Machine Learning Differentiates Extracorporeal Membrane Oxygenation Mortality Risk Profiles Among Trauma Patients.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is resource intensive with high mortality. Identifying trauma patients most likely to derive a survival benefit remains elusive despite current ECMO guidelines. Our objective was to identify unique patient risk profiles using the largest database of trauma patients available. METHODS: ECMO patients ≥16 years were identified using Trauma Quality Improvement Program data (2010-2019). Machine learning K-median clustering (ML) utilized 101 variables including injury severity, demographics, comorbidities, and hospital stay information to generate unique patient risk profiles. Mortality and patient and center characteristics were evaluated across profiles. RESULTS: A total of 1037 patients were included with 33% overall mortality, mean age 32 years, and median ISS = 26. The ML identified 3 unique patient risk profile groups. Although mortality rates were equivalent across the 3 groups, groups were distinguished by (Group 1) young (median 25 years), severely injured (ISS = 34) patients with thoracic and head injuries (99%) via blunt mechanism (93%), and a high prevalence of ARDS (77%); (Group 2) relatively young (median 30 years) and moderately injured (ISS = 22) patients with exposure-related injuries (11%); and (Group 3) older (median 46 years) patients with a high proportion of comorbidities (69%) and extremity injuries (100%). There were no differences based on center ECMO volume, teaching status, or ACS-Level across all 3 groups. CONCLUSION: Machine learning compliments traditional analyses by identifying unique mortality risk profiles for trauma patients receiving ECMO. These details can further inform treatment guidelines, clinical decision making, and institutional criteria for ECMO usage.

To the point: Utility of laparoscopy for operative management of stabbing abdominal trauma.

BACKGROUND: Algorithms for managing penetrating abdominal trauma are conflicting or vague regarding the role of laparoscopy. We hypothesized that laparoscopy is underutilized among hemodynamically stable patients with abdominal stab wounds. METHODS: Trauma Quality Improvement Program data (2016-2019) were used to identify stable (SBP ≥110 and GCS ≥13) patients ≥16yrs with stab wounds and an abdominal procedure within 24hr of admission. Patients with a non-abdominal AIS ≥3 or missing outcome information were excluded. Patients were analyzed based on index procedure approach: open, therapeutic laparoscopy (LAP), or LAP-conversion to open (LCO). Center, clinical characteristics and outcomes were compared according to surgical approach and abdominal AIS using non-parametric analysis. RESULTS: 5984 patients met inclusion criteria with 7 â€‹% and 8 â€‹% receiving therapeutic LAP and LCO, respectively. The conversion rate for patients initially treated with LAP was 54 â€‹%. Compared to conversion or open, therapeutic LAP patients had better outcomes including shorter ICU and hospital stays and less infection complications, but were younger and less injured. Assessing by abdominal AIS eliminated ISS differences, meanwhile LAP patients still had shorter hospital stays. At time of admission, 45 â€‹% of open patients met criteria for initial LAP opportunity as indicated by comparable clinical presentation as therapeutic laparoscopy patients. CONCLUSIONS: In hemodynamically stable patients, laparoscopy remains infrequently utilized despite its increasing inclusion in current guidelines. Additional opportunity exists for therapeutic laparoscopy in trauma, which appears to be a viable alternative to open surgery for select injuries from abdominal stab wounds. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Declining Military Surgical Cases and the Impact on Military Surgical Graduate Medical Education.

BACKGROUND: Several studies have indicated a decline in the number, types, and complexity of surgical procedures within military treatment facilities (MTFs). This study aims to determine what effect, if any, these downward trends have had on the relationship between the military health system (MHS) and surgical graduate medical education. METHODS: Graduating chief resident final ACGME case logs from 4 of thirteen military general surgery programs were evaluated from 2015 to 2020. The proportion of total cases performed by residents at military institutions were compared on a year over year basis. RESULTS: The proportion of cases performed within the military hospitals declined 3.27% each year between 2015 and 2020 (P < .0001) in 4 MTFs. All individual hospitals had significant declines in case volume except one (William Beaumont Army Medical Center) which increased 6.05% with each year, but also increased the number of MTF partnerships within its program (P < .0001). CONCLUSIONS: There has been a statistically significant decline over time in the proportion of cases logged by residents within the studied military treatment facilities. Investment into military hospitals to increase case numbers, case diversity, and complexity and/or acceptance of this gradual decline with greater shifting of educational workload onto civilian hospitals is required.

