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Abstract: Introduction : Improvements in combat casualty care have increased survival rates, but these patients are at particular risk of developing multiple organ failure (MOF). We investigated the incidence and severity of MOF in a cohort of severe combat casualties. Materials and Methods : This retrospective study included all on-duty French land army war casualties with a severe combat injury requiring intensive care unit admission during 2009-2023. Demographic data, advanced life support interventions, and outcomes were collected. Each organ failure was then analyzed during a 7-day trauma course according to the Sequential Organ Failure Assessment score. Results: Of the 100 patients who met the inclusion criteria, those with persistent MOF at day 4 (MOF group) represented 22% of the total population (median Sequential Organ Failure Assessment score 6.0 [5.3-8.0]). Compared to those without persistent MOF, these patients were more severely injured (median Military Injury Severity Score 38.0 [interquartile range 33.0-56.8] vs. 26.5 [20.0-34.0], P < 0.001) by an explosive mechanism (68.2%) and sustained more traumatic brain injury (40.9% vs. 14.1%, P = 0.013). The MOF group also received significantly more blood units (median 14.0 [8.3-24.8] vs. 6.0 [0.0-12.0], P < 0.001) and massive transfusions (68.2% vs. 32.1%, P = 0.002). Pulmonary and cardiovascular dysfunction were the most frequently observed trauma outcomes. A multivariable logistic regression model showed that MOF persistence at day 4 was significantly associated (odds ratios [95% confidence intervals]) with severe injuries (1.5 [1-2.3], P = 0.042). Conclusion : A high number of severe lesions significantly and independently increased risk of MOF persistence at day 4 after combat-related trauma. These findings are particularly relevant to current and anticipated large-scale combat operations that will challenge battlefield casualty care and evacuation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Abstract: Background : This study sought to predict time to patient hemodynamic stabilization during trauma resuscitations of hypotensive patient encounters using electronic medical record (EMR) data. Methods: This observational cohort study leveraged EMR data from a nine-hospital academic system composed of Level I, Level II, and nontrauma centers. Injured, hemodynamically unstable (initial systolic blood pressure, <90 mm Hg) emergency encounters from 2015 to 2020 were identified. Stabilization was defined as documented subsequent systolic blood pressure of >90 mm Hg. We predicted time to stabilization testing random forests, gradient boosting, and ensembles using patient, injury, treatment, EPIC Trauma Narrator, and hospital features from the first 4 hours of care. Results: Of 177,127 encounters, 1,347 (0.8%) arrived hemodynamically unstable; 168 (12.5%) presented to Level I trauma centers, 853 (63.3%) to Level II, and 326 (24.2%) to nontrauma centers. Of those, 747 (55.5%) were stabilized with a median of 50 min (interquartile range, 21-101 min). Stabilization was documented in 94.6% of unstable patient encounters at Level I, 57.6% at Level II, and 29.8% at nontrauma centers ( P < 0.001). Time to stabilization was predicted with a C-index of 0.80. The most predictive features were EPIC Trauma Narrator measures, documented patient arrival, provider examination, and disposition decision. In-hospital mortality was highest at Level I, 3.0% vs. 1.2% at Level II, and 0.3% at nontrauma centers ( P < 0.001). Importantly, nontrauma centers had the highest retriage rate to another acute care hospital (12.0%) compared to Level II centers (4.0%, P < 0.001). Conclusion: Time to stabilization of unstable injured patients can be predicted with EMR data., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, comorbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1β, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.

Abstract: Objective: To investigate the protective effect and possible mechanisms of vitamin B 6 against renal injury in patients with sepsis. Methods: A total of 128 patients with sepsis who met the entry criteria in multiple centers were randomly divided into experimental (intravenous vitamin B 6 therapy) and control (intravenous 0.9% sodium chloride therapy) groups based on usual care. Clinical data, the inflammatory response indicators interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor (TNF-α), and endothelin-1 (ET-1), the oxidative stress response indicators superoxide dismutase, glutathione and malondialdehyde, and renal function (assessed by blood urea nitrogen, serum creatinine, and renal resistance index monitored by ultrasound) were compared between the two groups. Results: After 7 d of treatment, the IL-6, IL-8, TNF-α, and ET-1 levels in the experimental group were significantly lower than those in the control group, the oxidative stress response indicators were significantly improved in the experimental group and the blood urea nitrogen, serum creatinine, and renal resistance index values in the experimental group were significantly lower than those in the control group ( P < 0.05). There was no statistical difference between the two groups in the rate of renal replacement therapy and 28 d mortality ( P > 0.05). However, the intensive care unit length of stay and the total hospitalization expenses in the experimental group were significantly lower than those in the control group ( P < 0.05). Conclusion: The administration of vitamin B 6 in the treatment of patients with sepsis attenuates renal injury, and the mechanism may be related to pyridoxine decreasing the levels of inflammatory mediators and their regulation by redox stress., Competing Interests: Competing interests: All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately. The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Abstract: Introduction: The global demand for intensive care has risen, given its effectiveness in lowering mortality rates. Mechanical ventilation (MV) is integral to intensive care but introduces risks such as ventilator-associated complications. Ethiopia experiences a high intensive care unit (ICU) mortality rate. Objective: This systematic review and meta-analysis aim to comprehensively synthesize evidence on the mortality of adults undergoing MV in Ethiopia and identify associated factors. Methods: The study extensively searched databases and gray literature for research on MV outcomes, trends, and associated factors in adult ICUs. Adhering to the 2020 PRISMA checklist, a systematic review and meta-analysis sought to establish the mortality rate and key determinants among adult ICU patients on MV. The search incorporated keywords and MeSH terms, excluding studies with unsound methodologies or missing data. Data extraction, quality assessment, and analysis followed established protocols, including the JBI tool for methodological quality evaluation. STATA version 17.0 facilitated analysis, assessing heterogeneity, publication bias, and performing sensitivity and meta-regression analyses. Results: The pooled mortality rate among adult ICU patients undergoing MV was 48.61% (95% CI: 40.82, 56.40%). Significant mortality-contributing factors included medical diagnosis, Glasgow Coma Scale score, sepsis/septic shock, sedation use, multiple-organ dysfunction syndrome, and cardiovascular disease. Although some pooled odds ratios seemed insignificant, closer examination revealed significant associations in individual studies. Conclusion : The study underscores the urgent need for further research, improved ICU infrastructure, and healthcare personnel training in Ethiopia to enhance outcomes for mechanically ventilated patients. Identified factors offer valuable insights for targeted interventions, guiding tailored treatment strategies to reduce mortality. This study contributes to understanding mortality and associated factors in MV patients, informing initiatives to improve critical care outcomes in Ethiopia., Competing Interests: Author conflict of interest statement: The authors declare that there is no conflict of interest regarding the publication of this article, "Prevalence of Mortality and Associated Factors Among ICU-Admitted Adult Patients with Mechanical Ventilation in Ethiopia: A Systematic Review and Meta-Analysis." The research was conducted objectively, and the authors have no financial or personal relationships that could influence or bias the findings and conclusions presented in this manuscript. This work was carried out with the sole purpose of contributing to the scientific understanding of mortality and associated factors in mechanically ventilated patients in Ethiopian ICUs. The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Abstract: We evaluated the participation of the endocannabinoid system in the paraventricular nucleus of the hypothalamus (PVN) on the cardiovascular, autonomic, and plasma vasopressin (AVP) responses evoked by hemorrhagic shock in rats. For this, the PVN was bilaterally treated with either vehicle, the selective cannabinoid receptor type 1 antagonist AM251, the selective fatty acid amide hydrolase amide enzyme inhibitor URB597, the selective monoacylglycerol-lipase enzyme inhibitor JZL184, or the selective transient receptor potential vanilloid type 1 antagonist capsazepine. We evaluated changes on arterial pressure, heart rate, tail skin temperature (ST), and plasma AVP responses induced by bleeding, which started 10 min after PVN treatment. We observed that bilateral microinjection of AM251 into the PVN reduced the hypotension during the hemorrhage and prevented the return of blood pressure to baseline values in the posthemorrhagic period. Inhibition of local 2-arachidonoylglycerol metabolism by PVN treatment with JZL184 induced similar effects in relation to those observed in AM251-treated animals. Inhibition of local anandamide metabolism via PVN treatment with URB597 decreased the depressor effect and ST drop induced by the hemorrhagic stimulus. Bilateral microinjection of capsazepine mitigated the fall in blood pressure and ST. None of the PVN treatments altered the increased plasma concentration of AVP and tachycardia induced by hemorrhage. Taken together, present results suggest that endocannabinoid neurotransmission within the PVN plays a prominent role in cardiovascular and autonomic, but not neuroendocrine, responses evoked by hemorrhage., Competing Interests: The authors report no conflict of interests., (Copyright © 2023 by the Shock Society.)

