at 6, 24, and 72 h after resuscitation. After killing, spleens were harvested to perform Nrf2 immunofluorescence histology. Splenic macrophages were isolated and cultured to measure cytokine secretion in the cell culture supernatant. Furthermore, macrophages isolated after 24-hour resuscitation were treated with 100 ng/mL of bacterial LPS to measure immunocompetence. Matrix-assisted laser desorption/ionization mass spectrometry imaging was performed to verify the distribution of SFN in the spleen after intraperitoneal injection. Results : We showed that administered SFN reached the spleen within the first hour after administration. Furthermore, we identified that SFN increased splenic Nrf2 activation and decreased cytokine expression in splenic macrophages after HS/R. In addition, we showed that SFN exhibited splenic anti-inflammatory properties of macrophages in vitro (IL-6/IL-10-ratio of the HS/R group: 51.79 ± 9.99 [at 6 h] and 15.70 ± 3.35 [at 24 h] vs. HS/R + SFN group: 20.54 ± 5.35 [at 6 h] and 8.60 ± 2.37 [at 24 h], P < 0.05). Furthermore, SFN improved in vitro splenic macrophage immunocompetence after HS/R, as evidenced by the increased secretion of inflammatory cytokines in response to LPS stimulation in vitro . Conclusions : Our study shows that SFN can reduce inflammatory cytokines secreted by splenic macrophages after HS/R and increase their immunocompetence toward a more anti-inflammatory profile.

1172: EVALUATION OF SHELF-STABLE BLOOD PRODUCTS FOR RESUSCITATION IN A CANINE MODEL OF HEMORRHAGIC SHOCK

Introduction: Hemorrhagic shock is a major cause of morbidity and mortality in trauma patients. Current resuscitation methods use blood products that require temperature control and have a limited lifespan, which present significant limitations for use in rural areas and combat zones. This study examined whether shelf stable blood product resuscitation strategies leveraging freeze-dried plasma (FDP), hemoglobin based oxygen carrier (HBOC), and lyophilized platelets (LP) provide an alternative to conventional resuscitation strategies in a canine model. We hypothesized that a combination of HBOC and FDP with or without LP would be non-inferior to chilled whole blood (CWB) for hemorrhagic shock resuscitation. Methods: Seven dogs were anesthetized and subjected to controlled hemorrhage of up to 40% of their blood volume (T0) over one hour to achieve a mean arterial blood pressure of 35-50 mmHg. They were maintained in shock for 45 minutes and were then randomized to receive: CWB, FDP+HBOC, or FDP+HBOC+LP over 30 minutes (T105-135). Citrated blood was collected at T0, T105, T135, and T180 for thromboelastography (TEG 5000). Samples were run in duplicates with kaolin activation to measure reaction time (r), kinetic time (k), alpha angle (alpha), and maximum amplitude (MA). Between-group comparisons were performed using a Kruskal-Wallis ANOVA and a Bonferroni correction. Results are reported as mean +/- standard deviation. Results: There was no difference in baseline parameters between groups or in TEG values between groups at the end of shock T0 and T105. There was a difference in alpha and MA between groups at T135 (p= 0.02 for both) and T180 (p=0.02 and 0.002, respectively). Specifically, alpha and MA were lower in the FDP+HBOC+LP group (alpha: 54.9 +/- 6.6 deg; MA: 43.5 +/- 11.5 mm) than in the CWB group (alpha: 64.4 +/- 5.2 deg; MA: 58.2 +/- 5.1 mm). There was no difference in r, alpha, and k between groups at any time point. Conclusions: In this canine model of controlled hemorrhage, TEG parameters between FDP+HBOC and CWB were not different. We demonstrated evidence of reduced coagulation function in FDP+HBOC+LP. The biological relevance of those findings should be determined in an uncontrolled hemorrhage model. Resuscitation with shelf-stable products appeared safe and satisfactory in this model.

