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.

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.

A canine model of chronic ischemic heart failure.

Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: group 1 (n = 4) (simple LAD: proximal and distal LAD ligation); group 2 (n = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and group 3 (n = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles). Dogs were followed until chronic severe HF developed defined as left ventricular ejection fraction (LVEF) < 40% and NH2-terminal-prohormone B-type natriuretic peptide (NT-proBNP) > 900 pmol/L. Overall early survival (48-h postligation) in 29 dogs was 83% and the survival rate at postligation 5 wk was 69%. Groups 1 and 2 had 100% and 71% early survival, respectively, yet only a 50% success rate of developing chronic HF. Group 3 had excellent survival at postligation 48 h (91%) and a 100% success in the development of chronic ischemic HF. The TLD approach, which limits full LAD and collateral flow to its perfusion bed, provides excellent early survival and reliable development of chronic ischemic HF in canine hearts.NEW & NOTEWORTHY The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.

Evaluation of esophageal injuries after defibrillation with transesophageal ultrasound probe in the mid-esophagus in pigs.

OBJECTIVE: Transesophageal echocardiography (TEE) is becoming increasingly utilized by emergency medicine providers during cardiac arrest. Intra-arrest, TEE confers several benefits including shorter pauses in chest compressions and direct visualization of cardiac compressions. Many ultrasound probe manufacturers recommend against performing defibrillation with the TEE probe in the mid-esophagus for fear of causing esophageal injury or damage to the probe, however no literature exists that has investigated this concern. To assess this, we performed cardiopulmonary resuscitation (CPR) and multiple defibrillations in 8 swine with a TEE probe in place. METHODS: We performed TEE on 8 adult swine during CPR and performed multiple 200 J defibrillations with the TEE probe in the mid-esophagus. Post-mortem, esophagi were dissected and inspected for evidence of injury. RESULTS: On macroscopic inspection of 8 esophagi, no evidence of hematoma, thermal injury, or perforation was noted. CONCLUSION: Our study suggests that performing defibrillation during CPR with a TEE probe in place in the mid-esophagus is likely safe and low risk for significant esophageal injury. This further bolsters the use of TEE in CPR and would enable continuous visualization of cardiac activity without the need to remove the TEE probe for defibrillation.

TEE guided REBOA deflation following ROSC for non-traumatic cardiac arrest.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is most commonly used to manage non-compressible torso hemorrhage. It is also emerging as a promising treatment for non-traumatic refractory cardiac arrest. Aortic occlusion during chest compressions increases cardio-cerebral perfusion, increasing the potential for sustained return of spontaneous circulation (ROSC) or serving as a bridge to extracorporeal cardiopulmonary resuscitation (ECPR). Optimal patient selection and post-ROSC management in such cases is uncertain and not well reported in the literature. We present a case of non-traumatic out-of-hospital cardiac arrest in which REBOA was placed in the emergency department with subsequent ROSC. Transesophageal echocardiography was used to guide post-ROSC REBOA management and balloon deflation.

Endovascular Perfusion Augmentation After Resuscitative Endovascular Balloon Occlusion of the Aorta Improves Renal Perfusion and Decreases Vasopressors.

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes a severe ischemia-reperfusion injury. Endovascular Perfusion Augmentation for Critical Care (EPACC) has emerged as a hemodynamic/mechanical adjunct to vasopressors and crystalloid for the treatment of post-REBOA ischemia-reperfusion injury. The objective of the study is to examine the impact of EPACC as a tool for a wean from complete REBOA compared to standard resuscitation techniques. METHODS: Nine swine underwent anesthesia and then a controlled 30% blood volume hemorrhage with 30 min of supraceliac total aortic occlusion to create an ischemia-reperfusion injury. Animals were randomized to standardized critical care (SCC) or 90 min of EPACC followed by SCC. The critical care phase lasted 270 min after injury. Hemodynamic markers and laboratory values of ischemia were recorded. RESULTS: During the first 90 min the intervention phase SCC spent 60% (54%-73%) and EPACC spent 91% (88%-92%) of the time avoiding proximal hypotension (<60 mm Hg), P = 0.03. There was also a statistically significant decrease in cumulative norepinephrine dose at the end of the experiment between SCC (80.89 mcg/kg) versus EPACC (22.03 mcg/kg), P = 0.03. Renal artery flow during EPACC was similar compared to SCC during EPACC, P = 0.19. But during the last hour of the experiment (after removal of aortic balloon) the renal artery flow in EPACC (2.9 mL/kg/min) was statistically significantly increased compared to SCC (1.57 mL/min/kg), P = 0.03. There was a statistically significant decrease in terminal creatinine in the EPACC (1.7 mg/dL) compared to SCC (2.1 mg/dL), P = 0.03. CONCLUSIONS: The 90 min of EPACC as a weaning adjunct in the setting of a severe ischemia-reperfusion injury after complete supraceliac REBOA provides improved renal flow with improvement in terminal creatinine compared to SCC with stabilized proximal hemodynamics and decreased vasopressor dose.