Abstract: Introduction : The optimal target of mean arterial pressure (MAP) during continuous renal replacement therapy (CRRT) is unknown. Method : We retrospectively collected the hourly MAP data in acute kidney injury patients requiring CRRT who admitted to the intensive care unit in the University of Tokyo hospital during 2011-2019. Patients who died within 48 h of CRRT start and whose average value of hourly MAPs during the first 48 h was <65 mm Hg were excluded. When the average value of MAP was ≤75 mm Hg or >75 mm Hg, patients were allocated to the low or high target group. We estimated the effect of MAP on mortality and RRT independence at 90 days, using multivariable the Cox regression model and Fine and Gray model. Result : Of the 275 patients we analyzed, 95 patients were in the low group. There are no differences in sex, baseline kidney function, and disease severity. At 90 days, the low target group had higher mortality with 38 deaths (40.0%) compared with 57 deaths (31.7%) in the high target group ( P < 0.05). The adjusted hazard ratio of the low target group (≤75 mm Hg) for mortality was 1.72 (95% CI, 1.08-2.74). In addition, the low target group had a lower rate of RRT independence, with 60 patients (63.2%) compared with 136 patients (75.6%) in the high target group ( P < 0.05). The multivariable analysis revealed that the adjusted hazard ratio of the low target group for RRT independence was 0.74 (95% CI, 0.54-1.01). Conclusion : This study found the association with low MAP and mortality. The association with low MAP and delayed renal recovery was not revealed., (Copyright © 2023 by the Shock Society.)

Abstract: Background: Resuscitative balloon occlusion of the aorta (REBOA) is an endovascular hemostasis method used for the management of traumatic abdominal and pelvic hemorrhages. However, REBOA-associated ischemia-reperfusion injury complication limits its blocking time. We hypothesized that mild therapeutic hypothermia would relieve ischemia-reperfusion injury caused by prolonged zone 1 REBOA. Methods: Ten pigs were anesthetized, intubated, and subsequently struck with the experimental sliding-chamber ballistic gun to inflict liver damage. Animals were randomized to hypothermia (60 min of zone 1 REBOA with external cooling for 180 min, n = 5) or control (60 min of zone 1 REBOA with no external cooling, n = 5). Physiological and laboratory parameters were monitored and assessed. Distal organs were obtained for histologic analysis. Results: At 180 min, compared with the control, the hypothermia animals exhibited significantly increased pH and significantly reduced lactate, hemoglobin, and hematocrit (all P < 0.05). The change of lactate from 0 to 180 min in hypothermia animals was less than that in the control ( P = 0.02). The total bleeding in the control group was significantly less than the hypothermia ( P < 0.01). In the hypothermia group, prothrombin time at 120 and 180 min was significantly longer than that at baseline (all P < 0.05). Compared with the control, animals in the hypothermia group showed slighter pathological injury of the distal organs and significantly lower overall injury score (all P < 0.05). Conclusions: Mild therapeutic hypothermia during prolonged zone 1 REBOA offered extraordinary distal organ preservation and decreased metabolic acidosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Abstract: Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N -formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y 1 -dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Abstract: Background and Objective: Although sepsis is heterogeneous, data on sepsis patients with normal lactate levels are very limited. We explored whether hypotension at the time of sepsis recognition (i.e., time zero) was significant in terms of survival when lactate levels were normal in sepsis patients. Patients and Design: This was a prospective multicenter observational study conducted in 19 hospitals (20 intensive care units [ICUs]). Adult sepsis patients with normal lactate levels (≤2 mmol/L) admitted to ICUs were divided by the mean arterial pressure at time zero into hypotensive (<65 mm Hg) and nonhypotensive groups (≥65 mm Hg). Measurements and Results: Of 2,032 patients with sepsis (not septic shock), 617 with normal lactate levels were included in the analysis. The hypotensive group (n = 237) was characterized by higher rates of abdominal or urinary infections, and bacteremia, whereas the nonhypotensive group (n = 380) was characterized by higher rates of pulmonary infections and systemic inflammatory response. However, the Simplified Acute Physiology Score 3 and Sequential Organ Failure Assessment score (excluding the cardiovascular score) were not different between the groups. During sepsis resuscitation, the rates of antibiotic administration within 1, 3, and 6 h of time zero were higher in the hypotensive than nonhypotensive group ( P < 0.05 for all time points), and the amounts of pre-ICU fluids given were also higher in the hypotensive group. However, despite a higher rate of vasopressor use in the hypotensive group, ICU and in-hospital mortality rates were not different between the groups (12.7% vs. 13.9% [ P = 0.648] and 19.4% vs. 22.4% [ P = 0.382], respectively). In multivariable analysis, the use of appropriate antibiotics and early lactate measurement were significant risk factors for in-hospital mortality. Conclusions: In sepsis patients with normal lactate levels, neither hypotension nor vasopressor use adversely impacted the hospital outcome. Our results emphasize the importance of early interventions and appropriate use of antibiotics regardless of whether a patient is or is not hypotensive., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Abstract: Introduction: The present study aimed to explore the clinical features and long-term outcomes associated with neurologic impairment in patients with cardiac arrest (CA) who received extracorporeal cardiopulmonary resuscitation (ECPR). Methods: A total of 37 adult CA patients who underwent venoarterial extracorporeal membrane oxygenation and were admitted to our department between January 2015 and February 2022 were divided according to neurologic impairment. Baseline and CPR- and ECMO-related characteristics were compared between the two groups. Long-term neurologic outcomes were collected via telephone follow-ups. Results: Twenty-four (64.9%) ECPR-supported patients developed neurologic impairments. The two groups differed significantly in median age (P = 0.026), proportion of intra-aortic balloon pump (IABP) support (P = 0.011), proportion of continuous renal replacement therapy (P = 0.025), and median serum creatinine (Cr) level (P = 0.012) pre-ECMO. The 28-day mortality (P = 0.001), hospital mortality (P = 0.003), median duration from CA to restoration of spontaneous circulation (P = 0.029), proportion of patients with nonpulsatile perfusion (NP) >12 hours (P = 0.040), and median ECMO duration (P = 0.047) were higher in the neurologic impairment group. In contrast, the group without neurologic impairment exhibited a longer median intensive care unit length of stay (P = 0.047), longer median hospital LOS (P = 0.031), and more successful ECMO weaning (P = 0.049). Moreover, NP >12 hours combined with IABP support (odds ratio [OR], 14.769; 95% confidence interval [CI], 1.417~153.889; P = 0.024) and serum Cr level (OR, 1.028; 95% CI, 1.001~1.056; P = 0.043) were independent risk factors for neurologic impairment. Furthermore, neurologic impairment was associated with significantly worse 90-day survival (hazards ratio, 4.218; 95% CI, 1.745~10.2; P = 0.0014). Conclusions: The incidence of neurologic impairment was higher in patients who received ECPR and was closely related to 28-day mortality and discharge survival. NP >12 hours combined with IABP support and serum Cr levels were independent risk factors for neurologic impairments in ECPR-supported patients. Neurologic impairment significantly adversely affected the long-term outcomes of ECPR-supported patients after discharge., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Abstract: Introduction: The endotheliopathy of trauma develops early after injury and consists of increased vascular permeability, inflammation, and dysfunctional coagulation. Persistence of these abnormalities ultimately leads to multiorgan failure. We hypothesized that extending an established 3-hour acute mouse model of hemorrhagic shock and trauma (HS/T) to a 24-hour survival model would allow for evaluation of persistent endotheliopathy and organ injury after HS/T. Methods: Adult male C57BL/6J mice underwent laparotomy, femoral artery cannulation, and blood withdrawal to induce HS to a MAP of 35 mm Hg for 90 minutes. Mice were resuscitated with either lactated Ringer's (LR) or fresh frozen plasma (FFP). Vascular permeability in the lung and gut was assessed by measuring extravasation of a fluorescent dextran dye. Lungs were evaluated for histopathologic injury, and immunofluorescent staining was used to evaluate intercellular junction integrity. Pulmonary inflammatory gene expression was evaluated using NanoString (Seattle, WA). All endpoints were evaluated at both 3 and 24 hours after initiation of shock. Results: Lactated Ringer's- and FFP-treated mice had an equal mortality rate of 17% in the 24-hour model. Lactated Ringer's-treated mice demonstrated increased vascular permeability in the lung and gut at 3 hours compared with sham mice (lung, P &lt; 0.01; gut, P &lt; 0.001), which was mitigated by FFP treatment (lung, P &lt; 0.05; gut, P &lt; 0.001). Twenty-four hours after shock, however, there were no differences in vascular permeability between groups. Similarly, although at 3 hours, the lungs of LR-treated mice demonstrated significant histopathologic injury, loss of tight and adherens junctions, and a pro-inflammatory gene expression profile at 3 hours, these endpoints in LR mice were similar to sham mice by 24 hours. Conclusions: In an established mouse model of HS/T, endotheliopathy and lung injury are evident at 3 hours but recover by 24 hours. Polytrauma models or larger animal models allowing for more severe injury coupled with supportive care are likely necessary to evaluate endotheliopathy and organ injury outside of the acute period., Competing Interests: The authors report no conflict of interests., (Copyright © 2022 by the Shock Society.)

