Early Vasopressor Requirement Among Hypotensive Trauma Patients: Does It Cause More Harm Than Good?

BACKGROUND: Optimal utilization of vasopressors during early post-injury resuscitation remains unclear. Our study aims to describe the relationship between the timing of vasopressor administration and outcomes among hypotensive trauma patients. METHODS: This was a retrospective analysis of the 2017-2018 ACS-TQIP database. We included adult (≥18 years) trauma patients presenting with hypotension (lowest SBP <90 mmHg) who received vasopressors within 6 hours of admission. We excluded patients who had a severe head injury (Head-AIS >3) and those with spinal cord injury (Spine-AIS >3). Patients were stratified based on the time to receive vasopressors. Multivariable regression analyses were performed to identify the independent association between timing of vasopressor initiation and outcomes. RESULTS: 1049 patients were identified. Mean age was 55 ± 20 years, and 70% of patients were male. The median ISS was 16 [9-24], 80% had a blunt injury, and the mean SBP was 61 ± 24 mmHg. The median time to first vasopressor administration was 319 [68-352] minutes. Overall, 24-hour and in-hospital mortality rates were 19% and 33%, respectively. Every one-hour delay in vasopressor administration beyond the first hour was independently associated with decreased odds of 24-hour mortality (aOR: 0.65, P < 0.001), in-hospital mortality (aOR: 0.65, P < 0.001), major complications (aOR: 0.77, P = 0.003), and increased odds of longer ICU LOS (ß + 2.53, P = 0.012). There were no associations between the timing of early vasopressor administration and 24-hour PRBC transfusion requirements (P > 0.05). CONCLUSION: Earlier vasopressor requirement among hypotensive trauma patients was independently associated with increased mortality and major complications. Further research on the utility and optimal timing of vasopressors during the post-injury resuscitative period is warranted. LEVEL OF EVIDENCE: III therapeutic/care management.

Elevated Shear Stress Modulates Heterogenous Cellular Subpopulations to Induce Vascular Remodeling.

Rationale: Elevated shear stress (ESS) induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arteriovenous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with a single-cell resolution before. Objective: Using an in vivo animal mode, single-cell RNA sequencing, and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling. Methods: AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote ESS. Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls. Findings: ESS promoted transcriptional homogeneity, and NSS promoted considerable heterogeneity. Specifically, ESS endothelial cells (ECs) showed a more homogeneous transcriptional response promoting angiogenesis and upregulating endothelial-to-mesenchymal transition inhibiting genes (Klf2). NSS ECs upregulated antiproliferation genes such as Cav1, Cst3, and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated, proinflammatory and thus proangiogenic myeloid phenotype, whereas NSS myeloid cells expressed the anti-inflammatory and antiangiogenetic marker Mrc1. Conclusion: ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.

Avenanthramide and ß-Glucan Therapeutics Accelerate Wound Healing Via Distinct and Nonoverlapping Mechanisms.

Objective: Given the significant economic, health care, and personal burden of acute and chronic wounds, we investigated the dose dependent wound healing mechanisms of two Avena sativa derived compounds: avenanthramide (AVN) and ß-Glucan. Approach: We utilized a splinted excisional wound model that mimics human-like wound healing and performed subcutaneous AVN and ß-Glucan injections in 15-week-old C57BL/6 mice. Histologic and immunohistochemical analysis was performed on the explanted scar tissue to assess changes in collagen architecture and cellular responses. Results: AVN and ß-Glucan treatment provided therapeutic benefits at a 1% dose by weight in a phosphate-buffered saline vehicle, including accelerated healing time, beneficial cellular recruitment, and improved tissue architecture of healed scars. One percent AVN treatment promoted an extracellular matrix (ECM) architecture similar to unwounded skin, with shorter, more randomly aligned collagen fibers and reduced inflammatory cell presence in the healed tissue. One percent ß-Glucan treatment promoted a tissue architecture characterized by long, thick bundles of collagen with increased blood vessel density. Innovation: AVN and ß-Glucan have previously shown promise in promoting wound healing, although the therapeutic efficacies and mechanisms of these bioactive compounds remain incompletely understood. Furthermore, the healed ECM architecture of these wounds has not been characterized. Conclusions: AVN and ß-Glucan accelerated wound closure compared to controls through distinct mechanisms. AVN-treated scars displayed a more regenerative tissue architecture with reduced inflammatory cell recruitment, while ß-Glucan demonstrated increased angiogenesis with more highly aligned tissue architecture more indicative of fibrosis. A deeper understanding of the mechanisms driving healing in these two naturally derived therapeutics will be important for translation to human use.

Protocol for the Splinted, Human-like Excisional Wound Model in Mice.

While wound healing in humans occurs primarily through re-epithelization, in rodents it also occurs through contraction of the panniculus carnosus, an underlying muscle layer that humans do not possess. Murine experimental models are by far the most convenient and inexpensive research model to study wound healing, as they offer great variability in genetic alterations and disease models. To overcome the obstacle of contraction biasing wound healing kinetics, our group invented the splinted excisional wound model. While other rodent wound healing models have been used in the past, the splinted excisional wound model has persisted as the most used model in the field of wound healing. Here, we present a detailed protocol of updated and refined techniques necessary to utilize this model, generate results with high validity, and accurately analyze the collected data. This model is simple to conduct and provides an easy, standardizable, and replicable model of human-like wound healing.