Dual Input Fuzzy Logic Controllers for Closed Loop Hemorrhagic Shock Resuscitation

Hemorrhage remains a leading cause of preventable death in emergency situations, including combat casualty care. This is partially due to the high cognitive burden that constantly adjusting fluid resuscitation rates can require, especially in austere or mass casualty situations. Closed-loop control systems have the potential to simplify hemorrhagic shock resuscitation if properly tuned for the application. We have previously compared 4 different controller types using a hardware-in-loop test platform that simulates hemorrhagic shock conditions, and we found that a dual input—(1) error from target and (2) rate of error change—fuzzy logic (DFL) controller performed best. Here, we highlight a range of DFL designs to showcase the tunability the controller can have for different hemorrhage scenarios. Five different controller setups were configured with different membership function logic to create more and less aggressive controller designs. Overall, the results for the different controller designs ranged from reaching the setup rapidly but often overshooting the target to more conservatively approaching the target, resulting in not reaching the target during high active hemorrhage rates. In conclusion, DFL controllers are well-suited for hemorrhagic shock resuscitation and can be tuned to meet the response rates set by clinical practice guidelines for this application.

Observation on the effectiveness and safety of sodium bicarbonate Ringer’s solution in the early resuscitation of traumatic hemorrhagic shock: a clinical single-center prospective randomized controlled trial

BackgroundTraumatic hemorrhagic shock (THS) is the main cause of death in trauma patients with high mortality. Rapid control of the source of bleeding and early resuscitation are crucial to clinical treatment. Guidelines recommend isotonic crystal resuscitation when blood products are not immediately available. However, the selection of isotonic crystals has been controversial. Sodium bicarbonate Ringer solutions (BRS), containing sodium bicarbonate, electrolyte levels, and osmotic pressures closer to plasma, are ideal. Therefore, in this study, we will focus on the effects of BRS on the first 6 h of resuscitation, complications, and 7-day survival in patients with THS.Methods/design.This single-center, prospective, randomized controlled trial will focus on the efficacy and safety of BRS in early THS resuscitation. A total of 400 adults THS patients will be enrolled in this study. In addition to providing standard care, enrolled patients will be randomized in a 1:1 ratio to receive resuscitation with BRS (test group) or sodium lactate Ringer’s solution (control group) until successful resuscitation from THS. Lactate clearance at different time points (0.5, 1, 1.5, 3, and 6 h) and shock duration after drug administration will be compared between the two groups as primary end points. Secondary end points will compare coagulation function, temperature, acidosis, inflammatory mediator levels, recurrence of shock, complications, medication use, and 7-day mortality between the two groups. Patients will be followed up until discharge or 7 days after discharge.DiscussionAt present, there are still great differences in the selection of resuscitation fluids, and there is a lack of systematic and detailed studies to compare and observe the effects of various resuscitation fluids on the effectiveness and safety of early resuscitation in THS patients. This trial will provide important clinical data for resuscitation fluid selection and exploration of safe dose of BRS in THS patients.Trial registration.Chinese Clinical Trial Registry (ChiCTR), ChiCTR2100045044. Registered on 4 April 2021.

198 Rapid Resuscitation for Hemorrhagic Shock: Hemodynamically Unstable Patients May Do Better Than Those Presenting with Normal Vitals

Early damage control resuscitation is the current standard for trauma and other hemorrhagic shock conditions. In 2017 a manual novel rapid fluid infuser (RFI) was added to the toolbox for managing the continuum of critical patients at this large urban-suburban Level 1 trauma health center. This study describes the emergency department experience with the RFI as it has been used for patients with hemorrhagic shock. The primary goal was to gather this data to inform QI initiatives around rapid response, maternal hemorrhage, and trauma.

An Automated Hardware-in-Loop Testbed for Evaluating Hemorrhagic Shock Resuscitation Controllers.