Validation of a miniaturized handheld arterial pressure monitor for guiding full and partial REBOA use during resuscitation.

PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a well-validated method for the control of noncompressible truncal hemorrhage. In lower resource or battlefield settings, the need for arterial line setup and monitoring is problematic and potentially prohibitive. We sought to evaluate the accuracy and precision of a miniaturized portable device (Centurion COMPASS®) versus standard arterial pressure monitoring using standard ER-REBOA and partial REBOA (pREBOA) as a high-fidelity and space-/time-conserving alternative. METHODS: A total of 40 swine underwent a four-phase validation/precision study (each phase using five ER-REBOAs and five pREBOAs). Phases I/II evaluated accuracy with full and pREBOA in uninjured animals. Phases III/IV duplicated the previous phases but in a severe hemorrhagic shock model. Carotid and femoral pressures were monitored with both intra-arterial pressure systems and the COMPASS® device. The vascular flow was measured by aortic flow probes. Correlation and Bland-Altman analysis were performed. RESULTS: There was a strong correlation in accuracy testing of proximal and distal COMPASS® devices compared to standard intra-arterial pressure monitoring (r = 0.94, 0.8; p < 0.005) as well as during precision testing (r = 0.98, 0.89 p < 0.005) in the uninjured phases. Similar accuracy and reliability were demonstrated in hemorrhagic shock, with a strong correlation for the proximal and distal COMPASS® devices (r = 0.98, 0.97; p < 0.005), as well as during precision testing (r = 0.99, 0.95; p < 0.005) in both full and pREBOA scenarios. Bland-Altman analysis showed extremely low bias between the COMPASS® and arterial line for both proximal (bias = 1.9) and distal (bias = 0.8) pressure measurements. CONCLUSION: The COMPASS® provides accurate and precise pressure measurements during standard and partial REBOA in both uninjured and shock conditions. This device may help extend and enhance capability in any low-resource/battlefield settings, or even eliminate the need for standard intra-arterial invasive pressure monitoring and external setup.

Mixed reality surgical mentoring of combat casualty care related procedures in a perfused cadaver model: Initial results of a randomized feasibility study.

BACKGROUND: Most telemedicine modalities have limited ability to enhance procedural and operative care. We developed a novel system to provide synchronous bidirectional expert mixed reality-enabled virtual procedural mentoring. In this feasibility study, we evaluated mixed reality mentoring of combat casualty care related procedures in a re-perfused cadaver model. METHODS: Novices received real-time holographic mentoring from experts using augmented reality via Hololens (Microsoft Inc, Redmond, WA). The experts maintained real-time awareness of the novice's operative environment using virtual reality via HTC-Vive (HTC Corp, Xindian District, Taiwan). Additional cameras (both environments) and novel software created the immersive, shared, 3-dimensional mixed reality environment in which the novice and expert collaborated. The novices were prospectively randomized to either mixed reality or audio-only mentoring. Blinded experts independently evaluated novice procedural videos using a 5-point Likert scale-based questionnaire. Nonparametric variables were evaluated using the Wilcoxon rank-sum test and comparisons using the χ2 analysis; significance was defined at P < .05. RESULTS: Surgeon and nonsurgeon novices (14) performed 69 combat casualty care-related procedures (38 mixed reality, 31 audio), including various vascular exposures, 4-compartment lower leg fasciotomy, and emergency neurosurgical procedures; 85% were performed correctly with no difference in either group. Upon video review, mixed reality-mentored novices showed no difference in procedural flow and forward planning (3.67 vs 3.28, P = .21) or the likelihood of performing individual procedural steps correctly (4.12 vs 3.59, P = .06). CONCLUSION: In this initial feasibility study, our novel mixed reality-based mentoring system successfully facilitated the performance of a wide variety of combat casualty care relevant procedures using a high fidelity re-perfused cadaver model. The small sample size and limited variety of novice types likely impacted the ability of holographically mentored novices to demonstrate improvement over the audio-only control group. Despite this, using virtual, augmented, and mixed reality technologies for procedural mentoring demonstrated promise, and further study is needed.

