Whole Blood Resuscitation is Safe in Pediatric Trauma Patients: A Multicenter Study.

INTRODUCTION: Whole blood (WB) resuscitation has been associated with a mortality benefit in trauma patients. Several small series report the safe use of WB in the pediatric trauma population. We performed a subgroup analysis of the pediatric patients from a large prospective multicenter trial comparing patients receiving WB or blood component therapy (BCT) during trauma resuscitation. We hypothesized that WB resuscitation would be safe compared to BCT resuscitation in pediatric trauma patients. METHODS: This study included pediatric trauma patients (0-17 y), from ten level-I trauma centers, who received any blood transfusion during initial resuscitation. Patients were included in the WB group if they received at least one unit of WB during their resuscitation, and the BCT group was composed of patients receiving traditional blood product resuscitation. The primary outcome was in-hospital mortality with secondary outcomes being complications. Multivariate logistic regression was performed to assess for mortality and complications in those treated with WB vs BCT. RESULTS: Ninety patients, with both penetrating and blunt mechanisms of injury (MOI), were enrolled in the study (WB: 62 (69%), BCT: 28 (21%)). Whole blood patients were more likely to be male. There were no differences in age, MOI, shock index, or injury severity score between groups. On logistic regression, there was no difference in complications. Mortality was not different between the groups (P = .983). CONCLUSION: Our data suggest WB resuscitation is safe when compared to BCT resuscitation in the care of critically injured pediatric trauma patients.

Predictors of Massive Transfusion Protocol Initiation Among Trauma Patients Transported From the Scene Via Flight Emergency Management Services.

OBJECTIVE: Early identification of the subset of trauma patients with acute hemorrhage who require resuscitation via massive transfusion protocol (MTP) initiation is vital because such identification can ensure the availability of resuscitation products immediately upon hospital arrival and result in improved clinical outcomes, including reduced mortality. However, there are currently few studies on the predictors of MTP in the unique setting of flight transport. METHODS: This was a retrospective study of adult trauma patients transported from the scene via flight to 6 trauma centers between March 1, 2019, and January 21, 2021. Patients were included if they had emergency medical service vitals documented. The variables collected included demographics, comorbidities, cause of injury, body regions injured, in-flight treatments, and transport vitals. The primary outcome was MTP initiated by the receiving hospital. RESULTS: A total of 212 patients were included, of whom 16 (8%) had MTP initiated. During flight transport, 24 (11%) received whole blood, 9 (4%) received packed red blood cells, 11 (5%) had a tourniquet placed, and 5 (2%) received tranexamic acid. In adjusted analyses, receiving whole blood during transport (odds ratio [OR] = 8.52, P < .01), systolic blood pressure ≤ 90 mm Hg (OR = 8.07, P < .01), and a Glasgow Coma Scale score < 13 (OR = 8.38, P < .01) were independently associated with MTP. CONCLUSIONS: This retrospective cohort study showed that 3 factors readily available in the flight setting-receipt of whole blood, systolic blood pressure, and Glasgow Coma Scale score-are strong predictors of MTP at the receiving facility, particularly when considered in aggregate.

Predictors of transfer from a remote trauma facility to an urban level I trauma center for blunt splenic injuries: a retrospective observational multicenter study.

