Resume: Mortality from major bleeding in trauma patients is highest within the first six hours post-injury. Advances in patient management, driven by national guidelines and clinical trials, have significantly improved outcomes. However, variability in patient profiles, clinical presentations, and standard care practices complicates the assessment of treatment efficacy in clinical trials. In June 2024, international experts convened at the Critical Care Clinical Trialists (3CT) Workshop to examine the evolution of massive bleeding management and the impact of patient and treatment heterogeneity on trial design. This opinion article builds on the workshop discussions and underscores key considerations for the interpretation of large-scale studies. Three main conclusions emerged: First, the need for standardized definitions of "massive bleeding," "life-threatening bleeding," and "massive transfusion" to ensure consistent patient classification and treatment strategies. Second, the importance of tailored approaches that account for patient heterogeneity, including the careful selection of target populations and the use of appropriate primary endpoints. Third, the necessity of methodological adaptations in emergency research settings, such as implementing deferred consent procedures, conducting interim analyses, and using automated adjudication systems to improve objectivity and trial efficiency. In summary, harmonizing terminology, embracing clinical diversity, and refining trial design are essential to enhance the quality, comparability, and clinical relevance of research in massive bleeding. These measures ultimately aim to improve outcomes for critically bleeding patients.

Nearly half of the burn patients in the United States are under the influence of alcohol at the time of injury and alcohol intoxication is associated with poor clinical outcomes. Ethanol has been shown to worsen burn-induced intestinal dysfunction and inflammation, facilitating bacterial translocation from the intestine to the mesenteric lymph nodes and systemic circulation. Regenerating islet-derived protein 3-gamma (REG3G), an antimicrobial peptide crucial for maintaining intestinal homeostasis, protects mice from ethanol-induced bacterial translocation. In this study, we utilized a murine model to determine whether REG3G protects against the combined effects of acute ethanol exposure and burn injury. Mice with intestinal epithelial cell-specific overexpression of REG3G (Reg3g-Tg) were evaluated for gut barrier function, intestinal and hepatic inflammatory cytokines, and antimicrobial peptide expression after ethanol and burn injury. Additionally, we performed 16S rRNA gene sequencing of fecal microbiota. Our results demonstrate that ethanol exposure before burn injury downregulates the antimicrobial peptide REG3G in the ileum, when compared to burn alone. Intestine-specific overexpression of REG3G reversed several gastrointestinal effects of the combined injury, reducing intestinal inflammation and preventing bacterial translocation to the lymph nodes. Moreover, Reg3g-Tg mice exhibited reduced liver inflammation after combined injury, suggesting that improving intestinal function can also influence extra-intestinal organs. These findings highlight the therapeutic potential of REG3G in mitigating the effects of burn injury and alcohol intoxication.

Preclinical models using animals are crucial for medical advancements despite their limitations and criticisms. Critical illnesses like sepsis, trauma, and burns remain huge causes of morbidity and mortality despite medical advances, and human studies may not always be feasible. In this part 1 of 2 reviews about animal models for critical illness, we discuss sepsis and the considerations one should take to optimize the rodent sepsis model. There are multiple models of sepsis used, each with advantages and disadvantages and they can be modified to reflect how patients are treated in the hospital, including intensive care unit care. Patient factors like age, sex, and comorbidities are important considerations given the different responses to sepsis. Aspects of sepsis that our patients encounter including muscle and neurocognitive dysfunction can be modeled to try and improve those aspects of outcomes. Choosing the right models for the question one is asking and optimizing that model is key to recapitulate the human condition to make animal models more translatable to humans. In other words, we suggest that, in lieu of abandoning animal models of sepsis, we seek to enhance translatability to the human condition.

