The degree of aortic occlusion in the setting of trauma alters the extent of acute kidney injury associated with mitochondrial preservation.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to control noncompressible hemorrhage not addressed with traditional tourniquets. However, REBOA is associated with acute kidney injury (AKI) and subsequent mortality in severely injured trauma patients. Here, we investigated how the degree of aortic occlusion altered the extent of AKI in a porcine model. Female Yorkshire-cross swine (n = 16, 68.1 ± 0.7 kg) were anesthetized and had carotid and bilateral femoral arteries accessed for REBOA insertion and distal and proximal blood pressure monitoring. Through a laparotomy, a 6-cm liver laceration was performed and balloon inflation was performed in zone 1 of the aorta for 90 min, during which animals were randomized to target distal mean arterial pressures of 25 or 45 mmHg via balloon volume adjustment. Blood draws were taken at baseline, end of occlusion, and time of death, at which point renal tissues were harvested 6 h after balloon deflation for histological and molecular analyses. Renal blood flow was lower in the 25-mmHg group (48.5 ± 18.3 mL/min) than in the 45-mmHg group (177.9 ± 27.2 mL/min) during the occlusion phase, which recovered and was not different after balloon deflation. AKI was more severe in the 25-mmHg group, as evidenced by circulating creatinine, blood urea nitrogen, and urinary neutrophil gelatinase-associated lipocalin. The 25-mmHg group had increased tubular necrosis, lower renal citrate synthase activity, increased tissue and circulating syndecan-1, and elevated systemic inflammatory cytokines. The extent of renal ischemia-induced AKI is associated with the magnitude of mitochondrial biomass and systemic inflammation, highlighting potential mechanistic targets to combine with partial REBOA strategies to prevent AKI.NEW & NOTEWORTHY Large animal models of ischemia-reperfusion acute kidney injury (IR-AKI) are lacking. This report establishes a titratable IR-AKI model in swine in which a balloon catheter can be used to alter distal pressures experienced by the kidney, thus controlling renal blood flow. Lower blood flow results in greater renal dysfunction and structural damage, as well as lower mitochondrial biomass, elevated systemic inflammation, and vascular dysfunction.

Review of machine learning for optical imaging of burn wound severity assessment.

Significance: Over the past decade, machine learning (ML) algorithms have rapidly become much more widespread for numerous biomedical applications, including the diagnosis and categorization of disease and injury. Aim: Here, we seek to characterize the recent growth of ML techniques that use imaging data to classify burn wound severity and report on the accuracies of different approaches. Approach: To this end, we present a comprehensive literature review of preclinical and clinical studies using ML techniques to classify the severity of burn wounds. Results: The majority of these reports used digital color photographs as input data to the classification algorithms, but recently there has been an increasing prevalence of the use of ML approaches using input data from more advanced optical imaging modalities (e.g., multispectral and hyperspectral imaging, optical coherence tomography), in addition to multimodal techniques. The classification accuracy of the different methods is reported; it typically ranges from ∼70% to 90% relative to the current gold standard of clinical judgment. Conclusions: The field would benefit from systematic analysis of the effects of different input data modalities, training/testing sets, and ML classifiers on the reported accuracy. Despite this current limitation, ML-based algorithms show significant promise for assisting in objectively classifying burn wound severity.

Real-Time Measurements of Oral Mucosal Carbon Dioxide (POMCO2) Reveals an Inverse Correlation With Blood Pressure in a Porcine Model of Coagulopathic Junctional Hemorrhage.