Hemorrhage remains a leading cause of death, with early goal-directed fluid resuscitation being a pillar of mortality prevention. While closed-loop resuscitation can potentially benefit this effort, development of these systems is resource-intensive, making it a challenge to compare infusion controllers and respective hardware within a range of physiologically relevant hemorrhage scenarios. Here, we present a hardware-in-loop automated testbed for resuscitation controllers (HATRC) that provides a simple yet robust methodology to evaluate controllers. HATRC is a flow-loop benchtop system comprised of multiple PhysioVessels which mimic pressure-volume responsiveness for different resuscitation infusates. Subject variability and infusate switching were integrated for more complex testing. Further, HATRC can modulate fluidic resistance to mimic arterial resistance changes after vasopressor administration. Finally, all outflow rates are computer-controlled, with rules to dictate hemorrhage, clotting, and urine rates. Using HATRC, we evaluated a decision-table controller at two sampling rates with different hemorrhage scenarios. HATRC allows quantification of twelve performance metrics for each controller configuration and scenario, producing heterogeneous results and highlighting the need for controller evaluation with multiple hemorrhage scenarios. In conclusion, HATRC can be used to evaluate closed-loop controllers through user-defined hemorrhage scenarios while rating their performance. Extensive controller troubleshooting using HATRC can accelerate product development and subsequent translation.

A Novel Therapeutic Approach With Sodium Pyruvate on Vital Signs, Acid-Base, and Metabolic Disturbances in Rats With a Combined Blast and Hemorrhagic Shock.

BackgroundBlast injuries from improvised explosive devices (IEDs) are known to cause blast traumatic brain injuries (bTBIs), hemorrhagic shock (HS), organ damage, mitochondrial dysfunction, and subsequent free radical production. A pre-citric acid cycle reagent, pyruvate, is suggested to improve mitochondrial ATP production through the activation of the mitochondrial gatekeeper enzyme “pyruvate dehydrogenase complex (PDH).” Our study aimed to investigate the role of physiologic, metabolic, and mitochondrial effects of hypertonic sodium pyruvate resuscitation in rats with a combined blast and HS injury.MethodsA pre-clinical rat model of combined injury with repetitive 20 PSI blast exposure accompanied with HS and fluid resuscitation (sodium pyruvate as metabolic adjuvant or hypertonic saline as control), followed by transfusion of shed blood was used in this study. Control sham animals (instrumental and time-matched) received anesthesia and cannulation, but neither received any injury nor treatment. The mean arterial pressure and heart rate were recorded throughout the experiment by a computerized program. Blood collected at T0 (baseline), T60 (after HS), and T180 (end) was analyzed for blood chemistry and mitochondrial PDH enzyme activity.ResultsSodium pyruvate resuscitation significantly improved the mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), hemodynamic stability (Shock index), and autonomic response (Kerdo index) after the HS and/or blast injury. Compared with the baseline values, plasma lactate and lactate/pyruvate ratios were significantly increased. In contrast, base excess BE/() was low and the pH was also acidotic <7.3, indicating the sign of metabolic acidosis after blast and HS in all animal groups. Sodium pyruvate infusion significantly corrected these parameters at the end of the experiment. The PDH activity also improved after the sodium pyruvate infusion.ConclusionIn our rat model of a combined blast and HS injury, hypertonic sodium pyruvate resuscitation was significantly effective in hemodynamic stabilization by correcting the acid–base status and mitochondrial mechanisms via its pyruvate dehydrogenase enzyme.

The publication impact of the first 100 THOR Network publications by bibliometric and social network analyses.