Is cerebral perfusion maintained during full and partial resuscitative endovascular balloon occlusion of the aorta in hemorrhagic shock conditions?

BACKGROUND: Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) is a technology that occludes aortic flow and allows for controlled deflation and restoration of varying distal perfusion. Carotid flow rates (CFRs) during partial deflation are unknown. Our aim was to measure CFR with the different pREBOA balloon volumes and correlate those to the proximal mean arterial pressure (PMAP) and a handheld pressure monitoring device (COMPASS; Mirador Biomedical, Seattle, WA). METHODS: Ten swine underwent a hemorrhagic injury model with carotid and iliac arterial pressures monitored via arterial lines. Carotid and aortic flow rates were monitored with Doppler flow probes. A COMPASS was placed to monitor proximal pressure. The pREBOA was inflated for 15 minutes then partially deflated for an aortic flow rate of 0.7 L/min for 45 minutes. It was then completely deflated. Proximal mean arterial pressures and CFR were measured, and correlation was evaluated. Correlation between CRF and COMPASS measurements was evaluated. RESULTS: Carotid flow rate increased 240% with full inflation. Carotid flow rate was maintained at 100% to 150% of baseline across a wide range of partial deflation. After full deflation, CFR transiently decreased to 45% to 95% of baseline. There was strong positive correlation (r > 0.85) between CFR and PMAP after full inflation, and positive correlation with partial inflation (r > 0.7). Carotid flow rate had strong correlation with the COMPASS with full REBOA (r > 0.85) and positive correlation with pREBOA (r > 0.65). CONCLUSION: Carotid flow rate is increased in a hemorrhagic model during full and partial inflation of the pREBOA and correlates well with PMAP. Carotid perfusion appears maintained across a wide range of pREBOA deflation and could be readily monitored with a handheld portable COMPASS device instead of a standard arterial line setup.

Real-time bedside management and titration of partial resuscitative endovascular balloon occlusion of the aorta without an arterial line: Good for pressure, not for flow!

BACKGROUND: Partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) attempts to minimize ischemia/reperfusion injury while controlling hemorrhage. There are little data on optimal methods to evaluate and titrate partial flow, which typically requires invasive arterial line monitoring. We sought to examine the use of a miniaturized handheld digital pressure device (COMPASS; Mirador Biomedical, Seattle, WA) for pREBOA placement and titration of flow. METHODS: Ten swine underwent standardized hemorrhagic shock. Carotid and iliac pressures were monitored with both arterial line and COMPASS devices, and flow was monitored by aortic and superior mesenteric artery flow probes. Partial resuscitative endovascular balloon occlusion of the aorta was inflated to control hemorrhage for 15 minutes before being deflated to try targeting aortic flow of 0.7 L/min (using only the COMPASS device) by an operator blinded to the arterial line pressures and aortic flow. Correlations between COMPASS and proximal/distal arterial line were evaluated, as well as actual aortic flow. RESULTS: There was strong correlation between the distal mean arterial pressure (MAP) and the distal COMPASS MAP (r = 0.979, p < 0.01), as well as between the proximal arterial line and the proximal COMPASS on the pREBOA (r = 0.989, p < 0.01). There was a significant but weaker correlation between the distal compass MAP reading and aortic flow (r = 0.47, p < 0.0001), although it was not clinically significant and predicted flow was not achieved in a majority of the procedures. Of 10 pigs, survival times ranged from 10 to 120 minutes, with a mean survival of 50 minutes, and 1 pig surviving to 120 minutes. CONCLUSION: Highly reliable pressure monitoring is achieved proximally and distally without arterial lines using the COMPASS device on the pREBOA. Despite accurate readings, distal MAPs were a poor indicator of aortic flow, and titration based upon distal MAPs did not provide reliable results. Further investigation will be required to find a suitable proxy for targeting specific aortic flow levels using pREBOA.

Rapid Sequence Induction Strategies Among Critically Injured U.S. Military During the Afghanistan and Iraq Conflicts.