INTRODUCTION: Shock states that occur during, for example, profound hemorrhage can cause global tissue hypoperfusion leading to organ failure. There is an unmet need for a reliable marker of tissue perfusion during hemorrhage that can be followed longitudinally. Herein, we investigated whether longitudinal POMCO2 tracks changes in hemodynamics in a swine model of coagulopathic uncontrolled junctional hemorrhage. MATERIALS AND METHODS: Female Yorkshire-crossbreed swine (n = 7, 68.1 ± 0.7 kg) were anesthetized and instrumented for continuous measurement of mean arterial pressure (MAP). Coagulopathy was induced by the exchange of 50 to 60% of blood volume with 6% Hetastarch over 30 minutes to target a hematocrit of <15%. A 4.5-mm arteriotomy was made in the right common femoral artery with 30 seconds of free bleeding. POMCO2 was continuously measured from baseline through hemodilution, hemorrhage, and a subsequent 3-h intensive care unit period. Rotational thromboelastometry and blood gases were measured. RESULTS: POMCO2 and MAP showed no significant changes during the hemodilution phase of the experiment, which produced coagulopathy evidenced by prolonged clot formation times. However, POMCO2 increased because of the uncontrolled hemorrhage by 11.3 ± 3.1 mmHg and was inversely correlated with the drop (17.9 ± 5.9 mmHg) in MAP (Y = -0.4122*X + 2.649, P = .02, r2 = 0.686). In contrast, lactate did not significantly correlate with the changes in MAP (P = .35) or POMCO2 (P = .37). CONCLUSIONS: Despite the logical appeal of measuring noninvasive tissue CO2 measurement as a surrogate for gastrointestinal perfusion, prior studies have only reported snapshots of this readout. The present investigation shows real-time longitudinal measurement of POMCO2 to confirm that MAP inversely correlates to POMCO2 in the face of coagulopathy. The simplicity of measuring POMCO2 in real time can provide an additional practical option for military or civilian medics to monitor trends in hypoperfusion during hemorrhagic shock.

A clinically-relevant mouse model that displays hemorrhage exacerbates tourniquet-induced acute kidney injury.

Hemorrhage is a leading cause of death in trauma. Tourniquets are effective at controlling extremity hemorrhage and have saved lives. However, tourniquets can cause ischemia reperfusion injury of limbs, leading to systemic inflammation and other adverse effects, which results in secondary damage to the kidney, lung, and liver. A clinically relevant animal model is critical to understanding the pathophysiology of this process and developing therapeutic interventions. Despite the importance of animal models, tourniquet-induced lower limb ischemia/reperfusion (TILLIR) models to date lack a hemorrhage component. We sought to develop a new TILLIR model that included hemorrhage and analyze the subsequent impact on kidney, lung and liver injuries. Four groups of mice were examined: group 1) control, group 2) hemorrhage, group 3) tourniquet application, and group 4) hemorrhage and tourniquet application. The hemorrhagic injury consisted of the removal of 15% of blood volume through the submandibular vein. The tourniquet injury consisted of orthodontic rubber bands applied to the inguinal area bilaterally for 80 min. Mice were then placed in metabolic cages individually for 22 h to collect urine. Hemorrhage alone did not significantly affect transcutaneous glomerular filtration rate (tGFR), blood urea nitrogen (BUN) or urinary kidney injury molecule-1 (KIM-1) levels. Without hemorrhage, TILLIR decreased tGFR by 46%, increased BUN by 162%, and increased KIM-1 by 27% (p < 0.05 for all). With hemorrhage, TILLIR decreased the tGFR by 72%, increased BUN by 395%, and increased urinary KIM-1 by 37% (p < 0.05 for all). These differences were statistically significant (p < 0.05). While hemorrhage had no significant effect on TILLIR-induced renal tubular degeneration and necrosis, it significantly increased TILLIR-induced lung total injury scores and congestion, and fatty liver. In conclusion, hemorrhage exacerbates TILLIR-induced acute kidney injury and structural damage in the lung and liver.

Surviving Sepsis After Burn Campaign.

INTRODUCTION: The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes. METHODS: The International Society for Burn Injuries (ISBI) reached out to regional or national burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific "patient/population, intervention, comparison and outcome" (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC participants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create "statements" based on the literature. The "summary statements" were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or "no consensus" was reported. RESULTS: The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as "static" comments but should rather be used as guidelines for future testing of the best treatments for sepsis in burn patients. They should be updated on a regular basis. CONCLUSION: Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients.

Evaluation of novel hemostatic agents in a coagulopathic swine model of junctional hemorrhage.