A specialized international multidisciplinary group of investigators wanted to determine the performance and impact of publications presented at an annual conference over a 6 year period. Specifically, the group wanted to know if the influence of the conference publications extended beyond conference publication authors and attendees. Bibliometric methods and network analyses were used to evaluate the performance and impact of 100 peer-reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 (published 2013-2018). Further analysis was performed on the affiliations of conference attendees who attended from the years of 2012 to 2017. This project used normative and relative bibliometric measures and social network analysis to evaluate the performance and impact of 100 peer-reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network RDCR Symposia from 2012 to 2017. Publication and citation data were from Elsevier Scopus, a bibliographic citation database. Metrics from Elsevier SciVal were selected for the project to normalize for group size, year of publication, and document type. A six-year period of publications presented at the Symposia, published from 2013 to 2018, was selected for analysis. The publication and citation data were further analyzed using Elsevier SciVal and the iCite database from the National Institutes of Health Office of Portfolio Analysis. Sci2, VOSviewer, and Gephi were used for social network analyses and visualization. The 100 publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 demonstrate reach and influence beyond the authors of the THOR publications or the THOR attendees. Citations to the THOR publications were published in 10 languages and 313 unique journals, with author affiliations from 62 countries. Citation metrics for the THOR publications exceed global averages with 65% of the THOR publications being in the 25% citation percentiles. When benchmarking the THOR publications using six homogenous comparator groups, the THOR publications demonstrate higher citation metrics than any of the comparator groups with more citations per publication, a higher average of cited publications, higher FWCI and outputs in the top citation percentiles among the six groups. The Office of Portfolio Analysis (OPA) iCite database was used to calculate potential to translate for the THOR publications with 57 of the THOR publications cited by clinical articles with an average approximate potential to translate score of 65.3%. The value of international groups with sharing of research and knowledge are instrumental in enhancing the uptake for best practices for in medicine and treatment of hemorrhagic shock resuscitation. The use of bibliometric methods and network analyses, along with benchmarking, demonstrated reach and impact beyond the THOR Network. Limitations include use of a single source for analysis of publication and citation; and that publication data alone does not provide a full overview of research performance. Despite these limitations, bibliometric methods, social network analyses, and benchmarking can help centers better understand their impact.

93. The Effects of Subnormothermic Plasma and Red Blood Cell Based Perfusion on the Function and Viability of Limb Allografts

Purpose: Vascularized composite allotranplantation (VCA) is an evolving area of modern transplantation medicine to reconstruct composite tissue defects such as abdominal wall, face, and limb. One of the challenges in VCA is the narrow window of tolerable ischemia time which limits the number of available donors and imposes a single center transplantation approach. Current standard of care, static cold storage, is only effective for short periods and may result in severe tissue damage and acute rejection when prolonged. Ex-situ perfusion has the potential to overcome these challenges by extending allowable pre-transplantation ischemia time. However, optimum perfusate composition, preservation temperature, and hemodynamic parameters of perfusion are still debated. Over the past decade, the benefits of addition of fresh plasma in hemorrhagic shock resuscitation and attenuation of subsequent reperfusion injury have been recognized. Whether these observations are due to high or low molecular weight (HMW and LMW, respectively) plasma proteins require further investigation. This study investigated the effects of the addition of plasma on the viability of perfused limb allografts with prolonged ischemia time. Methods: All limb transplantations were performed orthotopically between male Lewis rats (200-250 g). In group 1, amputated limbs were transplanted immediately to determine the effects of surgical trauma. In group 2, amputated limbs were preserved at 4°C simulating the clinical standard of care. In other groups, amputated limbs were perfused for 6 hours at 20° to 22°C using one of the following perfusates groups and transplanted to another recipient (in less than 90 minutes): RBC only (G3), RBC + whole plasma (G4), RBC + LMW plasma (G5), RBC + HMW plasma (G6). At 3 months post-transplantation, surviving recipients had end-point assessment using electromyography where compound muscle action potentials (CMAP) and extensor digitorum longus (EDL) muscle force generation were compared to contralateral healthy limb. Muscle and nerve histology samples were collected at the end of EMG testing. Results: Recipients in the group perfused with RBC and HMW plasma proteins had severe reperfusion injury and did not survive beyond 3 days. Among surviving recipients, the addition of whole plasma did not appear to improve amplitude and latency on gastrocnemius and EDL muscles compared to immediately transplanted limbs. Groups perfused with RBC only and RBC with LMW plasma demonstrated excellent amplitude and latencies on both muscle groups, with no significant difference compared to immediately transplanted limbs (p>0.05). The EDL muscle in these groups also generated similar tetanic and twitch forces compared to the immediate transplantation group (p>0.05). Conclusion: Ex-situ perfusion at 20° to 22°C for 6 hours using RBC and LMW plasma appears to protect both fast and slow twitch muscles, and improve axonal regeneration and myelin sheath thickness to a degree comparable with the immediately transplanted group.