Intraoperative Urinary Biomarkers and Acute Kidney Injury After Cardiac Surgery.

OBJECTIVES: To evaluate the association of intraoperative urinary biomarker excretion during cardiac surgery and the subsequent development of acute kidney injury (AKI). DESIGN: Prospective, nonrandomized, observational study. SETTING: Single tertiary-level, university-affiliated hospital. PARTICIPANTS: Ninety patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary samples were collected every 30 minutes intraoperatively and then at four, 12, and 24 hours after CPB. Samples were measured for interleukin 18 (IL-18), kidney injury molecule-1 (KIM1), and creatinine concentrations. Urinary biomarker excretion (raw and indexed to creatinine) for four intraoperative and three postoperative points were compared between patients with and those without subsequent AKI defined by increased serum creatinine concentration ≥0.3 mg/dL within the first 48 hours or ≥1.5 times baseline within seven days. Raw and indexed median IL-18 values were similar between AKI groups at all intraoperative points, but became significantly different at 12 hours after CPB. Raw and indexed median KIM1 values were significantly different between AKI groups at multiple intraoperative points and at four and 12 hours after CPB. During intraoperative and postoperative points, patients in the fourth quartile of KIM1 excretion had greater AKI incidence and longer intensive care and hospital lengths of stay than those in the first quartile. Only postoperatively did the differences in these outcomes between the fourth and first quartile of IL-18 excretion occur. CONCLUSIONS: Intraoperative KIM1 but not IL-18 excretion was associated with postoperative development of AKI.

Zone 3 REBOA does not provide hemodynamic benefits during nontraumatic cardiac arrest.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be a novel intervention to improve cardiopulmonary resuscitation (CPR) quality during cardiac arrest. Zone 1 supraceliac aortic occlusion improves coronary and cerebral blood flow. It is unknown if Zone 3 occlusion distal to the renal arteries offers a similar physiologic benefit while maintaining blood flow to organs above the point of occlusion. METHODS: Fifteen swine were anesthetized, instrumented, and placed into ventricular fibrillation. Mechanical CPR was immediately initiated. After 5 min of CPR, Zone 1 REBOA, Zone 3 REBOA, or no intervention (control) was initiated. Hemodynamic variables were continuously recorded for 30 min. RESULTS: There were no significant differences between groups before REBOA deployment. Once REBOA was deployed, Zone 1 animals had statistically greater diastolic blood pressure compared to control (median [IQR]: 19.9 mmHg [9.5-20.5] vs 3.9 mmHg [2.4-4.8], p = .006). There were no differences in diastolic blood pressure between Zone 1 and Zone 3 (8.6 mmHg [5.1-13.1], p = .10) or between Zone 3 and control (p = .10). There were no significant differences in systolic blood pressure, cerebral blood flow, or time to return of spontaneous circulation (ROSC) between groups. CONCLUSION: In our swine model of cardiac arrest, Zone 1 REBOA improved diastolic blood pressure when compared to control. Zone 3 does not offer a hemodynamic benefit when compared to no occlusion. Unlike prior studies, immediate use of REBOA after arrest did not result in an increase in ROSC rate, suggesting REBOA may be more beneficial in patients with prolonged no-flow time. INSTITUTIONAL PROTOCOL NUMBER: FDG20180024A.

Refinement of machine learning arterial waveform models for predicting blood loss in canines.