Traumatic brain injury (TBI) is a significant cause of death and disability, affecting nearly 300,000 Americans annually. Beyond the immediate physical damage, TBI induces chronic neuroinflammation and long-term neurodegeneration, leading to various neurologic and psychiatric disorders. This review examines the cerebrovascular unit (CVU), particularly the cerebral endothelial cells, and their critical role in the aftermath of TBI. Following TBI, the CVU undergoes functional changes to counteract inflammation, repair endothelial damage, and promote angiogenesis. However, dysregulation of these protective mechanisms can lead to chronic neuroinflammation, increased cerebrovascular permeability, and systemic endothelial dysfunction. The review explores the molecular and cellular responses of the CVU following TBI, highlighting the roles of inflammatory cytokines, oxidative stress, and various endothelial transport mechanisms. Moreover, TBI-related endothelial dysfunction may extend beyond the brain, potentially contributing to systemic complications such as acute respiratory distress syndrome (ARDS) and multisystem organ failure. Despite the gravity of these conditions, clinical breakthroughs remain limited. This review underscores the necessity for targeted therapeutic strategies to mitigate endothelial dysfunction and improve long-term outcomes for TBI patients. Future research is essential to elucidate the precise mechanisms driving CVU dysfunction and to develop interventions that can alleviate the chronic effects of TBI.

Thiamine has been utilized for metabolic resuscitation in septic shock (SS), but optimal thiamine dosing remains unknown. The purpose of this study was to assess variable thiamine dosing in critically ill patients with SS.

Traumatic injury induces a complex host response, comprising endothelial damage, and simultaneous pro- and anti-inflammatory responses. These may contribute to complications seen in some patients days or weeks later. Although there is ever-increasing evidence showing that resuscitation with blood products improves survival, their impact on the host response remains unclear. A terminally anaesthetised Large White pig model of traumatic haemorrhagic shock (THS) and prolonged care evaluated different resuscitation fluids (saline, fresh frozen plasma (FFP), packed red blood cells and FFP (1:1), or fresh whole blood (n = 9 per group)). Serial blood samples were collected for ELISA, haematology and flow cytometry, and post-mortem tissue samples collected for RT-qPCR and immunohistochemistry. THS significantly increased circulating markers of endothelial activation (angiopoietin-2 and vWF antigen; both p < 0.001) and glycocalyx shedding (hyaluronic acid; p < 0.001). THS also elicited a robust inflammatory response, with significant elevations in circulating interleukin-6 and HMGB-1 (both: p < 0.001), neutrophilia (p <0.001), lymphopenia (p < 0.001) and increased inflammatory gene expression across a number of tissues. Compared to saline, resuscitation with blood products reduced hyaluronic acid (p < 0.001) but not angiopoeitin-2 or vWF antigen (both p > 0.05). The effect of blood products on peripheral cytokine concentrations or immune cell populations was minimal, nor did they significantly alter tissue inflammatory gene expression, neutrophil or lymphocyte number compared to saline-treated animals. These data suggest resuscitation with blood products can protect the endothelial glycocalyx, but they have little impact on the acute (< 8 hour) host response(s) to THS and prolonged care compared to animals treated with saline.

Cardiomyopathy is a common complication of sepsis that contributes to increased morbidity and mortality. However, the molecular mechanisms underlying septic cardiomyopathy are poorly understood. Dichloroacetate (DCA) improves mitochondrial respiration and survival in a mouse model of sepsis by inhibiting pyruvate dehydrogenase kinase which inactivates pyruvate dehydrogenase (PDH) through phosphorylation of its subunits. In this study, we explore the role of DCA in septic cardiac dysfunction using a murine sepsis model.

Severe burn injury induces prolonged immune dysfunction, but the underlying molecular mechanisms remain poorly defined. We hypothesized that burn injury causes epigenetic and transcriptional training of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at 2, 9, and 14 days after 20% total body surface area (TBSA) contact burn. Targeted transcriptomics and chromatin profiling revealed a biphasic response: early transcriptional silencing of inflammatory genes (e.g., Stat3, Traf6, Nfkb1), followed by increased accessibility and expression of anti-inflammatory loci (Il10, Socs3). Metabolic genes showed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis indicated early IL-10 signaling activation and long-term repression of classical macrophage activation. Chromatin remodeling included nucleosome repositioning events, supporting dynamic, locus-specific regulation. These findings challenge the notion that burn-induced immune suppression is solely due to systemic inflammation and instead suggest durable, epigenetically programmed alterations in macrophage function.

