Comparing the effects of various fluid resuscitative strategies on Glycocalyx damage in a canine hemorrhage model.

Hemorrhagic shock and subsequent resuscitation can cause significant dysregulation of critical systems, including the vascular endothelium. Following hemorrhage, the endothelial lining (glycocalyx) can shed, causing release of glycocalyx components, endothelial activation, and systemic inflammation. A canine model of hemorrhagic shock was used to evaluate five resuscitation fluids, including Lactated Ringers+Hetastarch, Whole Blood (WB), Fresh Frozen Plasma+packed Red Blood Cells (FFP+pRBC), and two hemoglobin-based oxygen carrier (HBOC) fluids, for their impact on glycocalyx shedding. Under anesthesia, purpose-bred adult canines were instrumented and subjected to a controlled hemorrhage with blood being drawn until a mean arterial pressure of <50 mmHg was reached or 40 % of the estimated blood volume was removed. Canines were left in shock for 45 mins before being resuscitated with one of the resuscitation fluids over 30 mins. Following resuscitation, the dogs were monitored up to 2 weeks. Following an additional 3-4 weeks for washout, the canines repeated the protocol, undergoing each resuscitation fluid individually. Blood samples were collected during each round at various timepoints for serum isolation, which was used for detection of glycocalyx biomarker. Comparison of baseline and post-hemorrhage alone showed a significant reduction in serum protein (p<0.0001), heparan sulfate (p<0.001), and syndecan-1 (p<0.0001) concentrations, and a significant increase in hyaluronan (p<0.0001) concentration. Intercomparisons of resuscitation fluids indicated minimal differences in glycocalyx markers over time. Comparisons within each fluid showed dynamic responses in glycocalyx biomarkers over time. Relative to individual baselines, syndecan-1 was significantly reduced after resuscitation in most cases (p<0.0001), excluding WB and FFP+pRBC. In all cases, VE-cadherin was significantly elevated at 24 hr compared to baseline (p<0.001). Hyaluronan was significantly elevated by 3 hr in all cases (p<0.01), except for HBOC fluids. Total glycosaminoglycans were significantly reduced only at 3 hr (p<0.001) for non-HBOC fluids. Similarly, heparan sulfate was significantly reduced with all fluids between resuscitation and 24 hr (p<0.01), except WB. The temporal changes in canine glycocalyx biomarkers were atypical of hemorrhage response in other species. This suggests that the hemorrhage lacked severity and/or typical glycocalyx biomarkers do not reflect the canine endothelium compared to other species. Further research is needed to characterize the canine endothelium and the response to resuscitation fluids.

Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest.

BACKGROUND: Early administration of adrenaline is associated with improved survival after out-of-hospital cardiac arrest (OHCA). Delays in vascular access may impact the timely delivery of adrenaline. Novel methods for administering adrenaline before vascular access may enhance survival. The objective of this study was to determine whether an initial intramuscular (IM) adrenaline dose followed by standard IV/IO adrenaline is associated with improved survival after OHCA. METHODS STUDY DESIGN: We conducted a before-and-after study of the implementation of an early, first-dose IM adrenaline EMS protocol for adult OHCAs. The pre-intervention period took place between January 2010 and October 2019. The post-intervention period was between November 2019 and May 2024. SETTING: Single-center urban, two-tiered EMS agency. PARTICIPANTS: Adult, nontraumatic OHCA meeting criteria for adrenaline use. INTERVENTION: Single dose (5 mg) IM adrenaline. All other care, including subsequent IV or IO adrenaline, followed international guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital discharge. Secondary outcomes were time from EMS arrival to the first dose of adrenaline, survival to hospital admission, and favorable neurologic function at discharge. RESULTS: Among 1405 OHCAs, 420 (29.9%) received IM adrenaline and 985 (70.1%) received usual care. Fifty-two patients received the first dose of adrenaline through the IV or IO route within the post-intervention period and were included in the standard care group analysis. Age was younger and bystander CPR was higher in the IM adrenaline group. All other characteristics were similar between IM and standard care cohorts. Time to adrenaline administration was faster for the IM cohort [(median 4.3 min (IQR 3.0-6.0) vs. 7.8 min (IQR 5.8-10.4)]. Compared with standard care, IM adrenaline was associated with improved survival to hospital admission (37.1% vs. 31.6%; aOR 1.37, 95% CI 1.06-1.77), hospital survival (11.0% vs 7.0%; aOR 1.73, 95% CI 1.10-2.71) and favorable neurologic status at hospital discharge (9.8% vs 6.2%; aOR 1.72, 95% CI 1.07-2.76). CONCLUSION: In this single-center before-and-after implementation study, an initial IM dose of adrenaline as an adjunct to standard care was associated with improved survival to hospital admission, survival to hospital discharge, and functional survival. A randomized controlled trial is needed to fully assess the potential benefit of IM adrenaline delivery in OHCA.