Abstract: Objective: The aim of this study was to characterize early urinary gene expression differences between patients with sepsis and patients with sterile inflammation and summarize in terms of a reproducible sepsis probability score. Design: This was a prospective observational cohort study. Setting: The study was conducted in a quaternary care academic hospital. Patients: One hundred eighty-six sepsis patients and 78 systemic inflammatory response syndrome (SIRS) patients enrolled between January 2015 and February 2018. Interventions: Whole-genome transcriptomic analysis of RNA was extracted from urine obtained from sepsis patients within 12 hours of sepsis onset and from patients with surgery-acquired SIRS within 4 hours after major inpatient surgery. Measurements and Main Results: We identified 422 of 23,956 genes (1.7%) that were differentially expressed between sepsis and SIRS patients. Differentially expressed probes were provided to a collection of machine learning feature selection models to identify focused probe sets that differentiate between sepsis and SIRS. These probe sets were combined to find an optimal probe set (UrSepsisModel) and calculate a urinary sepsis score (UrSepsisScore), which is the geometric mean of downregulated genes subtracted from the geometric mean of upregulated genes. This approach summarizes the expression values of all decisive genes as a single sepsis score. The UrSepsisModel and UrSepsisScore achieved area under the receiver operating characteristic curves 0.91 (95% confidence interval, 0.86-0.96) and 0.80 (95% confidence interval, 0.70-0.88) on the validation cohort, respectively. Functional analyses of probes associated with sepsis demonstrated metabolic dysregulation manifest as reduced oxidative phosphorylation, decreased amino acid metabolism, and decreased oxidation of lipids and fatty acids. Conclusions: Whole-genome transcriptomic profiling of urinary cells revealed focused probe panels that can function as an early diagnostic tool for differentiating sepsis from sterile SIRS. Functional analysis of differentially expressed genes demonstrated a distinct metabolic dysregulation signature in sepsis., Competing Interests: Conflicts of Interest and Source of Funding: A.B. and T.O.-B. were supported by R01 GM110240 from the National Institute of General Medical Sciences. A.B. T.O.-B., M.-C.L., H.V.B., and M.S.S. were supported by Sepsis and Critical Illness Research Center Award P50 GM-111152 from the National Institute of General Medical Sciences. A.B. and P.R. were supported by R01 GM110240 from the National Institute of General Medical Sciences (NIH/NIGMS), by 1R01EB029699 and 1R21EB027344 from the National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB), and 1R01NS120924 from the National Institute of Neurological Disorders and Stroke (NIH/NINDS). P.R. was supported by the National Science Foundation CAREER award 1750192. A.B. was supported by UF Research AWD09458. T.O.-B. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health grant K01 DK120784 and by UF Research AWD09459 and the Gatorade Trust, University of Florida. T.J.L. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award K23 GM140268. The research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under University of Florida Clinical and Translational Science Awards UL1TR000064 and UL1TR001427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Abstractintroduction: Although a number of studies have demonstrated increased release of extracellular vesicles (EVs) and changes in their origin differentials after trauma, the biologic significance of EVs is not well understood. We hypothesized that EVs released after trauma/hemorrhagic shock (HS) contribute to endotheliopathy and coagulopathy. To test this hypothesis, adoptive transfer experiments were performed to determine whether EVs derived from severely injured patients in shock were sufficient to induce endothelial dysfunction and coagulopathy. Methods: Total EVs were enriched from plasma of severely injured trauma/HS patients or minimally injured patients by ultracentrifugation and characterized for size and numbers. Under isoflurane anesthesia, noninjured naive C57BL/6J mice were administered EVs at varying concentrations and compared with mice receiving equal volume vehicle (phosphate-buffered saline (PBS)) or to mice receiving EVs from minimally injured patients. Thirty minutes after injection, mice were sacrificed, and blood was collected for thrombin generation (thrombin-antithrombin, thrombin-antithrombin complex [TAT] assay) and syndecan-1 by enzyme-linked immunoabsorbent assay (ELISA). Lungs were harvested for examination of histopathologic injury and costained with von Willebrand factor and fibrin to identify intravascular coagulation. Bronchial alveolar lavage fluid was aspirated from lungs for protein measurement as an indicator of the endothelial permeability. Data are presented as mean ± SD, P < 0.05 was considered significant, and t test was used. Results: An initial proof-of-concept experiment was performed in naive mice receiving EVs purified from severely injured trauma/HS patients (Injury Severity Score [ISS], 34 ± 7) at different concentrations (5 × 106 to 3.1 × 109/100 μL/mouse) and compared with PBS (control) mice. Neither TAT nor syndecan-1 levels were significantly different between groups at 30 minutes after EV infusion. However, lung vascular permeability and histopathologic injury were significantly higher in the EV group, and lung tissues demonstrated intravascular fibrin deposition. Based on these data, EVs from severely injured trauma/HS patients (ISS, 32 ± 6) or EVs from minimally injured patients (ISS, 8 ± 3) were administered to naive mice at higher concentrations (1 × 109 to 1 × 1010 EV/100 μL/mouse). Compared with mice receiving EVs from minimally injured patients, plasma TAT and syndecan-1 levels were significantly higher in the trauma/HS EV group. Similarly, bronchial alveolar lavage protein and lung histopathologic injury were higher in the trauma/HS EV group, and lung tissues demonstrated enhanced intravascular fibrin deposition. Conclusion: These data demonstrate that trauma/HS results in the systemic release of EVs, which are capable of inducing endotheliopathy as demonstrated by elevated syndecan-1 and increased permeability and coagulopathy as demonstrated by increased TAT and intravascular fibrin deposition. Targeting trauma-induced EVs may represent a novel therapeutic strategy., Competing Interests: The authors report no conflict of interests., (Copyright © 2022 by the Shock Society.)