BACKGROUND: The decision-making for admission versus emergent transfer of patients with blunt splenic injuries presenting to remote trauma centers with limited resources remains a challenge. Although splenectomy is standard for hemodynamically unstable patients, the specific criterion for non-operative management continues to be debated. Often, lower-level trauma centers do not have interventional radiology capabilities for splenic artery embolization, leading to transfer to a higher level of a care. Thus, the aim of this study was to identify specific characteristics of patients with blunt splenic injuries used for admittance or transfer at a remote trauma center. METHODS: A retrospective observational study was performed to examine the management of splenic injuries at a mountainous and remote Level III trauma center. Trauma patients ≥ 18 years who had a blunt splenic injury and initially received care at a Level III trauma center prior to admittance or transfer were included. Data were collected over 4.5 years (January 1, 2016 - June 1, 2020). Patients who were transferred out in > 24 h were excluded. Patient demographics, injury severity, spleen radiology findings, and clinical characteristics were compared by decision to admit or transfer to a higher level of care ≤ 24 h of injury. Results were analyzed using chi-square, Fisher's exact, or Wilcoxon tests. Multivariable logistic models were used to identify predictors of transfer. RESULTS: Of the 73 patients included with a blunt splenic injury, 48% were admitted and 52% were transferred to a Level I facility. Most patients were male (n = 58), were a median age of 26 (21-42) years old, most (n = 62) had no comorbidities, and 47 had been injured from a ski/snowboarding accident. Compared to admitted patients, transferred patients were significantly more likely to be female (13/38 vs. 3/36, p = 0.007), to have an abbreviated injury scale score ≥ 3 of the chest (31/38 vs. 7/35, p = 0.002), have a higher injury severity score (16 (16-22) vs. 13 (9-16), p = 0.008), and a splenic injury grade ≥ 3 (32/38 vs. 12/35, p < 0.001). After adjustment, splenic injury grade ≥ 3 was the only predictor of transfer (OR: 12.1, 95% CI: 3.9-37.3, p < 0.001). Of the 32 transfers with grades 3-5, 16 were observed, and 16 had an intervention. Compared to patients who were observed after transfer, significantly more who received an intervention had a blush on CT (1/16 vs. 7/16, p = 0.02) and a higher median spleen grade of 4 (3-5) vs. 3 (3-3.5), p = 0.01). CONCLUSIONS: Our data suggest that most patients transferred from a remote facility had a splenic injury grade ≥ 3, with concomitant injuries but were hemodynamically stable and were successfully managed non-operatively. Stratifying by spleen grade may assist remote trauma centers with refining transfer criteria for solid organ injuries.

Use of Cold-Stored Whole Blood is Associated With Improved Mortality in Hemostatic Resuscitation of Major Bleeding: A Multicenter Study.

OBJECTIVE: The aim of this study was to identify a mortality benefit with the use of whole blood (WB) as part of the resuscitation of bleeding trauma patients. BACKGROUND: Blood component therapy (BCT) is the current standard for resuscitating trauma patients, with WB emerging as the blood product of choice. We hypothesized that the use of WB versus BCT alone would result in decreased mortality. METHODS: We performed a 14-center, prospective observational study of trauma patients who received WB versus BCT during their resuscitation. We applied a generalized linear mixed-effects model with a random effect and controlled for age, sex, mechanism of injury (MOI), and injury severity score. All patients who received blood as part of their initial resuscitation were included. Primary outcome was mortality and secondary outcomes included acute kidney injury, deep vein thrombosis/pulmonary embolism, pulmonary complications, and bleeding complications. RESULTS: A total of 1623 [WB: 1180 (74%), BCT: 443(27%)] patients who sustained penetrating (53%) or blunt (47%) injury were included. Patients who received WB had a higher shock index (0.98 vs 0.83), more comorbidities, and more blunt MOI (all P <0.05). After controlling for center, age, sex, MOI, and injury severity score, we found no differences in the rates of acute kidney injury, deep vein thrombosis/pulmonary embolism or pulmonary complications. WB patients were 9% less likely to experience bleeding complications and were 48% less likely to die than BCT patients ( P <0.0001). CONCLUSIONS: Compared with BCT, the use of WB was associated with a 48% reduction in mortality in trauma patients. Our study supports the use of WB use in the resuscitation of trauma patients.

An Educational Outreach Program: A Trauma System's 5-Year Experience.