Comparison of shelf-stable and conventional resuscitation products in a canine model of hemorrhagic shock.

BACKGROUND: Treatment of severe hemorrhagic shock typically involves hemostatic resuscitation with blood products. However, logistical constraints often hamper the wide distribution of commonly used blood products like whole blood. Shelf-stable blood products and blood substitutes are poised to be able to effectively resuscitate individuals in hemorrhagic shock when more conventional blood products are not readily available. METHODS: Purpose-bred adult dogs (n = 6) were anesthetized, instrumented, and subjected to hemorrhagic shock (mean arterial pressure <50 mm Hg or 40% blood volume loss). Then each dog was resuscitated with one of five resuscitation products: (1) lactated ringers solution and hetastarch (LRS/Heta), (2) canine chilled whole blood (CWB), (3) fresh frozen plasma (FFP) and packed red blood cells (pRBC), (4) canine freeze-dried plasma (FDP) and hemoglobin-based oxygen carrier (HBOC), or (5) HBOC/FDP and canine lyophilized platelets (LyoPLT). Each dog was allowed to recover after the hemorrhage resuscitation event and was then subjected to another hemorrhage event and resuscitated with a different product until each dog was resuscitated with each product. RESULTS: At the time when animals were determined to be out of shock as defined by a shock index <1, mean arterial pressure (mmHg) values (mean ± standard error) were higher for FFP/pRBC (n = 5, 83.7 ± 4.5) and FDP/HBOC+LyoPLT (n = 4, 87.8 ± 2.1) as compared with WB (n = 4, 66.0 ± 13.1). A transient increase in creatinine was seen in dogs resuscitated with HBOC and FDP. Albumin and base excess increased in dogs resuscitated with HBOC and FDP products compared with LRS/heta and CWB ( p < 0.01). CONCLUSION: Combinations of shelf-stable blood products compared favorably to canine CWB for resolution of shock. Further research is needed to ascertain the reliability and efficacy of these shelf-stable combinations of products in other models of hemorrhage that include a component of tissue damage as well as naturally occurring trauma.

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.

ChemoDOTS: a web server to design chemistry-driven focused libraries.

In drug discovery, the successful optimization of an initial hit compound into a lead molecule requires multiple cycles of chemical modification. Consequently, there is a need to efficiently generate synthesizable chemical libraries to navigate the chemical space surrounding the primary hit. To address this need, we introduce ChemoDOTS, an easy-to-use web server for hit-to-lead chemical optimization freely available at https://chemodots.marseille.inserm.fr/. With this tool, users enter an activated form of the initial hit molecule then choose from automatically detected reactive functions. The server proposes compatible chemical transformations via an ensemble of encoded chemical reactions widely used in the pharmaceutical industry during hit-to-lead optimization. After selection of the desired reactions, all compatible chemical building blocks are automatically coupled to the initial hit to generate a raw chemical library. Post-processing filters can be applied to extract a subset of compounds with specific physicochemical properties. Finally, explicit stereoisomers and tautomers are computed, and a 3D conformer is generated for each molecule. The resulting virtual library is compatible with most docking software for virtual screening campaigns. ChemoDOTS rapidly generates synthetically feasible, hit-focused, large, diverse chemical libraries with finely-tuned physicochemical properties via a user-friendly interface providing a powerful resource for researchers engaged in hit-to-lead optimization.

The use of a kaolin-based hemostatic dressing to attenuate bleeding in dogs: A series of 4 cases.