INTRODUCTION: Rapid sequence intubation of patients experiencing traumatic hemorrhage represents a precarious phase of care, which can be marked by hemodynamic instability and pulseless arrest. Military combat trauma guidelines recommend reduced induction dose and early blood product resuscitation. Few studies have evaluated the role of induction dose and preintubation transfusion on hemodynamic outcomes. We compared rates of postintubation systolic blood pressure (SBP) of < 70 mm Hg, > 30% drop in SBP, pulseless arrest, and mortality at 24 hours and 30 days among patients who did and did not receive blood products before intubation and then examined if induction agent and dose influenced the same outcomes. MATERIALS AND METHODS: A retrospective analysis was performed of battle-injured personnel presenting to surgical care facilities in Iraq and Afghanistan between 2004 and 2018. Those who received blood transfusions, underwent intubation, and had an Injury Severity Score of ≥15 were included. Intubation for primary head, facial, or neck injury, burns, operative room intubations, or those with cardiopulmonary resuscitation in progress were excluded. Multivariable logistic regression was performed with unadjusted and adjusted odds ratios for the five study outcomes among patients who did and did not receive preintubation blood products. The same analysis was performed for patients who received full or excessive versus partial induction agent dose. RESULTS: A total of 153 patients had a mean age of 24.9 (SD 4.5), Injury Severity Score 29.7 (SD 11.2), heart rate 122.8 (SD 24), SBP 108.2 (SD 26.6). Eighty-one (53%) patients received preintubation blood products and had similar characteristics to those who did not receive transfusions. Adjusted multivariate analysis found odds ratios as follows: 30% SBP decrease 9.4 (95% CI 2.3-38.0), SBP < 70 13.0 (95% CI 3.3-51.6), pulseless arrest 18.5 (95% CI 1.2-279.3), 24-hour mortality 3.8 (95% CI 0.7-21.5), and 30-day mortality 1.3 (0.4-4.7). In analysis of induction agent choice and comparison of induction agent dose, no statistically significant benefit was seen. CONCLUSION: Within the context of this historical cohort, the early use of blood products conferred a statistically significant benefit in reducing postintubation hypotension and pulseless arrest among combat trauma victims exposed to traumatic hemorrhage. Induction agent choice and dose did not significantly influence the hemodynamic or mortality outcomes.

Radiofrequency Identification of the ER-REBOA: Confirmation of Placement Without Fluoroscopy.

INTRODUCTION: Non-compressible torso hemorrhage accounts for 70% of battlefield deaths. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emerging technology used to mitigate massive truncal hemorrhage. Use of REBOA on the battlefield is limited by the need for radiographic guided balloon placement. Radiofrequency identification (RFID) is a simple, portable, real-time technology utilized to detect retained sponges during surgery. We investigated the feasibility of RFID to confirm the placement of ER-REBOA. MATERIALS AND METHODS: This was a single-arm prospective proof-of-concept experimental study approved by the institutional review board at Naval Medical Center San Diego. The ER-REBOA (Prytime Medical Devices, Inc, Boerne, TX, USA) was modified by placement of a RFID tag. The tagged ER-REBOA was placed in zone I or zone III of the aorta in a previously perfused cadaver. Exact location was documented with X-ray. Five blinded individuals used the RF Assure Detection System (Medtronic, Minneapolis, MN, USA) handheld detection wand to predict catheter tip location from the xiphoid process (zone I) or pubic tubercle (zone III). RESULTS: In zone I, actual distance (Da) of the catheter tip was 11 cm from the xiphoid process. Mean predicted distance (Dp) from Da was 1.52 cm (95% CI 1.19-1.85). In zone III, Da was 14 cm from the pubic tubercle. Mean Dp from Da was 4.11 cm (95% CI 3.68-4.54). Sensitivity of detection was 100% in both zones. Specificity (Defined as Dp within 2 cm of Da) was 86% in zone I and 16% in zone III. CONCLUSIONS: Using RFID to confirm the placement of ER-REBOA is feasible with specificity highest in zone I. Future work should focus on refining this technology for the forward-deployed setting.

Blood transfusion: In the air tonight?