Sepsis-induced acute lung injury (SI-ALI) is strongly influenced by ferroptosis, a regulated cell death pathway. Carnitine palmitoyltransferase 1A (CPT1A), known for its lysine succinyltransferase activity, regulates succinylation but its function in ferroptosis and SI-ALI remains to be elucidated. This study aim to determine the influence of CPT1A on ferroptotic processes in SI-ALI and to reveal the key regulatory mechanisms involved. The SI-ALI model was generated in C57BL/6 mice via cecal ligation and puncture (CLP), while alveolar epithelial cells MLE-12 were treated with lipopolysaccharides (LPS) to mimic SI-ALI in vitro. Quantitative PCR and Western blotting were employed to evaluate CPT1A levels in peripheral venous blood samples from SI-ALI patients, as well as in both the mouse and cellular models of SI-ALI. Ferroptosis was evaluated by measuring malondialdehyde, glutathione, Fe 2+ levels, and reactive oxygen species fluorescence intensity. To elucidate the underlying mechanisms, co-immunoprecipitation (co-IP) and standard IP techniques were utilized. Our findings indicated that CPT1A was downregulated in SI-ALI. Overexpression of CPT1A inhibited ferroptosis in the in vitro SI-ALI model by enhancing ACSL4 succinylation, thereby reducing ACSL4 expression. Notably, overexpression of ACSL4 counteracted CPT1A-mediated ferroptosis suppression in vitro. Moreover, CPT1A overexpression ameliorated pulmonary pathology and suppressed ferroptosis activation in the lungs of SI-ALI mice. Collectively, the results indicate that CPT1A alleviated SI-ALI through the inhibition of ferroptosis by promoting ACSL4 succinylation, providing a novel theoretical foundation and potential therapeutic target for SI-ALI treatment.

Impact of sepsis on human T-cell function and outcome was assessed. In sepsis survivors, IFNγ-production in response to T-cell stimulation remains intact, while sepsis non-survivors display exaggerated IFNγ responses to TCR-independent stimuli.

Frailty is an important determinant of outcomes in patients with cardiovascular disease; however, its impact on the management and prognosis of cardiogenic shock (CS) remains unclear. This study examined the association between frailty and in-hospital outcomes, focusing on sex-based differences in treatment and mortality.

Sepsis is a severe systemic inflammatory response, typically triggered by infection. When the body's response to infection becomes dysregulated, it can result in organ dysfunction, tissue damage, and even death. Sepsis can affect people of all ages, but older adults, individuals with weakened immune systems, and those with chronic illnesses are at greater risk. Timely diagnosis and immediate intervention are essential to enhance the chances of survival.

To analyze risk factors for cardiac rupture (CR) in acute myocardial infarction (AMI) patients and develop a validated prognostic prediction model.

Acute lung injury (ALI) caused by sepsis is a serious complication of sepsis and a major cause of death, and there is a lack of effective drug treatment. Transforming growth factor beta receptor II (TGFBR2) expression is related to sepsis and acute lung injury. Therefore, this study is to clarify the mechanism of TGFBR2 in sepsis-induced ALI.

Sepsis leads to long-term physical dysfunction. We report long-term habitual activity levels in free-living conditions, which may support future studies on early identification of at-risk patients for mobility loss post-sepsis.

Patients undergoing cardiac surgery with cardiopulmonary bypass (CSCPB) are at substantial postoperative risk, which may be influenced by alterations in gut microbiota and metabolites. The roles of these biological changes in postoperative outcomes remain inadequately explored.

Smoke inhalation injury induces airway edema, obstruction, and bronchospasm leading to hypoxia and acute respiratory distress syndrome (ARDS). When ARDS is refractory to conventional therapy, veno-venous extracorporeal membrane oxygenation (VV ECMO) is used as a rescue strategy. We hypothesized that nebulized epinephrine improves oxygenation by alleviating airway dysfunction during VV ECMO support.

Current data demonstrates that early blood product resuscitation and minimization of crystalloid improve outcomes. However, there is little data on crystalloid use after hemorrhage control. We hypothesized that administration of crystalloid during early post-resuscitation care may contribute to ongoing endothelial dysfunction.

Infants with congenital heart disease (CHD) frequently undergo surgery during their first year of life. Infants undergoing CHD surgery experience systemic inflammation and haemodilution that can deplete circulating immunoglobulins (Ig).

Despite the widespread use of intra-aortic balloon pump (IABP) support in contemporary cardiac care, the factors influencing transfusion practices remain insufficiently understood.

Guideline-based recommendations for post-hemostasis resuscitation in trauma patients remain limited. This study aimed to define an interpretable Markov Decision Process (MDP) to model intensive care unit (ICU) trauma resuscitation and evaluate its potential to support clinical decision-making using a previously established framework from sepsis care.