BACKGROUND: Hemostatic dressings are used extensively in both military and civilian trauma to control lethal noncompressible hemorrhage. The ideal topical hemostatic agent would provide reliable hemostasis in patients with profound acidosis, coagulopathy, and shock. This study aimed to compare next-generation hemostatic agents against the current military standard in a translational swine model of vascular injury and coagulopathy. METHODS: Female Yorkshire swine were randomized to eight groups (total n = 63; control n = 14, per group n = 7) of hemostatic agents and included: QuikClot Combat Gauze (Teleflex, Morrisville, NC), which served as the control; BloodSTOP IX (LifeScience Plus, Mountain View, CA); Celox Rapid (Medtrade Product, Crewe, United Kingdom); ChitoSAM 100 (Sam Medical, Tualatin, OR); EVARREST Fibrin Sealant Patch (Ethicon, Raritan, NJ); TAC Wrapping Gauze (H&H Medical, Williamsburg, VA); ChitoGauze XR Pro (Tricol Biomedical, Portland, OR); and X-Stat 30 (RevMedX, Wilsonville, OR). Hemodilution via exchange transfusion of 6% hetastarch was performed to induce acidosis and coagulopathy. An arteriotomy was created, allowing 30 seconds of free bleeding followed by application of the hemostatic agent and compression via an external compression device. A total of three applications were allowed for continued/recurrent bleeding. All blood loss was collected, and hemostatic agents were weighed to calculate blood volume loss. Following a 180-minute observation period, angiography was completed to evaluate for technical complication and distal perfusion of the limb. Finally, the limb was ranged five times to assess for rebleeding and clot stability. RESULTS: All swine were confirmed coagulopathic with rotational thromboelastography and acidotic (pH 7.2 ± 0.02). BloodSTOP IX allowed a significant increase in blood loss and number of applications required to obtain hemostasis compared with all other groups. BloodSTOP IX demonstrated a decreased survival rate (29%, p = 0.02). All mortalities were directly attributed to exsanguination as a result of device failure. In surviving animals, there was no difference in extravasation. BloodSTOP IX had an increased rebleeding rate after ranging compared with QuikClot Combat Gauze ( p = 0.007). CONCLUSION: Most novel hemostatic agents demonstrated comparable efficacy compared with the currently military standard hemostatic dressing, CG.

A Novel Sutureless Anastomotic Device in a Swine Model: A Proof of Concept Study.

INTRODUCTION: Vascular reconstruction requires technical expertise and is often time consuming. As a novel alternative to traditional hand-sewn vascular anastomoses, the VasoLock (VL), is a nonabsorbable, sutureless anastomosis device with traction anchors designed to hold free artery ends together. These anchors do not penetrate the vessel wall but adhere by leveraging the elasticity of the vessels to fasten blood vessels together. This pilot study assesses the performance and patency of this novel device in a porcine model of femoral artery injury. METHODS: Female swine (n = 7) underwent femoral artery exposure for a total of 10 VL implanted. Study animals underwent hemodilution to a target hematocrit of 15% and ROTEM was used to assess coagulopathy, followed by an arterial injury via transection. The VL was inserted without any sutures. Flow-probe monitors were positioned proximal and distal to the device and flow rates were measured continuously for a total of 90 min. Flow was analyzed and presented as a ratio of distal to proximal flow with the slope of this ratio across time subsequently determined. Angiographic assessment was completed to evaluate for patency and technical complications after 90 min of implant. RESULTS: The average animal weight was 44.1 ± 3.2 kg. The average mean arterial pressure at the time of implant was 51.2 ± 7.8 mmHg, median heart rate was 77.4 (IQR = 77.25-157.4) beats per minute, and average temperature was 36.1 ± 1.5°C. The baseline hematocrit was 13.5 ± 3.0%, average pH was 7.20 ± 0.1, average clotting time was 154.1 ± 58.7 s and average clot formation time was 103.4 ± 10.9 s all demonstrating the acidotic, hypothermic, and coagulopathic state of the swine at the time of insertion. During the 90-min observation period, the average flow gradient identified across the VL was 0.99 ± 0.24, indicating no significant change in flow across the VL. The average slope of the gradients was 0.0005 (P = 0.22), suggesting the ratio of proximal and distal flow did not change over the 90 min. Following 90 min of dwell time, all VL were patent without technical complication. Angiographic assessment at 90 min demonstrated no evidence of dissection, device migration, arterial extravasation, or thromboembolism with any of the 10 devices. CONCLUSIONS: This pilot study demonstrated technical feasibility of the novel VL device over a 90-min observation period. All VL were patent and no negative events or complications were identified. This technology demonstrated significant promise in a coagulopathic state: additional investigation, involving long-term survival, is warranted for further validation.