BACKGROUND: The American College of Surgeons Committee on Trauma requires Level I and II trauma centers to provide educational outreach to lower-level facilities. Although outreach is a required part of any trauma system, very little is published on the resources required for a successful program. OBJECTIVE: The purpose of this article is to provide a comprehensive roadmap of the required components to achieve a successful trauma outreach program. METHODS: This project describes the development and implementation of an educational outreach program from January 2016 to December 2020 that has grown from 27 facilities within one western state to 49 facilities across 14 different states. Program components measured include the number and attendance of trauma courses offered, including the Trauma Nursing Core Course (TNCC), Advanced Trauma Life Support (ATLS), Rural Trauma Team Development Course (RTTDC), the number of trauma meetings and webinars provided, total trauma center designation and reviews, total states reached, and total trauma center collaborations. RESULTS: From 2016 to 2020, the program more than doubled the number of TNCC and ATLS courses, maintained the number of RTTDC offered, and observed attendance rate increases of 33% and 11% for TNCC and ATLS courses, respectively. Outreach leadership attended 44 trauma meetings and educational webinars using virtual platform technology, nearly doubling the trauma center outreach with expansion across 14 states resulting in important changes in practice. CONCLUSION: With administrative support, effective leadership, and technology, outreach programs can serve as important resources for statewide trauma systems.

AMP5A modulates Toll-like receptors 7 and 8 single-stranded RNA immune responses in PMA-differentiated THP-1 and PBMC.

Background: Dysregulation of antiviral immunity has been implicated in the progression of acute respiratory syndrome coronavirus 2 infection into severe cases of coronavirus disease of 2019 (COVID-19). Imbalances in the inflammatory response drive the overabundant production of pro-inflammatory cytokines and chemokines. The low molecular weight fraction of 5% human serum albumin commercial preparation (AMP5A) is a novel biologic drug currently under clinical investigation for the treatment of osteoarthritis and the hyperinflammatory response associated with COVID-19. This study aims to elucidate AMP5A effects following the activation of immune cells with agonists of Toll-like receptor (TLR) 7 and/or 8, which detect ssRNA viral sequences. Methods: CXCL10 ELISAs were used to evaluate the dynamics of myeloid cells activated with CL075 and CL307, agonists of TLR7/8 and TLR7, respectively. In addition, enrichment analysis of gene sets generated by ELISA arrays was utilized to gain insight into the biologic processes underlying the identified differentially expressed cytokine profiles. Finally, relative potency (REP) was employed to confirm the involvement of mechanisms of action paramount to AMP5A activity. Results: AMP5A inhibits the release of CXCL10 from both CL075- and CL307-activated PMA-differentiated THP-1 and peripheral blood mononuclear cells. Furthermore, AMP5A suppresses a distinct set of pro-inflammatory cytokines (including IL-1ß, IL-6, IL-12, and CXCL10) associated with COVID-19 and pro-inflammatory NF-κB activation. REP experiments using antagonists specific for the immunomodulatory transcription factors, peroxisome proliferator-activated receptor γ, and aryl hydrocarbon receptor, also indicate that these pathways are involved in the ability of AMP5A to inhibit CXCL10 release. Conclusion: Due to the biphasic course of COVID-19, therapeutic approaches that augment antiviral immunity may be more beneficial early in infection, whereas later interventions should focus on inflammation suppression. In this study, we show that AMP5A inhibits TLR 7/8 signaling in myeloid cells, resulting in a decrease in inflammatory mediators associated with hyperinflammation and autoimmunity. Furthermore, data demonstrating that AMP5A activates immunomodulatory transcription factors found to be protective in lung disease is provided. These findings suggest that the modes and mechanisms of action of AMP5A are well suited to treat conditions involving dysregulated TLR 7/8 activation.

Characterization of peritoneal reactive ascites collected from acute appendicitis and small bowel obstruction patients.

BACKGROUND: Pathological abdominal adhesions can cause bowel obstructions. A history of appendectomy (appy) increases patient rehospitalization risk directly related to adhesions. To potentially identify strategies for adhesion treatment, we characterized reactive ascites (rA) collected during appy or adhesiolysis for small bowel obstruction (SBO). METHODS: This is a non-randomized, prospective observational study recruiting patients with non-perforated appendicitis or SBO from three Level 1 trauma centers in the United States. rA were analyzed via liquid chromatography-mass spectrometry (LC-MS) (n = 31), bead-based quantification cytokines and chemokines (n = 32) and soluble receptors (n = 30), and LC-MS metabolomics (n = 18). RESULTS: LC-MS showed that samples contained albumin, apolipoprotein A1, and transthyretin and that metabolites increased in SBO vs appy rA were biomarkers of oxidative stress. Multi-plex analyses showed levels of 17 cytokines/chemokines and 6 soluble receptors were significantly different in appy vs SBO rA. Top increased proteins in appy compared to SBO rA by 20.14-, 11.53-, and 8.18-fold were granulocyte-colony stimulating factor, C-X-C motif chemokine ligand 10, and interleukin-10, respectively. CONCLUSIONS: These data further define pro- and anti-inflammatory mediators and metabolites that may drive formation or perpetuate chronic abdominal adhesions. Future research is to further explore whether attenuation of these factors may decrease pathologic adhesion formation.