Background: Ischemia reperfusion injury causes a profound hyperdynamic distributive shock. Endovascular perfusion augmentation for critical care (EPACC) has emerged as a hemodynamic adjunct to vasopressors and crystalloid. The objective of this study was to examine varying levels of mechanical support for the treatment of ischemiareperfusion injury in swine., Methods: Fifteen swine underwent anesthesia and then a controlled 30% blood volume hemorrhage followed by 30 min of supra-celiac aortic occlusion to create an ischemia-reperfusion injury Animals were randomized to standardized critical care (SCC), EPACC with low threshold (EPACC-Low), and EPACC with high threshold (EPACC-High). The intervention phase lasted 270 min after injury Hemodynamic markers and laboratory values of ischemia were recorded., Results: During the intervention phase, SCC spent 82.4% of the time avoiding proximal hypotension (>60 mm Hg), while EPACC-Low spent 97.6% and EPACC-High spent 99.5% of the time avoiding proximal hypotension, P  < 0.001. Renal artery flow was statistically increased in EPACC-Low compared with SCC (2.29 mL/min/kg vs. 1.77 mL/ min/kg, P  < 0.001), while renal flow for EPACC-High was statistically decreased compared with SCC (1.25 mL/min/kg vs. 1.77 mL/min/kg, P  < 0.001). EPACC animals required less intravenous norepinephrine, (EPACC-Low: 16.23mcg/kg and EPACC-High: 13.72 mcg/kg), compared with SCC (59.45 mcg/kg), P = 0.049 and P = 0.013 respectively., Conclusions: Compared with SCC, EPACC-High and EPACC-Low had decreased norepinephrine requirements with decreased frequency of proximal hypotension. EPACC-Low paradoxically had increased renal perfusion despite having a mechanical resistor in the aorta proximal to the renal arteries. This is the first description of low volume mechanical hemodynamic support in the setting of profound shock from ischemia-reperfusion injury in swine demonstrating stabilized proximal hemodynamics and augmented distal perfusion., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: The pre-hospital use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is increasing, although it remains controversial, in part because of suggested contraindications such as acute cardiac tamponade (ACT). As both the pre-hospital and in-hospital use of REBOA might potentially occur with concurrent ACT, knowledge of the hemodynamic effect of REBOA in this setting is crucial. This study, therefore, aimed at investigating the physiological effects of REBOA in hemodynamic instability secondary to ACT in a porcine model. We hypothesize that REBOA can temporarily increase systemic blood pressure and carotid blood flow, and prolong survival, in hemodynamic shock caused by ACT., Methods: Fourteen pigs (24-38 kg) underwent ACT, through true cardiac injury and hemorrhage into the pericardial space, and were allowed to hemodynamically deteriorate. At a systolic blood pressure (SBP) of 50 mm Hg (SBP50) they were randomized to total occlusion REBOA in zone 1 or to a control group. Survival, hemodynamic parameters, carotid blood flow (CBF), femoral blood flow (FBF), cardiac output (CO), end-tidal CO2, and arterial blood gas parameters were analyzed., Results: REBOA intervention was associated with a significant increase in SBP (50 mm Hg to 74 mm Hg, P = 0.016) and CBF (110 mL/min to 195 mL/min, P = 0.031), with no change in CO, compared to the control group. At 20 min after SBP50, the survival rate in the intervention group was 86% and in the control group 14%, with time to death being significantly longer in the intervention group., Conclusions: This randomized animal study demonstrates that REBOA can help provide hemodynamic stabilization and prolong survival in hemodynamic shock provoked by ACT. It is important to stress that our study does not change the fact that urgent pericardiocentesis or cardiac surgery is, and should remain, the standard optimal treatment for ACT.Level of evidence: Prospective, randomized, experimental animal study. Basic science study, therapeutic., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Introduction: The Surviving Sepsis Campaign published the Hour-1 Sepsis Bundle in 2018. The first-hour management of patients with sepsis in the emergency department (ED) is important, as suggested in the Hour-1 Sepsis Bundle. The objectives of the present study were to evaluate 28-day mortality and delayed septic shock with use of a complete and incomplete Hour-1 Sepsis Bundle in the ED., Methods: This prospective cohort study included adult patients with sepsis from March to July 2019. We followed the sepsis protocol used in the ED of a tertiary care hospital., Results: We enrolled 593 patients, with 55.9% in the complete Hour-1 Sepsis Bundle group. The 28-day mortality was 3.9% overall and no significant difference between the complete and incomplete Hour-1 Sepsis Bundle groups (3.6% vs. 4.2%, P = 0.707). Complete Hour-1 Sepsis Bundle treatment was not associated with 28-day mortality (adjusted OR = 2.04, 95% confidence interval [CI] = 0.72-5.74, P = 0.176) or delayed septic shock (adjusted OR = 0.74, 95% CI = 0.30-1.78, P = 0.499). Completion of each bundle did not affect outcomes of 28-day mortality and delayed septic shock., Conclusions: The complete Hour-1 Sepsis Bundle treatment in the ED was not significantly associated with 28-day mortality and delayed septic shock., Trial Registration: The trial was registered in the Thai Clinical Trial Registry, TCTR 20200526013., Competing Interests: The authors report no funding and conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: Pediatric shock has a high mortality rate because many of the early clinical signs are subtle and have poor sensitivity and specificity. Pediatric shock was categorized either: compensated with normal blood pressure, poor skin perfusion (CRT >2 s, mottled, cool peripheries, peripheral cyanosis), weak peripheral pulse, age specific tachycardia, tachypnoea, and oliguria or decompensated with hypotension (SBP < 70 + (2× age in years) mm Hg and decreased mental status. The perfusion index is a non-invasive method for assessing peripheral perfusion and may be a useful marker for identifying shock early in pediatric patients., Objective: This prospective cohort study (November 2019 to August 2020) evaluated whether the perfusion index, lactate, and/or lactate clearance could predict mortality among pediatric shock patients., Methods: Fifty children (68% male) with shock underwent assessments at presentation to the emergency room to evaluate their heart rate, blood pressure, capillary refill time, central venous pressure, perfusion index, cardiac index, systemic vascular resistance, central venous oxygen saturation, and lactate clearance., Results: The perfusion index range was 0.03 to 2.2 and ≤0.18 as the cut-off for mortality prediction providing 74% sensitivity and 78% specificity. The serum lactate concentration range was 0 to 16 mmol/L and >5.7 mmol/L as the cut-off for mortality prediction provided 70% sensitivity and 96% specificity at presentation to the emergency room. The lactate clearance range was 3% to 75% and >10% as the cut-off for survival prediction after resuscitation and at 6 h later., Conclusion: Perfusion index (PI), lactate, and lactate clearance provided comparable sensitivity and specificity for predicting outcomes among pediatric patients with shock Therefore, we suggest that the PI is an inexpensive, rapid, and non-invasive tool that can be used to predict illness severity and mortality in busy pediatric intensive care units and emergency departments. This tool may guide better patient triage and an earlier diagnosis of shock in this setting., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Abstract: Patients with chronic neuropathic pain (NP) have a significantly increased risk of central nervous degeneration. Trigeminal neuralgia (TN) is a typical NP, and this manifestation is more obvious. In addition to severe pain, patients with TN are often accompanied by cognitive dysfunction and have a higher risk of central nervous system degeneration, but the mechanism is not clear. The NOD-like receptor 3 (NLRP3) inflammasome assembles inside of microglia on activation, which plays an important role in neurodegeneration such as Alzheimer disease. MCC950 is a specific blocker of NLRP3 inflammasome, which can improve the performance of degenerative diseases. Although NLRP3 inflammasome assembles inside of microglia on activation has been shown to be essential for the development and progression of amyloid pathology, its whether it mediates the neurodegeneration caused by NP is currently unclear. By constructing a rat model of chronic TN, we found that as the course of the disease progresses, TN rats have obvious cognitive and memory deficit. In addition, Tau hyperphosphorylation and Aβ expression increase in the cortex and hippocampus of the brain. At the same time, we found that NLRP3 expression increased significantly in model rats. Interestingly, NLRP3 specific blocker MCC950 can alleviate the neurodegeneration of trigeminal neuralgia rats to a certain extent. It is suggested that our NLRP3 inflammasome plays an important role in the neurodegeneration of trigeminal neuralgia rats. And it is related to the activation of central nervous system inflammation., Competing Interests: All the authors declared no conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2021 by the Shock Society.)