Meta-Analysis of Publicly Available Clinical and Preclinical Microbiome Data From Studies of Burn Injury.

Following burn injury, alterations in host commensal microbiota across body spaces may leave patients susceptible to opportunistic pathogens and serious sequelae such as sepsis. Generally, studies examining the microbiome postburn have had a limited sample size and lack of longitudinal data, which coupled with experimental and analytic variation, impacts overall interpretation. We performed a meta-analysis of publicly available sequencing data from preclinical and clinical burn studies to determine if there were consistent alterations in the microbiome across various anatomical sites and hosts. Ten human and animal 16S rRNA sequencing studies spanning respiratory, urinary, cutaneous, and gastrointestinal microbiomes were included. Taxonomic classification and alpha and beta diversity metrics were analyzed using QIIME2 v2021.8. Alpha diversity was consistently higher in control samples compared to burn-injured samples which were also different based on host and anatomical location; however, phylogenetic evaluation (ie, Faith PD) elucidated more significant differences compared to taxonomic metrics (ie, Shannon entropy). Beta diversity analysis based on weighted UniFrac showed that rodent specimens clustered less closely to humans than pig samples for both rectal and skin sources. Host species and performing institute were found to have a significant impact on community structure. In rectal samples, bacterial composition in pig and human burn samples included Bacteroidetes, Firmicutes, and Proteobacteria, while rodent samples were dominated by Firmicutes. Proteobacteria and Firmicutes increased on burned skin in each host species. Our results suggest that host species and the performing institute strongly influence microbiome structure. Burn-induced alterations in microbiome diversity and taxa exist across hosts, with phylogenetic metrics more valuable than others. Coordinated, multicenter studies, both clinical and preclinical, within the burn community are needed to more completely realize the diagnostic and therapeutic potential of the microbiome for improving outcomes postburn.

DIAGNOSTIC VALUE OF MITOCHONDRIAL DNA AND PERIPHERAL BLOOD MONONUCLEAR CELL RESPIROMETRY FOR BURN-RELATED SEPSIS.

ABSTRACT: Background: Sepsis is the leading cause of mortality among burn patients that survive acute resuscitation. Clinical criteria have poor diagnostic value for burn-induced sepsis, making it difficult to diagnose. Protein biomarkers (e.g., procalcitonin) have been examined with limited success. We aimed to explore other biomarkers related to mitochondria (mitochondrial DNA [mtDNA]) and mitochondrial function of peripheral blood mononuclear cells (PBMCs) for sepsis diagnosis in burn patients. Methods: We conducted a follow-up analysis of a single center, prospective observational study of subjects (n = 10 healthy volunteers, n = 24 burn patients) to examine the diagnostic value of mtDNA and PBMC respirometry. Patients were enrolled regardless of sepsis status and followed longitudinally. Patient samples were classified as septic or not based on empiric clinical criteria. Isolated PBMCs were loaded into a high-resolution respirometer, and circulating mtDNA was measured with a PCR-based assay. Sequential Organ Failure Assessment (SOFA) criteria were also compared. Results: The SOFA criteria comparing septic versus before/nonseptic patients revealed significantly higher heart rate ( P = 0.012) and lower mean arterial pressure ( P = 0.039) in burn sepsis. MtDNA was significantly elevated in septic burn patients compared with healthy volunteers ( P < 0.0001) and nonseptic patients ( P < 0.0001), with no significant difference between healthy volunteers and nonseptic burn patients ( P = 0.187). The area under the ROC curve (AUC) for mtDNA was 0.685 (95% confidence interval = 0.50-0.86). For PBMC respirometry, burn patients exhibited increased routine and maximal respiration potential compared with healthy volunteers. However, no difference was found between nonseptic and septic patient samples. A subanalysis revealed a significant mortality difference in PBMC respirometry after sepsis diagnosis, wherein survivors had higher routine respiration ( P = 0.003) and maximal respiration ( P = 0.011) compared with nonsurvivors. Conclusion: Our findings reveal that mtDNA may have diagnostic value for burn sepsis, whereas PBMC respirometry is nonspecifically elevated in burns, but may have value in mortality prognosis. A larger, multisite study is warranted for further validity of the diagnostic value of mtDNA and PBMC respirometry as biomarkers for prognosis of sepsis and outcomes in burn patients.