BACKGROUND: The use of prehospital blood transfusion (PBT) in air medical transport has become more widespread. However, the effect of PBT remains unknown. The aim of this study was to examine the impact of PBT on 24-hour and overall in-hospital mortality. METHODS: This is a retrospective cohort study of all trauma patients carried by air medical transport from the scene to a Level I trauma center from 2007 to 2013. We excluded patients who died on the helipad or in the emergency department. Primary outcomes measured were 24-hour and overall in-hospital mortality. Multivariable logistic regressions using all available patient data or the propensity score (for receiving PBT)-matched patient data were performed to study the effect of PBT on these outcomes. RESULTS: Of the 5,581 patients included in the study, 231 (4%) received PBT. Multivariable regression analyses did not show evidence of PBT effect on 24-hour in-hospital mortality (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.61-2.44) and on overall in-hospital mortality (OR, 1.20; 95% CI, 0.55-1.79). In addition, using 1:1 propensity score-matched data, the analysis did not show evidence of PBT effect on 24-hour in-hospital mortality (OR, 1.04; 95% CI, 0.54-1.98) and on overall in-hospital mortality (OR, 1.05; 95% CI, 0.56-1.96). Factors associated with increased 24-hour mortality were advanced age, penetrating injury, increased blood transfusion requirement in the first 24 hours, and decreased Glasgow Coma Scale (GCS) score (p < 0.05). These factors were also associated with overall mortality, in addition to increased Injury Severity Score (ISS) (p < 0.05). CONCLUSION: This is the largest study to date of trauma patients who received PBT and were transported from the scene by air medical transport. Our results show no effect of PBT on 24-hour and overall in-hospital mortality. Previous studies also suggest no benefit of PBT, which is counterintuitive to damage-control resuscitation. Prospective data on PBT are needed to assess risk, cost, and benefit. LEVEL OF EVIDENCE: Therapeutic study, level III.

Vagus nerve stimulation blocks vascular permeability following burn in both local and distal sites.

Recent studies have shown that vagus nerve stimulation (VNS) can block the burn-induced systemic inflammatory response (SIRS). In this study we examined the potential for VNS to modulate vascular permeability (VP) in local sites (i.e. skin) and in secondary sites (i.e. lung) following burn. In a 30% total body surface area burn model, VP was measured using intravascular fluorescent dextran for quantification of the VP response in skin and lung. A peak in VP of the skin was observed 24h post-burn injury, that was blocked by VNS. Moreover, in the lung, VNS led to a reduction in burn-induced VP compared to sham-treated animals subjected to burn alone. The protective effects of VNS in this model were independent of the spleen, suggesting that the spleen was not a direct mediator of VNS. These studies identify a role for VNS in the regulation of VP in burns, with the translational potential of attenuating lung complications following burn.

Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) may alter sympathetic tone causing autonomic abnormalities and organ dysfunction. Vagal nerve stimulation (VNS) has been shown to decrease inflammation and distant organ injury after TBI. It is unknown whether VNS may reduce blood-brain barrier (BBB) dysfunction after TBI.We hypothesize that VNS prevents TBI-induced breakdown of the BBB, subsequent brain edema, and neuronal injury. METHODS: A weight-drop model was used to create severe TBI in balb/c mice. Animals were divided into three groups: TBI-TBI only; TBI or VNS--animals that were treated with 10 minutes of VNS immediately before TBI; and sham--animals with opening of the skull but no TBI and VNS treatment. Brain vascular permeability to injected (Mr 70,000) FITC-dextran was measured by radiated fluorescence 6 hours after injury. Injured tissue sections were stained for perivascular aquaporin 4 (AQP-4), an important protein causing BBB--mediated brain edema. Fluorescence was quantified under laser scanning by confocal microscopy. RESULTS: Six hours after TBI, cerebral vascular permeability was increased fourfold compared with sham (mean [SD], 6.6(E+08) [5.5(E+07)] arbitrary fluorescence units [afu] vs. 1.5(E+08) [2.9(E+07)] afu; p G 0.001). VNS prevented the increase in permeability when compared with TBI alone (mean [SD], 3.5 (E+08) [8.3(E+07)] afu vs. 6.6(E+08) [5.5(E+07)] afu; p G 0.05). Perivascular expression of AQP-4 was increased twofold in TBI animals compared with sham (mean [SD], 0.96 [0.12] afu vs. 1.79 [0.37] afu; p G 0.05). Similarly, VNS decreased post-TBI expression of AQP-4 to levels similar to sham (mean [SD], 1.15 [0.12] afu; p G 0.05). CONCLUSION: VNS attenuates cerebral vascular permeability and decreases the up-regulation of AQP-4 after TBI. Future studies are needed to assess the mechanisms by which VNS maintains the BBB.