Abstract: The incidence and mortality of acute respiratory distress syndrome (ARDS) are high, but the relevant mechanism for this disorder remains unclear. Autophagy plays an important role in the development of ARDS. The mitochondrial outer membrane protein FUNDC1 is involved in hypoxia-mediated mitochondrial autophagy, which may contribute to ARDS development. This study explored whether FUNDC1 regulates autophagy by inhibiting ROS-NLRP3 signaling to avoid apoptosis in the lung in a lipopolysaccharide-induced mouse model. In this study, FUNDC1 knockout mice were constructed, and a lipopolysaccharide-induced mouse model was generated. HE staining of pathological sections from the lung, wet/dry lung measurements, myeloperoxidase concentration/neutrophil counts in BALF and survival time of mice were examined to determine the effect of modeling. The release of cytokines (TNF-α, IL-1β, IL-6, and IL-10) in response to LPS in the BALF and plasma was assessed using ELISA. The effects of oxidative stress (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase) in lung tissue in response to LPS were detected by biochemical analysis. Oxidative stress damage was validated by iNOS staining, and apoptosis was assessed by TUNEL staining after LPS. Finally, the expression of autophagy-associated proteins and inflammasome-associated proteins in lung tissue after LPS intervention was analyzed by western blot. We found that wild-type control, FUNDC1 knockout control, lipopolysaccharide-induced wild-type, and FUNDC1 knockout mouse models were used to investigate whether FUNDC1-mediated autophagy is involved in lung injury and its possible molecular mechanisms. Compared with the normal control group, lung tissue FUNDC1 and LC3 II increased and p62/SQSTM1 decreased after LPS intervention, and increased ROS levels led to a decrease in corresponding antioxidant enzymes along with an increased inflammatory response and apoptosis. Levels of autophagy in lipopolysaccharide-induced mice deficient in FUNDC1 were significantly decreased, but the expression of ROS and inflammatory factors in lung tissue was more severe than in lipopolysaccharide-induced wild-type mice, and the survival rate was significantly decreased. Western blot analysis showed that autophagy was significantly inhibited in the FUNDC1 KO+LPS group, and there was a significant increase in NLRP3, caspase-1, IL-1β, and ASC compared with the lipopolysaccharide-induced wild-type group. In summary, lipopolysaccharide-induced wild-type mice exhibit ROS-dependent activation of autophagy, and knocking out FUNDC1 promotes inflammasome activation and exacerbates lung injury., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Introduction: It is difficult to estimate the ischemic consequences when using partial resuscitative endovascular balloon occlusion of the aorta (REBOA). The aim was to investigate if end-tidal carbon dioxide (ETCO2) is correlated to degree of aortic occlusion, measured as distal aortic blood flow, and distal organ metabolism, estimated as systemic oxygen consumption (VO2), in a porcine model of normovolemia and hemorrhagic shock., Materials and Methods: Nine anesthetized pigs (25-32 kg) were subjected to incremental steps of zone 1 aortic occlusion (reducing distal aortic blood flow by 33%, 66%, and 100%) during normovolemia and hemorrhagic grade IV shock. Hemodynamic and respiratory variables, and blood samples, were measured. Systemic VO2 was correlated to ETCO2 and measures of partial occlusion previously described., Results: Aortic occlusion gradually lowered distal blood flow and pressure, whereas ETCO2, VO2 and carbon dioxide production decreased at 66% and 100% aortic occlusion. Aortic blood flow correlated significantly to ETCO2 during both normovolemia and hemorrhage (R = 0.84 and 0.83, respectively) and to femoral mean pressure (R = 0.92 and 0.83, respectively). Systemic VO2 correlated strongly to ETCO2 during both normovolemia and hemorrhage (R = 0.91 and 0.79, respectively), blood flow of the superior mesenteric artery (R = 0.77 and 0.85, respectively) and abdominal aorta (R = 0.78 and 0.78, respectively), but less to femoral blood pressure (R = 0.71 and 0.54, respectively)., Conclusion: ETCO2 was correlated to distal aortic blood flow and VO2 during incremental degrees of aortic occlusion thereby potentially reflecting the degree of aortic occlusion and the ischemic consequences of partial REBOA. Further studies of ETCO2, and potential confounders, in partial REBOA are needed before clinical use., Competing Interests: The authors wish to report no conflicts of interest related to the subject matter., (Copyright © 2021 by the Shock Society.)

Abstract: Extracorporeal life support (ECLS) is a support modality for patients with severe acute respiratory distress syndrome (ARDS) who have failed conventional treatments including low tidal volume ventilation, prone positioning, and neuromuscular blockade. In addition, ECLS can be used for hemodynamic support for patients with cardiogenic shock or following cardiac arrest. Injured patients may also require ECLS support for ARDS and other indications. We review the use of ECLS for ARDS patients, trauma patients, cardiogenic shock patients, and post-cardiac arrest patients. We then describe how these principles are applied in the management of the novel coronavirus disease 2019 pandemic. Indications, predictors, procedural considerations, and post-cannulation management strategies are discussed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Abstract: The ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines were endorsed by the Shock Society in 2012, but to date there has been no systematic evaluation of research reporting quality for Shock. We systematically assessed 100 randomly selected animal-based research articles published between 2014 and 2018 for reporting quality and statistical practice, compared with 40 pre-ARRIVE studies. More than half of surveyed papers omitted verifiable ethical oversight information and basic animal descriptive information. Few papers reported best-practice methods, such as sample size justification (10%), randomization (43%), randomization method (7%), blinding (23%). Only one paper reported effect sizes to interpret study results. Most troubling was inadequate reporting of welfare-related information (anesthesia, analgesia, humane endpoints, euthanasia). Almost a decade after ARRIVE endorsement, our findings show that reporting deficiencies have persisted with little sign of correction. There is a clear need for investigators to increase transparency of research methods reporting, and drastically improve skills in experimental design. Improvement in standards and greater attention paid to reporting will lead to improvement in reproducibility, replicability, and research quality. It is incumbent upon the research community to improve reporting practices; accurate and transparent reporting is integral to producing rigorous and ethical science., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Objective: Diaphragm dysfunction often occurs in patients with prolonged mechanical ventilation (MV) after resuscitation. Mild hypothermia (MHT) is a classical treatment to improve the outcomes of cardiac arrest (CA); however, the effect of MHT on diaphragm function remains unclear. In the present study, we aim to investigate the effect of MHT on diaphragmatic microcirculation and function using a murine cardiopulmonary resuscitation model., Methods: Thirty-two rats were randomly assigned into a resuscitation normothermia group (RNT), an intraresuscitation hypothermia group (IRH), a postresuscitation hypothermia group (PRH), or a sham control group. CA was induced by airway occlusion, and resuscitation was implemented by precordial compression and MV. The diaphragmatic microvascular blood flow velocity, diaphragmatic microcirculation flow index (MFI), and perfused vascular density (PVD) were measured. The diaphragm was then removed for in vitro contractile property examination and cross-sectional area measurement. The lipid peroxidation and superoxide dismutase (SOD) levels in the diaphragm were also assayed., Results: Either early or delayed MHT intervention did not improve the diaphragmatic microvascular blood flow velocity, MFI, and PVD, which were significantly decreased during prolonged MV after resuscitation. Compared with the RNT group, treatment with MHT increased the diaphragm contractility, fiber dimensions, and SOD levels and decreased diaphragm lipid peroxidation. A more significant change in these indices was observed in the IRH group compared with that in the PRH group., Conclusion: MHT preserves the diaphragm contractility and fiber dimensions and decreases oxidative stress but does not improve the microcirculatory blood supply during prolonged MV after resuscitation. Early MHT intervention is more efficient in preventing diaphragm dysfunction than delayed intervention after CA.