The Potential of Arterial Pulse Wave Analysis in Burn Resuscitation: A Pilot In Vivo Study.

While urinary output (UOP) remains the primary endpoint for titration of intravenous fluid resuscitation, it is an insufficient indicator of fluid responsiveness. Although advanced hemodynamic monitoring (including arterial pulse wave analysis [PWA]) is of recent interest, the validity of PWA-derived indices in burn resuscitation extremes has not been established. The goal of this paper is to test the hypothesis that PWA-derived cardiac output (CO) and stroke volume (SV) indices as well as pulse pressure variation (PPV) and systolic pressure variation (SPV) can play a complementary role to UOP in burn resuscitation. Swine were instrumented with a Swan-Ganz catheter for reference CO and underwent a 40% TBSA burns with varying resuscitation paradigms, and were monitored for 24 hours in an ICU setting under mechanical ventilation. The longitudinal changes in PWA-derived indices were investigated, and resuscitation adequacy was compared as determined by UOP vs PWA indices. The results indicated that PWA-derived indices exhibited trends consistent with reference CO and SV measurements: CO and SV indices were proportional to reference CO and SV, respectively (CO: postcalibration limits of agreement [LoA] = ±24.7 [ml/min/kg], SV: postcalibration LoA = ±0.30 [ml/kg]) while PPV and SPV were inversely proportional to reference SV (PPV: postcalibration LoA = ±0.32 [ml/kg], SPV: postcalibration LoA = ±0.31 [ml/kg]). The results also indicated that PWA-derived indices exhibited notable discrepancies from UOP in determining adequate burn resuscitation. Hence, it was concluded that the PWA-derived indices may have complementary value to UOP in assessing and guiding burn resuscitation.

A natural history study of coagulopathy in a porcine 40% total body surface area burn model reveals the time-dependent significance of functional assays.

Various studies have reported discordant results on the magnitude and direction of burn-induced coagulopathy (BIC), which has recently been associated with multiple organ dysfunction syndrome (MODS) and death. The increased mechanistic understanding of BIC is due, in part, to novel assays that have expanded the armamentarium beyond traditional tests like PT and aPTT. Still, BIC is a dynamic process, and the progression is difficult to define in the thermally-injured. To this end, we aimed to enhance the understanding of burn-induced coagulation abnormalities by employing functional assessments of platelet aggregation, viscoelastic kinetics, and thrombin generation in an extensive burn model in swine. Anesthetized Yorkshire pigs sustained 40% total body surface area (TBSA) full-thickness contact burns and recovered in metabolic cages. Blood was collected at baseline (BL), as well as 6, 24, and 48 h after injury. A significant effect of burn (P < 0.0001) was seen on platelets, with mild thrombocytopenia apparent at 24 h. While slight decreases in aPTT were not significant, rotational thromboelastometry (ROTEM) analysis revealed hypercoagulation 6 and 24 h after burn by a decreased clotting time. Maximum clot firmness increased after burn, but was not statistically significant until 48 h. Hypercoagulation was not supported by platelet aggregation, as the response to ADP was greatly and persistently diminished, and the response to collagen was unchanged. Endogenous thrombin potential was significantly reduced at 6 and 24 h after burn (P < 0.0001), and also correlated with a number of ROTEM parameters and collagen-induced platelet aggregation. In contrast, PT was not correlated with other measured parameters. Taken together, novel coagulation parameters may be more sensitive than PT in characterizing coagulopathy in the setting of burns. The data presented herein makes initial strides to report the natural history of several of these variables over time in a large animal model of extensive burns, indicating early hypercoagulability followed by hypocoagulation. Future work will elucidate the effects of standard of care.

Next-Generation REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) Device Precisely Achieves Targeted Regional Optimization in a Porcine Model of Hemorrhagic Shock.