Targeting α-7 nicotinic acetylcholine receptor in the enteric nervous system: a cholinergic agonist prevents gut barrier failure after severe burn injury.

We have previously shown that vagal nerve stimulation prevents intestinal barrier loss in a model of severe burn injury in which injury was associated with decreased expression and altered localization of intestinal tight junction proteins. α-7 Nicotinic acetylcholine receptor (α-7 nAchR) has been shown to be necessary for the vagus nerve to modulate the systemic inflammatory response, but the role of α-7 nAchR in mediating gut protection remained unknown. We hypothesized that α-7 nAchR would be present in the gastrointestinal tract and that treatment with a pharmacological agonist of α-7 nAchR would protect against burn-induced gut barrier injury. The effects of a pharmacological cholinergic agonist on gut barrier integrity were studied using an intraperitoneal injection of nicotine 30 minutes after injury. Intestinal barrier integrity was examined by measuring permeability to 4-kDa fluorescein isothiocyanate-dextran and by examining changes in expression and localization of the intestinal tight junction proteins occludin and ZO-1. Nicotine injection after injury prevented burn-induced intestinal permeability and limited histological gut injury. Treatment with nicotine prevented decreased expression and altered localization of occludin and ZO-1, as seen in animals undergoing burn alone. Defining the interactions among the vagus nerve, the enteric nervous system, and the intestinal epithelium may lead to development of targeted therapeutics aimed at reducing gut barrier failure and intestinal inflammation after severe injury.

Vagal nerve stimulation blocks peritoneal macrophage inflammatory responsiveness after severe burn injury.

Large surface area burn injuries lead to activation of the innate immune system, which can be blocked by parasympathetic inputs mediated by the vagus nerve. We hypothesized that vagal nerve stimulation (VNS) would alter the inflammatory response of peritoneal macrophages after severe burn injury. Male BALB/c mice underwent right cervical VNS before 30% total body surface area steam burn and were compared with animals subjected to burn alone. Peritoneal macrophages were harvested at several time points following injury and exposed to lipopolysaccharide (LPS) in culture conditions. The inflammatory response of peritoneal macrophages was measured by analyzing changes in nuclear factor κB p65 phosphorylation using flow cytometry. We found that peritoneal macrophages isolated from mice subjected to burn injury were hyperresponsive to LPS challenge, suggesting burn-induced macrophage activation. We identified a protective role for VNS in blocking peritoneal macrophage activation. Analysis of the phosphorylation state of nuclear factor κB pathway mediator, p65 Rel A, revealed a VNS-mediated reduction in p65 phosphorylation levels after exposure to LPS compared with burn alone. In combination, these studies suggest VNS mediates the inflammatory response in peritoneal macrophages by affecting the set point of LPS responsiveness.

Cell surface localization and release of the candidate tumor suppressor Ecrg4 from polymorphonuclear cells and monocytes activate macrophages.

We identified fresh human leukocytes as an abundant source of the candidate epithelial tumor suppressor gene, Ecrg4, an epigenetically regulated gene, which unlike other tumor suppressor genes, encodes an orphan-secreted, ligand-like protein. In human cell lines, Ecrg4 gene expression was low, Ecrg4 protein undetectable, and Ecrg4 promoter hypermethylation high (45-90%) and reversible by the methylation inhibitor 5-AzaC. In contrast, Ecrg4 gene expression in fresh, normal human PBMCs and PMNs was 600-800 times higher than in cultured cell lines, methylation of the Ecrg4 promoter was low (<3%), and protein levels were readily detectable in lysates and on the cell surface. Flow cytometry, immunofluorescent staining, and cell surface biotinylation established that full-length, 14-kDa Ecrg4 was localized on PMN and monocyte cell surfaces, establishing that Ecrg4 is a membrane-anchored protein. LPS treatment induced processing and release of Ecrg4, as detected by flow and immunoblotting, whereas an effect of fMLF treatment on Ecrg4 on the PMN cell surface was detected on the polarized R2 subpopulation of cells. This loss of cell surface Ecrg4 was associated with the detection of intact and processed Ecrg4 in the conditioned media of fresh leukocytes and was shown to be associated with the inflammatory response that follows severe, cutaneous burn injury. Furthermore, incubation of macrophages with a soluble Ecrg4-derived peptide increased the P-p65, suggesting that processing of an intact sentinel Ecrg4 on quiescent circulating leukocytes leads to processing from the cell surface following injury and macrophage activation.