Introduction: Inflammasomes are recognized as key components of the innate immune response in sepsis. We aimed to describe the transcriptional expression of nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3), and serum interleukin-1β (IL-1 β) in critically ill patients, their changes over the first week and their prognostic value in septic patients., Methods: Prospective study including patients with sepsis based on Sepsis-3 definitions and a control group of critically ill patients without sepsis. We measured the circulating levels of IL-1β as well as the transcriptional expression of NLRP3 at admission and on days 3 and 7. Caspase-1 and caspase-3 activation was analyzed in a matched cohort of patients with septic shock (four dead and four survivors)., Results: Fifty-five septic patients and 11 non-septic patients were studied. Levels on day 0 and 3 of IL-1 β and NLRP3 inflammasome expression were significantly higher in patients with sepsis than in controls. NLRP3 was significantly higher in septic patients who survived at day 7 without significant difference between survivors and non-survivors at baseline and on day 3. In survivors, an increased caspase-1 protein expression with reduced expression caspase-3 was observed with the opposite pattern in those who died., Conclusions: NLRP3 is activated in critically ill patients but this up-regulation is more intense in patients with sepsis. In sepsis, a sustained NLRP3 activation during the first week is protective and sepsis. An increased caspase-1 protein expression with reduced expression caspase-3 is the pattern observed in septic shock patients who survive.

Hemorrhagic shock can be mitigated by timely and accurate resuscitation designed to restore adequate delivery of oxygen (DO2) by increasing cardiac output (CO). However, standard care of using systolic blood pressure (SBP) as a guide for resuscitation may be ineffective and can potentially be associated with increased morbidity. We have developed a novel vital sign called the compensatory reserve measurement (CRM) generated from analysis of arterial pulse waveform feature changes that has been validated in experimental and clinical models of hemorrhage. We tested the hypothesis that thresholds of DO2 could be accurately defined by CRM, a noninvasive clinical tool, while avoiding over-resuscitation during whole blood resuscitation following a 25% hemorrhage in nonhuman primates. To accomplish this, adult male baboons (n = 12) were exposed to a progressive controlled hemorrhage while sedated that resulted in an average (± SEM) maximal reduction of 508 ± 18 mL of their estimated circulating blood volume of 2,130 ± 60 mL based on body weight. CRM increased from 6 ± 0.01% at the end of hemorrhage to 70 ± 0.02% at the end of resuscitation. By linear regression, CRM values of 6% (end of hemorrhage), 30%, 60%, and 70% (end of resuscitation) corresponded to calculated DO2 values of 5.9 ± 0.34, 7.5 ± 0.87, 9.3 ± 0.76, and 11.6 ± 1.3 mL O2·kg·min during resuscitation. As such, return of CRM to ∼65% during resuscitation required only ∼400 mL to restore SBP to 128 ± 6 mmHg, whereas total blood volume replacement resulted in over-resuscitation as indicated by a SBP of 140 ± 7 mmHg compared with an average baseline value of 125 ± 5 mmHg. Consistent with our hypothesis, thresholds of calculated DO2 were associated with specific CRM values. A target resuscitation CRM value of ∼65% minimized the requirement for whole blood while avoiding over-resuscitation. Furthermore, 0% CRM provided a noninvasive metric for determining critical DO2 at approximately 5.3 mL O2·kg·min.

Abstract: Background: Sepsis-induced cardiomyopathy (SIC), one of the most common complications of sepsis, seriously affects the prognosis of critically ill patients. Choline metabolism is an important biological process in the organism, and the mechanism of its interaction with SIC is unclear. The aim of this study was to reveal the choline metabolism genes (CMGs) associated with SIC and to provide effective targets for the treatment of SIC.Methods: Through a comprehensive analysis of the microarray dataset GSE79962 (comprising 20 SIC patients and 11 healthy controls) from the GEO database, suspected co-expression modules and differentially expressed genes (DEGs) in SIC were identified. Hub CMGs were obtained by intersecting choline metabolism database with DEGs and key model genes. Afterward, hub CMGs most significantly involved in prognosis were further analyzed for the verification of major pathways of enrichment analysis. Finally, the expression of hub CMGs in in vivo and in vitro SIC model was verified by immunohistochemistry staining and quantitative real-time polymerase chain reaction analysis (qPCR).Results: WGCNA identified 1 hub gene panel and 3867 hub genes, which were intersected with DEGs and CMGs to obtain the same 3 hub CMGs:HIF-1α, DGKD and PIK3R1. Only HIF-1α shows significant association with mortality (P = 0.009). Subsequent differential analysis based on the high and low HIF-1α expression yielded 63 DEGs and then they were uploaded into Cytoscape software to construct a protein-protein interaction (PPI) network and 6 hub genes with the highest priority were obtained (CISH, THBS1, IMP1, MYC, SOCS3 and VCAN). Finally, a multifactorial COX analysis revealed a significant correlation between HIF-1α and survival in SIC patients, which was further validated by in vitro and in vivo experiments.Conclusion: Our findings will provide new insights into the pathogenesis of SIC, and HIF-1α may have important applications as a potential biomarker for early detection and therapeutic intervention in SIC., Competing Interests: Competing interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 by the Shock Society.)

Abstract: Pelvic fractures are severe traumatic injuries often accompanied by potentially fatal massive bleeding. Rapid control of hemorrhages in prehospital emergency settings is critical for improving outcomes in traumatic bleeding. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a promising technique for controlling active bleeding from pelvic fractures. By inserting a balloon catheter into the aorta, REBOA helps maintain blood flow to vital organs such as the brain and heart. This paper provides a comprehensive overview of the initial management of noncompressive trunk hemorrhage caused by pelvic fractures, introduces the technical principles and developments of REBOA, and explores its extensive application in prehospital emergency care. It delves into the operational details and outlines strategies for effectively managing potential complications. We aim to offer a theoretical framework for the future utilization of REBOA in managing uncontrollable hemorrhage associated with pelvic fractures in prehospital emergencies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Abstract: Objective: To explore the effect of a stratified dose of norepinephrine (NE) on cellular immune response in patients with septic shock, and to construct a prognostic model of septic shock. Methods: A total of 160 patients with septic shock (B group) and 58 patients with sepsis (A group) were given standard cluster therapy. Patients with septic shock were divided into four groups (B1-B4 groups: 0.01-0.2, 0.2-0.5, 0.5-1.0, and >1 μg/kg/min) according to the quartile method of the early (72 h) time-weighted average dose of NE and clinical application. The cellular immune indexes at 24 h (T0) and 4-7 days (T1) after admission were collected. The difference method was used to explore the effect of NE stratified dose on cellular immune effect in patients with septic shock. A multivariate COX proportional risk regression model was used to analyze the independent prognostic risk factors, and a prognostic risk model was constructed. Results: The differences of ΔIL-1β, ΔIL-6, ΔIL-10, absolute value difference of T lymphocyte (ΔCD3+/CD45+#) and Th helper T cell (ΔCD3+ CD4+/CD45+#), CD64 infection index difference, ΔmHLA-DR, regulatory T lymphocyte ratio difference (ΔTregs%) between group A, B1, B2, B3, and B4 were statistically significant ( P < 0.05). There was a nonlinear relation between the stratified dose of NE and ΔIL-6, ΔIL-10, ΔCD3+/CD45+#, ΔmHLA-DR%. The threshold periods of NE-induced proinflammatory and anti-inflammatory immune changes were 0.3-0.5 μg/kg/min. Multivariate COX model regression analysis showed that age, nutritional patterns, weighted average dose of norepinephrine, IL-6, absolute value of T lymphocytes, and mHLA-DR were independent risk factors affecting the prognosis of patients with septic shock ( P < 0.05). The prognostic risk model was constructed (AUC value = 0.813, 95% CI: 0.752-0.901). Conclusion: NE has a certain inhibitory effect on cellular immune function in patients with septic shock. A prognostic risk model was constructed with stronger prediction efficiency for the prognosis of patients with septic shock., Competing Interests: Conflicts of Interest: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 by the Shock Society.)