INTRODUCTION: Limitations such as time-dependent distal ischemia have slowed the adoption of resuscitative endovascular balloon occlusion of the aorta (REBOA) for noncompressible hemorrhage. Next-generation REBOA technologies may allow for controlled partial flow, known as targeted regional optimization, to reduce distal ischemia. We aimed to characterize the efficacy of one such catheter in a porcine model of lethal hemorrhagic shock. METHODS: Noncompressible hemorrhage from an iliac injury was induced in anesthetized swine (Sus scrofa) (70-90 kg), targeting 30% total blood volume. Animals were then randomized to partial aortic occlusion (PO) with targeted distal mean arterial pressure (MAP) of 35-40 mm of mercury (mm Hg) and complete aortic occlusion (CO) (n = 8 per group) for 90 min. All groups were then resuscitated during a two-h critical care (CC) phase, with flow rate and MAP recorded continuously at the distal infrarenal aorta and proximal carotid artery, and analyzed with two-way repeated measures analysis of variance with S-N-K post-hoc test. RESULTS: During aortic occlusion, MAP distal to the balloon was consistently maintained at 35.8 ± 0.3 mm Hg in the PO group compared to 27.1 ± 0.3 mm Hg in the CO group (P < 0.05), which also corresponded to higher flow rates (202.9 ± 4.8 mL/min PO versus 25.9 ± 0.8 mL/min CO; P < 0.05). MAP proximal to the balloon was significantly higher with CO versus PO (109.2 ± 2.3 mm Hg versus 85.2 ± 2.3 mm Hg; P < 0.05). During the CC phase, distal aortic flow and MAP were not significantly different between groups. However, creatinine returned to baseline levels by the end of the study in the PO group, but not the CO group. One animal died in the CO group, whereas none died in the PO group. CONCLUSIONS: This is the first examination of the next-generation pREBOA-PRO in a porcine model of lethal hemorrhagic shock. We show technical feasibility of this technique to precisely achieve targeted regional optimization without device failure or complication. The ability to titrate balloon inflation and thus distal flow/pressure may extend the therapeutic window of REBOA by mitigating distal ischemia.

Advantages and Disadvantages of Using Small and Large Animals in Burn Research: Proceedings of the 2021 Research Special Interest Group.

Multiple animal species and approaches have been used for modeling different aspects of burn care, with some strategies considered more appropriate or translatable than others. On April 15, 2021, the Research Special Interest Group of the American Burn Association held a virtual session as part of the agenda for the annual meeting. The session was set up as a pro/con debate on the use of small versus large animals for application to four important aspects of burn pathophysiology: burn healing/conversion, scarring, inhalation injury, and sepsis. For each of these topics, two experienced investigators (one each for small and large animal models) described the advantages and disadvantages of using these preclinical models. The use of swine as a large animal model was a common theme due to anatomic similarities with human skin. The exception to this was a well-defined ovine model of inhalation injury; both of these species have larger airways which allow for incorporation of clinical tools such as bronchoscopes. However, these models are expensive and demanding from labor and resource standpoints. Various strategies have been implemented to make the more inexpensive rodent models appropriate for answering specific questions of interest in burns. Moreover, modeling burn-sepsis in large animals has proven difficult. It was agreed that the use of both small and large animal models has merit for answering basic questions about the responses to burn injury. Expert opinion and the ensuing lively conversations are summarized herein, which we hope will help inform experimental design of future research.

Advanced partial occlusion controller allows for increased precision during targeted regional optimization in a porcine model of hemorrhagic shock.

BACKGROUND: Targeted regional optimization (TRO), a partial resuscitative endovascular balloon occlusion of the aorta strategy, may mitigate distal ischemia and extend the window of effectiveness for this adjunct. An automated device may allow greater control and precise regulation of flow past the balloon, while being less resource-intensive. The objective of this study was to assess the technical feasibility of the novel advanced partial occlusion controller (APOC) in achieving TRO at multiple distal pressures. METHODS: Female swine (n = 48, 68.1 ± 0.7 kg) were randomized to a target distal mean arterial pressure (MAP) of 25 mm Hg, 35 mm Hg, or 45 mm Hg by either manual (MAN) or APOC regulation (n = 8 per group). Uncontrolled hemorrhage was generated by liver laceration. Targeted regional optimization was performed for 85 minutes, followed by surgical control and a 6-hour critical care phase. Proximal and distal MAP and flow rates were measured continuously. RESULTS: At a target distal MAP of 25 mm Hg, there was no difference in the MAP attained (APOC: 26.2 ± 1.05 vs. MAN: 26.1 ± 1.78 mm Hg) but the APOC had significantly less deviance (10.9%) than manual titration (14.9%, p < 0.0001). Similarly, at a target distal MAP of 45 mm Hg, there was no difference in mean pressure (44.0 ± 0.900 mm Hg vs. 45.2 ± 1.31 mm Hg) but APOC had less deviance (9.34% vs. 11.9%, p < 0.0001). There was no difference between APOC and MAN in mean (34.6 mm Hg vs. 33.7 mm Hg) or deviance (9.95% vs. 10.4%) at a target distal MAP of 35 mm Hg, respectively. The APOC made on average 77 balloon volume adjustments per experiment compared with 29 by manual titrations. CONCLUSION: The novel APOC consistently achieved and sustained precisely regulated TRO across all groups and demonstrated reduced deviance at the 25 mm Hg and 45 mm Hg groups compared with manual titration.