C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.

Processes for Trauma Care at Six Level I Trauma Centers During the COVID-19 Pandemic.

INTRODUCTION: As the COVID-19 pandemic spread, patient care guidelines were published and elective surgeries postponed. However, trauma admissions are not scheduled and cannot be postponed. There is a paucity of information available on continuing trauma care during the pandemic. The study purpose was to describe multicenter trauma care process changes made during the COVID-19 pandemic. METHODS: This descriptive survey summarized the response to the COVID-19 pandemic at six Level I trauma centers. The survey was completed in 05/2020. Questions were asked about personal protective equipment, ventilators, intensive care unit (ICU) beds, and negative pressure rooms. Data were summarized as proportions. RESULTS: The survey took an average of 5 days. Sixty-seven percent reused N-95 respirators; 50% sanitized them with 25% using ultraviolet light. One hospital (17%) had regional resources impacted. Thirty-three percent created ventilator allocation protocols. Most hospitals (83%) designated more beds to the ICU; 50% of hospitals designated an ICU for COVID-19 patients. COVID-19 patients were isolated in negative pressure rooms at all hospitals. CONCLUSIONS: In response to the COVID-19 pandemic, Level I trauma centers created processes to provide optimal trauma patient care and still protect providers. Other centers can use the processes described to continue care of trauma patients during the COVID-19 pandemic.

LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC.

BACKGROUND: Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-ß, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. METHODS: ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1ß relative potency were then employed to confirm the involvement of enriched pathways and TFs. RESULTS: LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1ß, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1ß release. CONCLUSION: In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the "cytokine storm" in COVID-19 patients: a hypothesis.

BACKGROUND: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a "cytokine storm". While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. PRESENTATION OF THE HYPOTHESIS: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. TESTING THE HYPOTHESIS: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. IMPLICATIONS OF HYPOTHESIS: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. CONCLUSIONS: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.

Associations of Antithrombotic Timing and Regimen with Ischemic Stroke and Bleeding Complications in Blunt Cerebrovascular Injury.

BACKGROUND: Blunt cerebrovascular injuries (BCVIs) are associated with long-term neurological effects. The first-line treatment for BCVIs is antithrombotics, but consensus on the optimal choice and timing of treatment is lacking. METHODS: This was a retrospective study on patients aged at least 18 years admitted to 6 level 1 trauma centers between 1/1/2014 and 12/31/2017 with grade 1-4 BCVI and treated with antithrombotics. Differences in treatment practices were examined across the 6 centers. The primary outcome was ischemic stroke, and secondary outcomes were related to bleeding complications: blood transfusion and intracranial hemorrhage (ICH). Treatment characteristics examined were time to diagnosis and first computerized tomography angiography, time of total treatment course, time on each antithrombotic (anticoagulants, antiplatelets, combination), time from hospital arrival to antithrombotic initiation, and treatment interruption, i.e., treatment halted for a surgical procedure and restarted postoperatively. Chi-square, Fisher exact, Spearman's rank-order correlation, Wilcoxon rank-sum, Kruskal-Wallis, and Cox proportional hazards models with time-varying covariates were used to evaluate associations with the outcomes. RESULTS: A total of 189 patients with BCVI were included. The median (IQR) time from arrival to antithrombotic initiation was 27 (8-61) hours, and 28% of patients had treatment interrupted. The ischemic stroke rate was 7.5% (n = 14), with most strokes (64%, n = 9) occurring between arrival and treatment initiation. Treatment interruption was associated with ischemic stroke (75% of patients with stroke had an interruption versus 24% of patients with no stroke; P < .01). Time on anticoagulants was not associated with ischemic stroke (P = .78), transfusion (P = .43), or ICH (P = .96). Similarly, time on antiplatelets (P = .54, P = .65, P = .60) and time on combination therapy (P = .96, P = .38, P = .57) were not associated with these outcomes. CONCLUSIONS: The timing and consistency of antithrombotic administration are critical in preventing adverse outcomes in patients with BCVI. Most ischemic strokes in this study population occurred between arrival and antithrombotic initiation, representing events that may potentially be intervened upon by earlier treatment. Future studies should examine the safety of continuing treatment through surgical procedures.