Abstract: Crush syndrome (CS), also known as traumatic rhabdomyolysis, is the leading cause of death following extrication from structural collapse due to earthquakes. Due to the unfeasibility of human studies, animal models are used to study crush syndrome pathophysiology, including biochemistry and treatment regimes. The aim of this systematic literature review was to identify the differences and benefits of various animal models used in the study of CS and provide valuable information for design of future research. A systematic search was conducted in two methods: with the filters "(crush syndrome) AND (crush muscle injury)" and with the keywords "(crush syndrome) AND (animal model)" covering all articles in the PubMed databases. The search generated 378 articles. After screening abstracts, 91 articles were retrieved and read, then 11 repeated articles were removed and 2 reference papers were included. We finally reviewed 82 original articles. There appear to be two primary methods employed for inducing crush syndrome in animal models, which are chemically induced injury and physically induced injury. Chemical method mainly includes intramuscular (IM) injection of tissue extract solution and IM injection of 50% glycerine. Physical method can be classified into invasive and non-invasive physical compression by elasticated material, inflatable band and heavy load. Various species of animals have been used to study CS, including mice (13.4%), rats (68.3%), rabbits (11.0%), canines (4.9%), goats (1.2%), and pigs (1.2%). Small animals are suitable for researches exploring the mechanism of disease or drug efficacy while large animals can work better with clinical application-related researches. In regard to the choice of modeling method, compressing the certain muscle of animals by heavy things is superior to others to cause systemic trauma-related rhabdomyolysis signs. In addition, due to the significant burden of crush injuries on animals, further attention shall be paid to the selection of the most suitable anesthetics and appropriate analgesics., (Copyright © 2022 by the Shock Society.)

Hemorrhage, and particularly noncompressible torso hemorrhage remains a leading cause of potentially preventable prehospital death from trauma in the United States and globally. A subset of severely injured patients either die in the field or develop irreversible hemorrhagic shock before they can receive hospital definitive care, resulting in poor outcomes. The focus of this opinion paper is to delineate (a) the need for existing trauma systems to adapt so that potentially life-saving advanced resuscitation and truncal hemorrhage control interventions can be delivered closer to the point-of-injury in select patients, and (b) a possible mechanism through which some trauma systems can train and incorporate select prehospital advanced resuscitative care teams to deliver those interventions., Competing Interests: No financial conflicts of interest for any author. ZQ is the medical director of the RAPToR course but receives no financial benefit or contribution from this role.

Purpose: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is now performed in many trauma centers, it is used at more than 250 hospitals in the United States and there is an increase rate of publications with the experience in these centers, but there is a gap of knowledge regarding the use of REBOA in Latin-America. This paper endeavors to describe the utilization of REBOA at a high level Latin-American Trauma Center and the transition from a large caliber to a low-profile device with the concomitant reduction in the groin access complications., Methods: A prospective, observational, single-center study was conducted. We included all trauma patients who underwent REBOA. We recorded data from admission parameters, complications, and clinical outcomes., Results: Fifty patients were included. Most of the REBOA catheters were inserted in the operating room [47 (94%)], and the arterial access was done by surgical cutdown [40 (80%)]. All the complications were associated with the catheter of 11 Fr Sheath used in 36 patients [n = 8/36 (22%) vs. n = 0/14 (0%); P = 0.05]., Conclusion: REBOA can be used safely in blunt or penetrating thoracic, abdominal, and pelvic trauma. The insertion of a 7 Fr Sheath was associated with lower complications, so its use should be preferred over larger calibers., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Background: "Cytokine storm" has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a "cytokine storm" resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a "cytokine storm" has yet to be defined., Methods: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient., Results: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 = 34 pg/mL; Crohn's disease, IL-6 = 5 pg/mL), yet respond dramatically to cytokine inhibitors., Conclusion: The misleading term "cytokine storm" implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term "cytokine storm". "Cytokine storm" should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Abstract: Cardiac output (CO) is an important parameter in fluid management decisions for treating hemodynamically unstable patients in intensive care unit. The gold standard for CO measurements is the thermodilution method, which is an invasive procedure with intermittent results. Recently, electrical impedance tomography (EIT) has emerged as a new method for noninvasive measurements of stroke volume (SV). The objectives of this paper are to compare EIT with an invasive pulse contour analysis (PCA) method in measuring SV during mini-fluid challenge in animals and determine preload responsiveness with EIT. Five pigs were anesthetized and mechanically ventilated. After removing 25% to 30% of the total blood from each animal, multiple fluid injections were conducted. The EIT device successfully tracked changes in SV beat-to-beat during varying volume states, i.e., from hypovolemia and preload responsiveness to target volume and volume overload. From a total of 50 100-mL fluid injections on five pigs (10 injections per pig), the preload responsiveness value was as large as 32.3% in the preload responsiveness state while in the volume overload state it was as low as -4.9%. The bias of the measured SV data using EIT and PCA was 0 mL, and the limits of agreement were ±3.6 mL in the range of 17.6 mL to 51.0 mL. The results of the animal experiments suggested that EIT is capable of measuring beat-to-beat SV changes during mini-fluid challenge and determine preload responsiveness. Further animal and clinical studies will be needed to demonstrate the feasibility of the EIT method as a new tool for fluid management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Abstract: Resuscitative endovascular balloon occlusion of the aorta (REBOA) allows for effective temporization of exsanguination from non-compressible hemorrhage (NCTH) below the diaphragm. However, the therapeutic window for aortic occlusion is time-limited given the ischemia-reperfusion injury generated. Significant effort has been put into translational research to develop new strategies to alleviate the ischemia-reperfusion injury and extend the application of endoaortic occlusion. Targeted regional optimization (TRO) is a partial REBOA strategy to augment proximal aortic and cerebral blood flow while targeting minimal threshold of distal perfusion beyond the zone of partial aortic occlusion. The objective of TRO is to reduce the degree of ischemia caused by complete aortic occlusion while providing control of distal hemorrhage. This review provides a synopsis of the concept of TRO, pre-clinical, translational experiences with TRO and early clinical outcomes. Early results from TRO strategies are promising; however, further studies are needed prior to large-scale implementation into clinical practice., Competing Interests: DGB is employed by Prytime Medical Inc. and help to write and edit portions of this manuscript as part of his employment responsibilities. AER, MJM, JDB, JEP, DMB, TER, and JMW have no significant financial conflicts of interest related to this paper. DGB is employed by Prytime Medical and help to write and edit portions of this manuscript as part of his employment responsibilities. Prytime Medical produces some of the devices discussed in this manuscript. AER, MJM, JDB, JEP, DMB, TER, and JMW have no significant financial conflicts of interest related to this paper., (Copyright © 2021 by the Shock Society.)

Sepsis is a life-threatening syndrome of organ dysfunction caused by a dysregulated host response to infection characterized by excessive neutrophil infiltration into vital organs. In sepsis, patients often die of organ failure and therapies directed against endothelial cell dysfunction and tissue damage are important targets for treatment of this disease. Novel approaches are required to understand the underlying pathophysiology of neutrophil dysregulation and neutrophil-endothelial cell interactions that play a critical role in the early course of organ damage and disruption of endothelial protective barrier. Here, we review methodologies that our laboratories have employed to study neutrophil-endothelial interaction and endothelial barrier function in in vivo and in vitro models of sepsis. We will focus on in vivo rodent models of sepsis and in vitro tools that use human cell culture models under static conditions and the more physiologically relevant biomimetic microfluidic assays. This Methods paper is based on our presentation in the Master Class Symposium at the 41st Annual Conference on Shock 2018.

As outlined in the "International Guidelines for Management of Sepsis and Septic Shock: 2016," initial fluid resuscitation and administration of antibiotics are key steps in the early management of sepsis and septic shock. However, such clear guidelines do not exist for preclinical sepsis models. To address these shortcomings, the Wiggers-Bernard conference on preclinical sepsis models was held in Vienna in May 2017. The participants reviewed 260 of the most highly cited papers between 2003 and 2012 that used sepsis models. The review demonstrated that over 70% of experiments either did not use or failed to report resuscitation and/or antibiotic treatment. This information served as the basis to create a series of recommendations and considerations for preclinical sepsis models; this Part III report details the recommendations for fluid resuscitation and antibiotic treatment that should be addressed in sepsis models. Similar to human sepsis, fluid resuscitation is recommended in the experimental setting unless part of the study. Iso-osmolar crystalloid solutions are preferred. The administration route and its timing should be adjusted to the specific requirements of the model with preference given to dynamic rather than static hemodynamic monitoring. Predefined endpoints for fluid resuscitation and avoidance of fluid overload should be considered. Preclinical sepsis studies display serious inconsistencies in the use of antimicrobial protocols. To remedy this, antimicrobials are recommended for preclinical studies, with choice and dose adjusted to the specific sepsis model and pathogen (s). Ideally, the administration of antimicrobials should closely mimic clinical practice, taking into account the drug's pharmacokinetic profile, alterations in absorption, distribution and clearance, and host factors such as age, weight, and comorbidities. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