OBJECTIVE: To describe the use of a synthetic hemostatic dressing, QuikClot Combat Gauze (QCG), in dogs with bleeding wounds. CASE SERIES SUMMARY: Two dogs presented with bleeding traumatic wounds, and QCG was used to achieve hemostasis during stabilization of these dogs. In the other 2 dogs, QCG was used to help attenuate bleeding associated with a surgical procedure. NEW OR UNIQUE INFORMATION PROVIDED: While hemostatic dressings have been widely studied and used in human medicine, there is minimal information on the use and efficacy of these hemostatic dressings in veterinary medicine. This case series describes the use of QCG in dogs with hemorrhaging wounds. QCG could be a valuable resource in veterinary emergency and critical care settings.

Near-infrared spectroscopy for kidney oxygen monitoring in a porcine model of hemorrhagic shock, hemodilution, and REBOA.

Acute kidney injury is a common complication of trauma and hemorrhagic shock. In a porcine model of hemorrhagic shock, resuscitative endovascular balloon aortic occlusion (REBOA) and hemodilution, we hypothesized that invasive kidney oxygen concentration measurements would correlate more strongly with noninvasive near infra-red spectroscopy (NIRS) oxygen saturation measurements when cutaneous sensors were placed over the kidney under ultrasound guidance compared to placement over the thigh muscle and subcutaneous tissue. Eight anesthetized swine underwent hemorrhagic shock 4 of which were resuscitated with intravenous fluids prior to the return of shed blood (Hemodilution protocol) and 4 of which underwent REBOA prior to resuscitation and return of shed blood (REBOA protocol). There was a moderate correlation between the NIRS and kidney tissue oxygen measurements (r = 0.61 p < 0.001; r = 0.67 p < 0.001; r = 0.66 p < 0.001for left kidney, right kidney, and thigh NIRS respectively). When the animals were separated by protocol, the Hemodilution group showed a weak or nonsignificant correlation between NIRS and kidney tissue oxygen measurements (r = 0.10 p < 0.001; r = 0.01 p = 0.1007; r = 0.28 p < 0.001 for left kidney, right kidney, and thigh NIRS respectively). This contrasts with the REBOA group, where left and right kidney as well as thigh NIRS were moderately correlated with kidney tissue oxygen (r = 0.71 p < 0.001; r = 0.74 p < 0.001; r = 0.70 p < 0.001; for left kidney, right kidney, and thigh NIRS respectively). There was a strong correlation between both kidney NIRS signals and thigh NIRS measurements (r = 0.85 p < 0.001; r = 0.88 p < 0.001;for left kidney vs thigh and right kidney vs thigh respectively). There was also a strong correlation between left and right kidney NIRS (r = 0.90 p < 0.001). These relationships were maintained regardless of the resuscitation protocol. These results suggest that kidney NIRS measurements were more closely related to thigh NIRS measurements than invasive kidney tissue oxygen concentration.

Canine Model of Ischemia-Induced Ventricular Tachycardia.

INTRODUCTION: Despite advances in antiarrhythmia therapies, ventricular tachycardia (VT) is a leading cause of sudden cardiac death. Investigation into the characteristics and new treatments for this arrhythmia is required to improve outcomes and a reproducible model of VT would be useful in these endeavors. We therefore created a canine model of ischemia-induced VT. MATERIALS AND METHODS: A pacing lead was implanted in the right ventricle in canines (n = 13) and the left anterior descending artery was occluded in two locations for 2 h and subsequently released to create an ischemia-reperfusion injury. In the 10 dogs that survived the first 48 h following the initial study, a terminal study was conducted 4-7 d later and VT was induced using premature stimulation or burst pacing through the right ventricle lead. The arrhythmia was terminated using either antitachycardia pacing or a defibrillatory shock. Multiple inductions into sustained VT were attempted. RESULTS: Sustained VT was induced in eight of 10 dogs with an average cycle length of 335 ± 70 bpm. Multiple episodes of VT were induced. Episodes of VT exhibited different electrocardiogram morphologies and cycle lengths in individual animals. CONCLUSIONS: This canine model provides a consistent technique for inducing multiple episodes of sustained VT. It may be useful for investigating VT mechanisms and testing novel therapeutics and treatments for patients with VT.