Quantity of hemoperitoneum is associated with need for intervention in patients with stable blunt splenic injury.

BACKGROUND: In patients with hemodynamically stable blunt splenic injury (BSI), there is no consensus on whether quantity of hemoperitoneum (HP) is a predictor for intervention with splenic artery embolization (SAE) or failing nonoperative management (fNOM). We sought to analyze whether the quantity of HP was associated with need for intervention. METHODS: This retrospective cohort study included adult trauma patients with hemodynamically stable BSI admitted to six trauma centers between 2014 and 2016. Quantity of HP was defined as small (perisplenic blood or blood in Morrison's pouch), moderate (blood in one or both pericolic gutters), or large (additional finding of free blood in the pelvis). Multivariate logistic regression was performed to identify predictors of intervention with SAE or fNOM versus successful observation. RESULTS: There were 360 patients: hemoperitoneum was noted in 214 (59%) patients, of which the quantity was small in 92 (43%), moderate in 76 (35.5%), and large in 46 (21.5%). Definitive management was as follows: 272 (76%) were observed and 88 (24%) had intervention (83 SAE, 5 fNOM). The rate of intervention was univariately associated with quantity of HP, even after stratification by American Association for the Surgery of Trauma (AAST) grade. After adjustment, larger quantities of HP significantly increased odds of intervention (p=0.01). Compared with no HP, the odds of intervention were significantly increased for moderate HP (OR=3.51 (1.49 to 8.26)) and large HP (OR=2.89 (1.03 to 8.06)), with similar odds for small HP (OR=1.21 (0.46 to 2.76)). Other independent predictors of intervention were higher AAST grade, older age, and presence of splenic vascular injury. CONCLUSION: Greater quantity of HP was associated with increased odds of intervention, with no difference in risk for moderate versus large HP. These findings suggest quantity of HP should be incorporated in the management algorithm of BSI as a consideration for angiography and/or embolization to maximize splenic preservation and reduce the risk of splenic rupture. LEVEL OF EVIDENCE: III, retrospective epidemiological study.

A descriptive survey on the use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for pelvic fractures at US level I trauma centers.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is not widely adopted for pelvic fracture management. Western Trauma Association recommends REBOA for hemodynamically unstable pelvic fractures, whereas Eastern Association for the Surgery of Trauma and Advanced Trauma Life Support do not. METHOD: Utilizing a prospective cross-sectional survey, all 158 trauma medical directors at American College of Surgeons-verified Level I trauma centers were emailed survey invitations. The study aimed to determine the rate of REBOA use, REBOA indicators, and the treatment sequence of REBOA for hemodynamically unstable pelvic fractures. RESULTS: Of those invited, 25% (40/158) participated and 90% (36/40) completed the survey. Nearly half of trauma centers [42% (15/36)] use REBOA for pelvic fracture management. All participants included hemodynamic instability as an indicator for REBOA placement in pelvic fractures. In addition to hemodynamic instability, 29% (4/14) stated REBOA is used for patients who are ineligible for angioembolization, 14% (2/14) use REBOA when interventional radiology is unavailable, 7% (1/14) use REBOA for patients with a negative FAST. Fifty percent (7/14) responded that hemodynamically unstable pelvic fractures exclusively indicates REBOA placement. Hemodynamic instability for pelvic fractures was most commonly defined as systolic blood pressure of < 90 [56% (20/36)]. At centers using REBOA, REBOA was the first line of treatment for hemodynamically unstable pelvic fractures 40% (6/15) of the time. CONCLUSIONS: There is little consensus on REBOA use for pelvic fractures at US Level I Trauma Centers, except that hemodynamically unstable pelvic fractures consistently indicated REBOA use.