Introduction: Hemorrhage remains a leading cause of death in civilian and military trauma. Hemorrhages also extend to military working dogs, who can experience injuries similar to those of the humans they work alongside. Unfortunately, current physiological monitoring is often inadequate for early detection of hemorrhage. Here, we evaluate if features extracted from the arterial waveform can allow for early hemorrhage prediction and improved intervention in canines. Methods: In this effort, we extracted more than 1,900 features from an arterial waveform in canine hemorrhage datasets prior to hemorrhage, during hemorrhage, and during a shock hold period. Different features were used as input to decision tree machine learning (ML) model architectures to track three model predictors-total blood loss volume, estimated percent blood loss, and area under the time versus hemorrhaged blood volume curve. Results: ML models were successfully developed for total and estimated percent blood loss, with the total blood loss having a higher correlation coefficient. The area predictors were unsuccessful at being directly predicted by decision tree ML models but could be calculated indirectly from the ML prediction models for blood loss. Overall, the area under the hemorrhage curve had the highest sensitivity for detecting hemorrhage at approximately 4 min after hemorrhage onset, compared to more than 45 min before detection based on mean arterial pressure. Conclusion: ML methods successfully tracked hemorrhage and provided earlier prediction in canines, potentially improving hemorrhage detection and objectifying triage for veterinary medicine. Further, its use can potentially be extended to human use with proper training datasets.

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.

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.

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.

Ectonucleotidases in Ischemia Reperfusion Injury: Unravelling the Interplay With Mitochondrial Dysfunction in Liver Transplantation.

Ischemia-reperfusion injury (IRI) profoundly impacts organ transplantation, especially in orthotopic liver transplantation (OLT). Disruption of the mitochondrial respiratory chain during ischemia leads to ATP loss and ROS production. Reperfusion exacerbates mitochondrial damage, triggering the release of damage-associated molecular patterns (DAMPs) and inflammatory responses. Mitochondrial dysfunction, a pivotal aspect of IRI, is explored in the context of the regulatory role of ectonucleotidases in purinergic signaling and immune responses. CD39, by hydrolyzing ATP and ADP; and CD73, by converting AMP to adenosine, emerge as key players in mitigating liver IRI, particularly through ischemic preconditioning and adenosine receptor signaling. Despite established roles in vascular health and immunity, the impact of ectonucleotidases on mitochondrial function during hepatic IRI is unclear. This review aims to elucidate the interplay between CD39/73 and mitochondria, emphasizing their potential as therapeutic targets for liver transplantation. This article explores the role of CD39/73 in tissue hypoxia, emphasizing adenosine production during inflammation. CD39 and CD73 upregulation under hypoxic conditions regulate immune responses, demonstrating protective effects in various organ-specific ischemic models. However, prolonged adenosine activation may have dual effects, beneficial in acute settings but detrimental in chronic hypoxia. Herein, we raise questions about ectonucleotidases influencing mitochondrial function during hepatic IRI, drawing parallels with cancer cell responses to chemotherapy. The review underscores the need for comprehensive research into the intricate interplay between ectonucleotidases, mitochondrial dynamics, and their therapeutic implications in hepatic IRI, providing valuable insights for advancing transplantation outcomes.

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.

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.

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.

Resuscitative endovascular balloon occlusion of the aorta in out-of-hospital cardiac arrest - A Delphi consensus study for uniform data collection.

Background: Evolving research on resuscitative endovascular balloon occlusion of the aorta (REBOA) as an adjunct treatment for out-of-hospital cardiac arrest mandates uniform recording and reporting of data. A consensus on which variables need to be collected may enable comparing and merging data from different studies. We aimed to establish a standard set of variables to be collected and reported in future REBOA studies in out-of-hospital cardiac arrest. Methods: A four-round stepwise Delphi consensus process first asked experts to propose without restraint variables for future REBOA research in out-of-hospital cardiac arrest. The experts then reviewed the variables on a 5-point Likert scale and ≥75% agreement was defined as consensus. First authors of published papers on REBOA in out-of-hospital cardiac arrest over the last five years were invited to join the expert panel. Results: The data were collected between May 2022 and December 2022. A total of 28 experts out of 34 primarily invited completed the Delphi process, which developed a set of 31 variables that might be considered as a supplement to the Utstein style reporting of research in out-of-hospital cardiac arrest. Conclusions: This Delphi consensus process suggested 31 variables that enable future uniform reporting of REBOA in out-of-hospital cardiac arrest.

Real-Time Monitoring and Modulation of Blood Pressure in a Rabbit Model of Ischemic Stroke.