Although the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review has not been done for preclinical models. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling reviewed the 260 most highly cited papers between 2003 and 2012 using sepsis models to create a series of recommendations. This Part II report provides recommendations for the types of infections and documentation of organ injury in preclinical sepsis models. Concerning the types of infections, the review showed that the cecal ligation and puncture model was used for 44% of the studies while 40% injected endotoxin. Recommendation #8 (numbered sequentially from Part I): endotoxin injection should not be considered as a model of sepsis; live bacteria or fungal strains derived from clinical isolates are more appropriate. Recommendation #9: microorganisms should replicate those typically found in human sepsis. Sepsis-3 states that sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, but the review of the papers showed limited attempts to document organ dysfunction. Recommendation #10: organ dysfunction definitions should be used in preclinical models. Recommendation #11: not all activities in an organ/system need to be abnormal to verify organ dysfunction. Recommendation #12: organ dysfunction should be measured in an objective manner using reproducible scoring systems. Recommendation #13: not all experiments must measure all parameters of organ dysfunction, but investigators should attempt to fully capture as much information as possible. These recommendations are proposed as "best practices" for animal models of sepsis.

New definitions of sepsis and septic shock were published in early 2016, updating old definitions that have not been revisited since 2001. These new definitions should profoundly affect sepsis research. In addition, these papers present clinical criteria for identifying infected patients who are highly likely to have or to develop sepsis or septic shock. In contrast to previous approaches, these new clinical criteria are evidence based. In this review, two of the authors of the new definitions detail the content of the papers and explore the implications for shock and sepsis researchers.

Shock is deadly and unpredictable if it is not recognized and treated in early stages of hemorrhage. Unfortunately, measurements of standard vital signs that are displayed on current medical monitors fail to provide accurate or early indicators of shock because of physiological mechanisms that effectively compensate for blood loss. As a result of new insights provided by the latest research on the physiology of shock using human experimental models of controlled hemorrhage, it is now recognized that measurement of the body's reserve to compensate for reduced circulating blood volume is the single most important indicator for early and accurate assessment of shock. We have called this function the "compensatory reserve," which can be accurately assessed by real-time measurements of changes in the features of the arterial waveform. In this paper, the physiology underlying the development and evaluation of a new noninvasive technology that allows for real-time measurement of the compensatory reserve will be reviewed, with its clinical implications for earlier and more accurate prediction of shock.

Despite widespread use, there is currently no consensus on how extracorporeal blood purification therapies should be applied or studied in patients with sepsis. One major obstacle has been the lack of clear descriptions of specific sepsis phenotypes tied to mechanisms that would permit the identification of molecular targets. Current evidence suggests that sepsis-related morbidity and mortality involve widely different clinical phenotypes that variably include mitochondrial dysfunction, abnormalities of vascular biology including endothelial dysfunction and coagulopathy, epithelial dysfunction, and immune suppression and dysregulation. While most cases of sepsis involve some element of all of these pathobiologic processes, the magnitude of each varies greatly from patient to patient in part as a result of the pathogen and in part related to host-specific factors. Thus, the purpose of the fourteenth international consensus conference of acute dialysis quality initiative was to develop consensus for a conceptual model of sepsis-induced organ failure that can be treated by extracorporeal blood purification and possibly also with drugs or other therapies. We assembled a group of experts from around the world and used a modified Delphi method to reach consensus. Specific findings and recommendations for future research are provided in the four accompanying papers.

In the intensive care unit (ICU) of our tertiary care university medical center, central venous pressure (CVP) measurements derived from bedside monitors differ considerably from measurements by trained intensivists using paper tracings. To quantify these differences, printed CVP tracings and concurrent respiratory waveforms were collected from 100 consecutive critically ill patients along with the corresponding monitor-displayed CVP. Four blinded intensivists interpreted the tracings. The mean difference between the intensivists and the monitor was -0.26 mmHg (95% confidence interval, +7.19 to -7.71 mmHg). Seventy-six percent of the paired measurements were within 2 mmHg, whereas 7% differed by more than 5 mmHg. To determine the potential clinical impact of these differences, we used the original Surviving Sepsis Campaign Guidelines for fluid administration based upon the measurement of CVP. For individual physicians, protocol-driven fluid management strategy would have differed in 19.2% to 25.3% of cases, dependent upon which measured value was chosen. Although protocol-driven strategies to direct fluid infusion therapy may improve outcomes, these interventions in a specific patient are dependent upon the method by which the CVP is measured.

The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, i.v.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8+/-2.9 and 25.1+/-5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 microL) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.

Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.

Endotoxin-induced microvascular lung injury in mice is a commonly used experimental model of the acute respiratory distress syndrome (ARDS). The present paper aimed to characterize this popular model in a comprehensive and systematic fashion. Male C57bl/6 mice (n = 5) were administered an LD55 dose of E. coli endotoxin (15 mg/kg, i.p.), and lungs were harvested at several time points and evaluated for injury as well as for expression of a variety of inflammatory mediators. Endotoxin induced many features characteristic of acute microvascular lung injury. These included early (1-2 h) expression of inflammatory mediators (IL-1alpha, IL-1beta, IL-4, IL-6, IL-10, TNF-alpha, interferon-alpha, interferon gamma, and MCP-1) and leukocyte accumulation in lung tissue (lung myeloperoxidase activity 18.5 +/- 7.8 U/g tissue, P < 0.05), followed by pulmonary edema (lung water content index 17.4% +/- 2.5%, P < 0.05) and mortality. Histopathological evaluation of lung tissue was compatible with these findings. The characterization of this murine model of endotoxin-induced microvascular injury will facilitate its utilization in ARDS research.

The management of Systemic Inflammatory Response Syndrome (SIRS)/Multiple Organ Failure (MOF) remains the greatest challenge in the field of critical care. There has been uniform difficulty in translating the results of basic science research into effective therapeutic regimes. We propose that this is due in part to a failure to account for the complex, nonlinear nature of the inflammatory process of which SIRS/MOF represents a disordered state. Attempts to manipulate this process without an understanding of the dynamics of the system may potentially produce unintended consequences. Agent-Based Computer Simulation (ABCS) provides a means to synthesize the information acquired from the linear analysis of basic science into a model that preserves the complexity of the inflammatory system. We have constructed an abstracted version of the inflammatory process using an ABCS that is based at the cellular level. Despite its abstraction, the simulation produces non-linear behavior and reproduces the dynamic structure of the inflammatory response. Furthermore, adjustment of the simulation to model one of the unsuccessful initial anti-inflammatory trials of the 1990's demonstrates the adverse outcome that was observed in those clinical trials. It must be emphasized that the current model is extremely abstract and simplified. However, it is hoped that future ABCSs of sufficient sophistication eventually may provide an important bridging tool to translate basic science discoveries into clinical applications. Creating these simulations will require a large collaborative effort, and it is hoped that this paper will stimulate interest in this form of analysis.

The purpose of this preliminary study was to investigate the advantages of the time-frequency analysis through the Continuous Wavelet Transform (CWT) compared to classical Fourier analysis using the Fast Fourier Transform (FFT) in arterial pressure signals from anesthetized mongrel dogs before and during standardized hemorrhages. Systemic arterial pressure pulsations were recorded using catheter-tip manometers. CWT and FFT were applied to arterial pressure pulsations to obtain module coefficients of this transformation and its associated contours during the evolution of progressive hemorrhages, in amounts of 15, 34, and 66% of the estimated total blood volume. This mathematical analysis enabled us to identify the evolution of the frequency components of aortic valve functions, heart dynamics, respiratory influences, and vasomotor activities. Furthermore, we isolated the modulating signal of amplitude modulation phenomenon present in the arterial pressure records, as described in previous papers, being the heart rate carrier frequency. The CWT is a very sensitive and reliable procedure to analyze (time-frequency) the oscillatory phenomena in two dimensions, and to provide more information than the FFT. This new analytical procedure may provide new insights in the study of shock pathophysiology.