Vagus nerve and postinjury inflammatory response.

OBJECTIVE: To determine whether injured patients who received a vagotomy would have worse outcomes after injury. DESIGN: Retrospective analysis of the Nationwide Inpatient Sample (NIS) database over 10 years. PATIENTS: Patients admitted for trauma (primary International Classification of Diseases, Ninth Revision [ICD-9 ] diagnosis codes 800-959) who had a vagotomy (ICD-9 procedure codes 44.00, 44.01, and 44.03) were included. A second cohort of injured patients without vagotomy was extracted and matched 3 to 1 on the following criteria: age, race, sex, concurrent splenectomy, survival risk ratio, payer status, comorbidities, and calendar year. MAIN OUTCOME MEASURES: The primary outcome measured was in-hospital mortality. Secondary outcomes included septicemia, systemic inflammatory response syndrome, acute respiratory distress syndrome, ulcer disease, length of stay, and total charges. RESULTS: A total of 56 and 115 patients were included in the vagotomy and control groups, respectively, and were similar in demographic characteristics, comorbidities, and injury severity. We found that the vagotomy group had elevated mortality (27.27% vs 9.57% for controls; P = .003). Patients who received vagotomy also had more septicemia (26.79% vs 3.48%; P < .001) and ulcer disease (71.43% vs 2.61%; P < .001) but not systemic inflammatory response syndrome or acute respiratory distress syndrome. Patients who received vagotomy also had an increased length of hospital stay (36.4 vs 9.6 mean days; P < .001) and total cost ($211 899.90 vs $59 321.64; P < .001). CONCLUSIONS: Vagotomy after traumatic injury is associated with an increase in ulcer disease, septicemia, and mortality. This may reflect a loss of control over the systemic response to injury and warrants further study.

CPSI-121 pharmacologically prevents intestinal barrier dysfunction after cutaneous burn through a vagus nerve-dependent mechanism.

BACKGROUND: We have recently demonstrated the protective effects of electrical stimulation of the vagus nerve in prevention of gut injury after severe burn. Here we evaluate the potential for a pharmacologic agonist of the vagus nerve as an approach to regulate outcomes in preclinical models. We tested a new generation of guanylhydrazone-derived compounds, CPSI-121; a compound that may activate the parasympathetic nervous system through poorly understood mechanisms to determine whether we could prevent intestinal mucosal barrier breakdown. METHODS: Male balb/c mice were subjected to a full-thickness, 30% total body surface area steam burn, and the efficacy of CPSI-121 was tested against vagus nerve stimulation (VNS) postburn at 4 hours. Surgical vagotomy was used to disrupt the neuroenteric axis and gut injury prevention was assessed. Gut barrier dysfunction was quantified by permeability to 4-kDa fluorescein isothiocyanate-dextran. Gut injury was assessed by histologic evaluation. Tight junction protein expression (ZO-1 and occludin) was characterized by immunofluorescence and immunoblot. RESULTS: VNS and CPSI-121 administration significantly reduced the permeability to 4-kDa fluorescein isothiocyanate-dextran and maintained normal histology compared with burn. However, abdominal vagotomy eliminated the protective effects of both VNS and CPSI-121. ZO-1 and occludin expression was similar to sham in VNS and CPSI-121-treated burn animals, but significantly altered in burn-vagotomized animals. Splenectomy did not alter the effect of CPSI-121. CONCLUSION: Similar to direct electrical VNS, CPSI-121 effectively protects the intestinal mucosal barrier from breakdown after severe burn. We suggest that this could represent a noninvasive therapy to prevent end-organ dysfunction after trauma that would be administered during resuscitation.