Evaluation of a Proportional-Integral-Derivative Controller for Hemorrhage Resuscitation Using a Hardware-in-Loop Test Platform.

Hemorrhage is a leading cause of preventable death in trauma, which can often be avoided with proper fluid resuscitation. Fluid administration can be cognitive-demanding for medical personnel as the rates and volumes must be personalized to the trauma due to variations in injury severity and overall fluid responsiveness. Thus, automated fluid administration systems are ideal to simplify hemorrhagic shock resuscitation if properly designed for a wide range of hemorrhage scenarios. Here, we highlight the development of a proportional–integral–derivative (PID) controller using a hardware-in-loop test platform. The controller relies only on an input data stream of arterial pressure and a target pressure; the PID controller then outputs infusion rates to stabilize the subject. To evaluate PID controller performance with more than 10 controller metrics, the hardware-in-loop platform allowed for 11 different trauma-relevant hemorrhage scenarios for the controller to resuscitate against. Overall, the two controller configurations performed uniquely for the scenarios, with one reaching the target quicker but often overshooting, while the other rarely overshot the target but failed to reach the target during severe hemorrhage. In conclusion, PID controllers have the potential to simplify hemorrhage resuscitation if properly designed and evaluated, which can be accomplished with the test platform shown here.

Effectiveness and safety of hypotension fluid resuscitation in traumatic hemorrhagic shock: A systematic review and meta-analysis of randomized controlled trials.

BackgroundAlthough the resuscitation of an adult trauma patient has been researched and written about for the past century, the ideal fluid strategy to infuse during the initial resuscitation period remains unresolved. This work was aimed at assessing the effect of hypotensive versus conventional resuscitation strategies in traumatic hemorrhagic shock patients on mortality, and the need for blood transfusions including adverse events.MethodsThis systematic review and meta-analysis were performed following the PRISMA guidelines. Electronic databases were searched for randomized controlled trials (RCT) comparing the effect of hypotension versus conventional fluid resuscitation for traumatic hemorrhagic shock patients. Two reviewers independently performed the screening, data extraction, and bias assessment. The data analysis was completed using the Cochrane Collaboration’s software RevMan 5.4.ResultsData from 28 RCTs on 4503 patients were included in the final meta-analysis. Patients receiving hypotension fluid resuscitation compared with conventional fluid resuscitation experienced less mortality (12.5% vs. 21.4%; RR = 0.58; 95% CI: 0.51–0.66; p < 0.001), fewer adverse events (10.8% vs. 13.4%; RR = 0.70; 95% CI: 0.59–0.83; p < 0.001), including fever acute respiratory distress syndrome (7.8% vs. 16.8%) or multiple organ dysfunction syndrome (8.6% vs. 21.6%).ConclusionsThis meta-analysis showed that hypotensive fluid resuscitation significantly reduced the mortality of hypovolemic shock patients. Findings are low in certainty and should be interpreted with caution. Therefore, there is an urgent need for larger, multicenter, randomized trials to confirm these findings.

The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.

OBJECTIVES:Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models.DESIGN:Randomized prospective treatment study.SETTING:University laboratory.SUBJECTS:Male Sprague-Dawley rats.INTERVENTIONS:First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes.MEASUREMENTS AND MAIN RESULTS:INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios.CONCLUSIONS:Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.