Targeted Regional Optimization in Action: Dose-dependent End-organ Ischemic Injury with Partial Aortic Occlusion in the Setting of Ongoing Liver Hemorrhage.

INTRODUCTION: Targeted regional optimization (TRO) describes partial resuscitative endovascular balloon occlusion of the aorta strategy that allows for controlled distal perfusion to balance hemostasis and tissue perfusion. This study characterized hemodynamics at specific targeted distal flow rates in a swine model of uncontrolled hemorrhage to determine if precise TRO by volume was possible. METHODS: Anesthetized swine were subjected to liver laceration and randomized into TRO at distal flows of 300 mL/min (n = 8), 500 mL/min (n = 8), or 700 mL/min (n = 8). After 90 min, the animals received damage control packing and were monitored for 6 h. Hemodynamic parameters were measured continuously, and hematology and serologic labs obtained at predetermined intervals. RESULTS: During TRO, the average percent deviation from the targeted flow was lower than 15.9% for all cohorts. Average renal flow rates were significantly different across all cohorts during TRO phase (P < 0.0001; TRO300 = 63.1 ±â€Š1.2; TRO500 = 133.70 ±â€Š1.93; TRO700 = 109.3 ±â€Š2.0), with the TRO700 cohort having less renal flow than TRO500. The TRO500 and TRO700 average renal flow rates inverted during the intensive care unit phase (P < 0.0001; TRO300 = 86.20 ±â€Š0.40; TRO500 = 148.50 ±â€Š1.45; TRO700 = 181.1 ±â€Š0.70). There was higher blood urea nitrogen, creatinine, and potassium in the TRO300 cohort at the end of the experiment, but no difference in lactate or pH between cohorts. CONCLUSION: This study demonstrated technical feasibility of TRO as a strategy to improve outcomes after prolonged periods of aortic occlusion and resuscitation in the setting of ongoing solid organ hemorrhage. A dose-dependent ischemic end-organ injury occurs beginning with partial aortic occlusion that progresses through the critical care phase, with exaggerated effect on renal function.

Experimental models of acute kidney injury for translational research.

Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI.

Tourniquet-induced lower limb ischemia/reperfusion reduces mitochondrial function by decreasing mitochondrial biogenesis in acute kidney injury in mice.

The mechanisms by which lower limb ischemia/reperfusion induces acute kidney injury (AKI) remain largely uncharacterized. We hypothesized that tourniquet-induced lower limb ischemia/reperfusion (TILLIR) would inhibit mitochondrial function in the renal cortex. We used a murine model to show that TILLIR of the high thigh regions inflicted time-dependent AKI as determined by renal function and histology. This effect was associated with decreased activities of mitochondrial complexes I, II, V and citrate synthase in the kidney cortex. Moreover, TILLIR reduced mRNA levels of a master regulator of mitochondrial biogenesis PGC-1α, and its downstream genes NDUFS1 and ATP5o in the renal cortex. TILLIR also increased serum corticosterone concentrations. TILLIR did not significantly affect protein levels of the critical regulators of mitophagy PINK1 and PARK2, mitochondrial transport proteins Tom20 and Tom70, or heat-shock protein 27. TILLIR had no significant effect on mitochondrial oxidative stress as determined by mitochondrial ability to generate reactive oxygen species, protein carbonylation, or protein levels of MnSOD and peroxiredoxin1. However, TILLIR inhibited classic autophagic flux by increasing p62 protein abundance and preventing the conversion of LC3-I to LC3-II. TILLIR increased phosphorylation of cytosolic and mitochondrial ERK1/2 and mitochondrial AKT1, as well as mitochondrial SGK1 activity. In conclusion, lower limb ischemia/reperfusion induces distal AKI by inhibiting mitochondrial function through reducing mitochondrial biogenesis. This AKI occurs without significantly affecting PINK1-PARK2-mediated mitophagy or mitochondrial oxidative stress in the kidney cortex.