Ghrelin prevents disruption of the blood-brain barrier after traumatic brain injury.

Significant effort has been focused on reducing neuronal damage from post-traumatic brain injury (TBI) inflammation and blood-brain barrier (BBB)-mediated edema. The orexigenic hormone ghrelin decreases inflammation in sepsis models, and has recently been shown to be neuroprotective following subarachnoid hemorrhage. We hypothesized that ghrelin modulates cerebral vascular permeability and mediates BBB breakdown following TBI. Using a weight-drop model, TBI was created in three groups of mice: sham, TBI, and TBI/ghrelin. The BBB was investigated by examining its permeability to FITC-dextran and through quantification of perivascualar aquaporin-4 (AQP-4). Finally, we immunoblotted for serum S100B as a marker of brain injury. Compared to sham, TBI caused significant histologic neuronal degeneration, increases in vascular permeability, perivascular expression of AQP-4, and serum levels of S100B. Treatment with ghrelin mitigated these effects; after TBI, ghrelin-treated mice had vascular permeability and perivascular AQP-4 and S100B levels that were similar to sham. Our data suggest that ghrelin prevents BBB disruption after TBI. This is evident by a decrease in vascular permeability that is linked to a decrease in AQP-4. This decrease in vascular permeability may diminish post-TBI brain tissue damage was evident by decreased S100B.

Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury.

Traumatic brain injury (TBI) releases a cascade of inflammatory cytokines. Vagal nerve stimulation (VNS) and ghrelin have known anti-inflammatory effects; furthermore, ghrelin release is stimulated by acetylcholine. We hypothesized VNS decreases post-TBI inflammation through a ghrelin-mediated mechanism. TBI was created in five groups of mice: sham, TBI, TBI/ghrelin, TBI/VNS, and TBI/VNS/ghrelin receptor antagonist (GRa). Serum and tissue ghrelin, and serum TNF-α were measured. Ghrelin increased following VNS 2 h post-TBI compared to sham or TBI. At 6 h, TBI and TBI/VNS/GRa had increased TNF-α compared to sham while TBI/VNS and TBI/ghrelin had TNF-α level comparable to sham. The highest ghrelin was measured in stomach where TBI decreased ghrelin in contrast to an increase by VNS. In conclusion, VNS increased serum ghrelin and decreased TNF-α following TBI. This was abrogated with GRa. Our data suggests that ghrelin plays an important role in the anti-inflammatory effects of VNS following TBI.

Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis.

BACKGROUND: The purpose of this study was to assess acute lung injury when protection to the gut mucosal barrier offered by vagus nerve stimulation is eliminated by an abdominal vagotomy. METHODS: Male balb/c mice were subjected to 30% total body surface area steam burn with and without electrical stimulation to the right cervical vagus nerve. A cohort of animals were subjected to abdominal vagotomy. Lung histology, myeloperoxidase and ICAM-1 immune staining, myeloperoxidase enzymatic assay, and tissue KC levels were analyzed 24 hours after burn. Additionally, lung IkB-α, NF-kB immunoblots, and NF-kB-DNA binding measured by photon emission analysis using NF-kB-luc transgenic mice were performed. RESULTS: Six hours post burn, phosphorylation of both NF-kB p65 and IkB-α were observed. Increased photon emission signal was seen in the lungs of NF-kB-luc transgenic animals. Vagal nerve stimulation blunted NF-kB activation similar to sham animals whereas abdominal vagotomy eliminated the anti-inflammatory effect. After burn, MPO positive cells and ICAM-1 expression in the lung endothelium was increased, and lung histology demonstrated significant injury at 24 hours. Vagal nerve stimulation markedly decreased neutrophil infiltration as demonstrated by MPO immune staining and enzyme activity. Vagal stimulation also markedly attenuated acute lung injury at 24 hours. The protective effects of vagal nerve stimulation were reversed by performing an abdominal vagotomy. CONCLUSION: Vagal nerve stimulation is an effective strategy to protect against acute lung injury following burn. Moreover, the protective effects of vagal nerve stimulation in the prevention of acute lung injury are eliminated by performing an abdominal vagotomy. These results establish the importance of the gut-lung axis after burn in the genesis of acute lung injury.