Control of blood pressure, in terms of both absolute values and its variability, affects outcomes in ischemic stroke patients. However, it remains challenging to identify the mechanisms that lead to poor outcomes or evaluate measures by which these effects can be mitigated because of the prohibitive limitations inherent to human data. In such cases, animal models can be utilized to conduct rigorous and reproducible evaluations of diseases. Here we report refinement of a previously described model of ischemic stroke in rabbits that is augmented with continuous blood pressure recording to assess the impacts of modulation on blood pressure. Under general anesthesia, femoral arteries are exposed through surgical cutdowns to place arterial sheaths bilaterally. Under fluoroscopic visualization and roadmap guidance, a microcatheter is advanced into an artery of the posterior circulation of the brain. An angiogram is performed by injecting the contralateral vertebral artery to confirm occlusion of the target artery. With the occlusive catheter remaining in position for a fixed duration, blood pressure is continuously recorded to allow for tight titration of blood pressure manipulations, whether through mechanical or pharmacological means. At the completion of the occlusion interval, the microcatheter is removed, and the animal is maintained under general anesthesia for a prescribed length of reperfusion. For acute studies, the animal is then euthanized and decapitated. The brain is harvested and processed to measure the infarct volume under light microscopy and further assessed with various histopathological stains or spatial transcriptomic analysis. This protocol provides a reproducible model that can be utilized for more thorough preclinical studies on the effects of blood pressure parameters during ischemic stroke. It also facilitates effective preclinical evaluation of novel neuroprotective interventions that might improve care for ischemic stroke patients.

Non-invasive central nervous system assessment of a porcine model of neuropathic pain demonstrates increased latency of somatosensory-evoked potentials.

BACKGROUND: The study of chronic pain and its treatments requires a robust animal model with objective and quantifiable metrics. Porcine neuropathic pain models have been assessed with peripheral pain recordings and behavioral responses, but thus far central nervous system electrophysiology has not been investigated. This work aimed to record non-invasive, somatosensory-evoked potentials (SEPs) via electroencephalography in order to quantitatively assess chronic neuropathic pain induced in a porcine model. NEW METHOD: Peripheral neuritis trauma (PNT) was induced unilaterally in the common peroneal nerve of domestic farm pigs, with the contralateral leg serving as the control for each animal. SEPs were generated by stimulation of the peripheral nerves distal to the PNT and were recorded non-invasively using transcranial electroencephalography (EEG). The P30 wave of the SEP was analyzed for latency changes. RESULTS: P30 SEPs were successfully recorded with non-invasive EEG. PNT resulted in significantly longer P30 SEP latencies (p < 0.01 [n = 8]) with a median latency increase of 14.3 [IQR 5.0 - 17.5] ms. Histological results confirmed perineural inflammatory response and nerve damage around the PNT nerves. COMPARISON WITH EXISTING METHOD(S): Control P30 SEPs were similar in latency and amplitude to those previously recorded invasively in healthy pigs. Non-invasive recordings have numerous advantages over invasive measures. CONCLUSIONS: P30 SEP latency can serve as a quantifiable neurological measure that reflects central nervous system processing in a porcine model of chronic pain. Advancing the development of a porcine chronic pain model will facilitate the translation of experimental therapies into human clinical trials.

Noninvasive and Invasive Renal Hypoxia Monitoring in a Porcine Model of Hemorrhagic Shock.

Up to 50% of patients with trauma develop acute kidney injury (AKI), in part due to poor renal perfusion after severe blood loss. AKI is currently diagnosed based on a change in serum creatinine concentration from baseline or prolonged periods of decreased urine output. Unfortunately, baseline serum creatinine concentration data is unavailable in most patients with trauma, and current estimation methods are inaccurate. In addition, serum creatinine concentration may not change until 24-48 h after the injury. Lastly, oliguria must persist for a minimum of 6 h to diagnose AKI, making it impractical for early diagnosis. AKI diagnostic approaches available today are not useful for predicting risk during the resuscitation of patients with trauma. Studies suggest that urinary partial pressure of oxygen (PuO2) may be useful for assessing renal hypoxia. A monitor that connects the urinary catheter and the urine collection bag was developed to measure PuO2 noninvasively. The device incorporates an optical oxygen sensor that estimates PuO2 based on luminescence quenching principles. In addition, the device measures urinary flow and temperature, the latter to adjust for confounding effects of temperature changes. Urinary flow is measured to compensate for the effects of oxygen ingress during periods of low urine flow. This article describes a porcine model of hemorrhagic shock to study the relationship between noninvasive PuO2, renal hypoxia, and AKI development. A key element of the model is the ultrasound-guided surgical placement in the renal medulla of an oxygen probe, which is based on an unsheathed optical microfiber. PuO2 will also be measured in the bladder and compared to the kidney and noninvasive PuO2 measurements. This model can be used to test PuO2 as an early marker of AKI and assess PuO2 as a resuscitative endpoint after hemorrhage that is indicative of end-organ rather than systemic oxygenation.