Burn Shock and Resuscitation: Review and State of the Science.

Burn shock and acute fluid resuscitation continue to spark intense interest and debate among burn clinicians. Following a major burn injury, fluid resuscitation of burn shock is life-saving, but paradoxically can also be a source of increased morbidity and mortality because of the unintended consequence of systemic edema formation. Considerable research over the past two decades has been devoted to understanding the mechanisms of edema formation, and to develop strategies to curb resuscitation fluids and limit edema development. Recognition of burn endotheliopathy - injury to the endothelium's glycocalyx layer- is one of the most important recent developments in our understanding of burn shock pathophysiology. Newer monitoring approaches and resuscitation endpoints, along with alternative resuscitation strategies to crystalloids alone, such as administration of albumin, or plasma, or high dose ascorbic acid, have had mixed results in limiting fluid creep. Clear demonstration of improvements in outcomes with all of these approaches remains elusive. This comprehensive review article on burn shock and acute resuscitation accompanies the American Burn Association's State of the Science meeting held in New Orleans, LA on November 2-3, 2021 and the Proceedings of that conference published in this journal.

A Prospective Observational Study Comparing Clinical Sepsis Criteria to Protein Biomarkers Reveals a Role for Vascular Dysfunction in Burn Sepsis.

OBJECTIVES: To compare the diagnostic value of clinical sepsis criteria to novel protein biomarkers in the burn patient. DESIGN: Prospective observational study. SETTING: American Burn Association verified Burn Center ICU. PATIENTS: Burn patients (n = 24) and healthy volunteers (n = 10). INTERVENTIONS: Enrolled burn patients (n = 24) were stratified based on whether or not they met a clinical definition of sepsis. Four separate clinical criteria for sepsis were analyzed for their diagnostic sensitivity and specificity, which were compared to a panel of protein biomarkers. The most significant protein biomarkers were further analyzed via the area under the receiver operating characteristic curves (AUROCs). MEASUREMENTS AND MAIN RESULTS: Of the clinical criteria, SEPSIS-2 criteria led to the highest AUROC (0.781; p < 0.001), followed by the quick Sequential Organ Failure Assessment score (AUROC = 0.670; p = 0.022). Multiplexing revealed a number of inflammatory proteins (complement C5) and matrix metalloproteinases (MMP1, MMP7) that were significantly elevated in septic samples compared with both healthy controls and nonseptic burn samples. Furthermore, three proteins associated with endothelial dysfunction and glycocalyx shedding revealed diagnostic potential. Specifically, syndecan-1, p-selectin, and galectin-1 were all significantly elevated in sepsis, and all resulted in an AUROC greater than 0.7; analyzing the sum of these three markers led to an AUROC of 0.808. CONCLUSIONS: These data reveal several potential biomarkers that may help with sepsis diagnosis in the burn patient. Furthermore, the role of endotheliopathy as a mechanistic etiology for sepsis after burns warrants further investigation.

A case study demonstrating tolerance of the gut to large volumes of enteral fluids as a complement to IV fluid resuscitation in burn shock.

Appropriate intravenous fluid resuscitation has improved early post burn outcomes. However, clinical and pre-clinical evidence suggests that enteral or oral resuscitation may complement intravenous fluid administration. While this strategy is often discussed in the context of resource-limited settings, its implementation could reduce overall IV fluid requirements and simplify management during routine care. Conversely, concerns about this strategy have been raised over impaired gut perfusion and function leading to adverse effects. We present a case of an 82-year-old man with a total burn size of 14% who was encouraged to ingest the oral rehydration solution Drip Drop® starting 7 hours post-burn. In the ensuing 17 hours he consumed over 5 L of oral rehydration solution, which was nearly 1 L more than the total amount of IV fluids he received. There were no adverse gastrointestinal side effects. This demonstrates tolerance of a significant volume of voluntary oral fluids in combination with IV resuscitation. Clinical trials are warranted.