The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy.

BACKGROUND: Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. METHODS: Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated. RESULTS: The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. CONCLUSIONS: Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.

Predictors of splenic artery embolization as an adjunct to non-operative management of stable blunt splenic injury: a multi-institutional study.

BACKGROUND: We sought to identify predictors of splenic artery embolization (SAE) over observation for hemodynamically stable patients with blunt splenic injury (BSI), by Organ Injury Scale (OIS) grade. METHODS: This was a multi-institutional retrospective study of all adults (≥18) with BSI who were initially managed non-operatively between 2014 and 2016. Multivariate logistic regression analysis was used to identify predictors of SAE by OIS grade. Covariates included radiographic characteristics (presence/quantity of hemoperitoneum, blush, vascular injury), demographics (age, sex, cause), Injury Severity Score, vital signs, and hemoglobin values. We also examined outcomes of death, length of stay (LOS), intensive care unit (ICU) admission, blood products, and failed non-operative management (NOM). RESULTS: Among 422 patients with stable BSI, 93 (22%) had SAE and 329 (78%) were observed. The rate of SAE increased by grade (p<0.001). In grade I and II BSI, 7% had SAE; significant predictors of SAE were blush (OR: 5.9, p=0.02), moderate or large hemoperitoneum (OR: 3.0, p=0.01), and male sex (OR: 6.3, p=0.05). In grade III BSI, 26% had SAE; significant predictors included moderate or large hemoperitoneum (OR: 3.9, p=0.04), motor vehicle crash (OR: 6.1, p=0.005), and age (OR=1.4, 40% with each decade increase in age, p=0.02). The rate of SAE was 52% for grade IV and 85% for grade V BSI; there were no independent predictors of SAE in either grade. Clinical outcomes were comparable by NOM strategy and grade, except longer LOS with SAE in grades I-III (p<0.05) and longer ICU LOS with SAE in grades I-IV (p<0.05). Only 5 (1.2%) patients failed NOM (4 observation, 1 SAE). CONCLUSION: These results strongly support SAE consideration for patients with stable grade IV and V BSI even if there are no other high-risk clinical or radiographic findings. For grades I-III, the identified predictors may help refine consideration for SAE. LEVEL OF EVIDENCE: Level III, retrospective epidemiological study.

Comparative effectiveness analysis of two regional analgesia techniques for the pain management of isolated multiple rib fractures.

Background: Catheter-based regional analgesia has been proposed as an alternative to systemic analgesia for patients with multiple rib fractures (MRF). This study sought to compare the efficacy of regional techniques for decreasing pain and improving clinical outcomes. Study design: This was a multi-institutional, retrospective cohort study of adult (≥18 years) patients admitted to four nonacademic trauma centers over two years (from 07/1/2014 to 06/30/2016). Study inclusion was MRF (≥3 fractures) with no other severe injuries. Two primary regional analgesia techniques were utilized and compared: continuous intercostal nerve blocks (CINB) and epidural (EPI) analgesia. The primary outcome, average pain scores on treatment, was examined using a repeated measures, linear regression mixed model. Secondary outcomes included hospital LOS, ICU LOS, ICU admission and hospital readmission, pulmonary complications, and incentive spirometry volumes during treatment, and were examined with univariate statistics. Results: There were 339 patients with isolated MRF; 85 (25%) required regional analgesia (CINB, n=41; EPI, n=44) and the remaining 75% received systemic analgesia only (IV, n=195; PO, n=59). There were demographic and clinical differences between regional analgesia and systemic analgesia groups; on the contrary, there were no demographic or clinical differences between the CINB and EPI groups. Adjusted pain scores were similar for the EPI and CINB groups (4.0 vs 4.4, p=0.49). Secondary outcomes were worse in the EPI group compared to the CINB group: less improvement in incentive spirometry volume (p=0.004), longer ICU LOS (p=0.03), longer hospital LOS (p<0.001), and more ICU admission (p<0.001). Conclusion: In patients requiring regional analgesia, pain management was equivalent with CINB and EPI, but CINB was associated with significantly better clinical outcomes. CINB might offer an efficient alternative for pain control in patients with MRF.

Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways.

Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation.

Intravenous Low-Dose Ketamine Provides Greater Pain Control Compared to Fentanyl in a Civilian Prehospital Trauma System: A Propensity Matched Analysis.

Objective: A few studies report comparable analgesic efficacy between low-dose ketamine and opioids such as morphine or fentanyl; however, limited research has explored the safety and effectiveness of intravenous low-dose ketamine as a primary analgesic in a civilian prehospital setting. The objective of this study is to compare pain control between low-dose ketamine and fentanyl when administered intravenously (IV) for the indication of severe pain. Methods: This was a retrospective, observational review of prehospital adult patients (≥18 years) who presented with severe pain (numeric rating scale, 7-10) and were treated solely with either low-dose ketamine IV or fentanyl IV between January 1, 2014 and December 31, 2016. Propensity matched analysis was performed adjusting for all baseline variables with p ≤ 0.10 and for baseline pain score to match ketamine and fentanyl patients on a one-to-one ratio. The primary outcome was change in pain score from baseline to after treatment and evaluated with a paired t-test. Secondary outcomes were changes in vital signs and Glasgow coma scale (GCS) from baseline to after treatment, as well as incidence of clinically significant adverse events (AEs); AEs were followed from scene arrival through emergency department discharge. Results: Propensity matched analysis produced 79 matched pairs. Ketamine IV patients, receiving a mean (SD) dose of 0.3 (0.1) mg/kg, showed a significantly larger mean decrease in pain after treatment, compared to the fentanyl IV patients (-5.5 (3.1) vs. -2.5 (2.4), p < 0.001). A significantly greater proportion of patients receiving ketamine IV achieved at least a 50% reduction in pain compared to those receiving fentanyl IV (67% vs. 19%, p < 0.001), marking 52 ketamine IV patients as responders to treatment. Vital signs demonstrated a nonsignificant decrease in blood pressure, respiratory rate, heart rate, and GCS. No clinically significant AEs were reported for patients receiving ketamine IV. Conclusion: The significant reduction in pain, significantly high proportion of ketamine responders, and the lack of clinically significant AEs characterizing patients receiving low-dose ketamine IV compared to fentanyl IV, all provide further support for its use as an effective prehospital analgesic. Level of Evidence: Level III, therapeutic.

The anti-inflammatory effect of LMWF5A and N-acetyl kynurenine on macrophages: Involvement of aryl hydrocarbon receptor in mechanism of action.

After a traumatic insult, macrophages can become activated leading to general inflammation at the site of injury. Activated macrophages are partially regulated by the aryl hydrocarbon receptor (AhR) which when activated suppresses inflammation by limiting the secretion of pro-inflammatory cytokines and promoting the over expression of immuno-modulatory mediators. This study aims to determine whether the low molecular weight fraction of 5% human serum albumin (LMWF5A) and N-acetyl kynurenine (NAK), an N-acetyl tryptophan (NAT) breakdown product in LMWF5A, can regulate inflammation by inhibiting macrophage activation through the AhR since kynurenine is a known AhR agonist. Using LCMS, we demonstrate that NAT is non-enzymatically degraded during accelerated aging of LMWF5A with high heat accelerating degradation. More importantly, NAK is a major degradation product found in LMWF5A. THP-1 monocytes were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) and pre-treated with 2-fold dilutions of LMWF5A or synthetic NAK with or without an AhR antagonist (CH223191) prior to overnight stimulation with lipopolysaccharide (LPS). Treatment with LMWF5A caused a 50-70% decrease in IL-6 release throughout the dilution series. A dose-response inhibition of IL-6 release was observed for NAK with maximal inhibition (50%) seen at the highest NAK concentration. Finally, an AhR antagonist partially blocked the anti-inflammatory effect of LMWF5A while completely blocking the effect of NAK. A similar inhibitory effect was observed for CXCL-10, but the AhR antagonist was not effective suggesting additional mechanisms for CXCL-10 release. These preliminary findings suggest that LMWF5A and NAK partially promote the suppression of activated macrophages via the AhR receptor. Therefore, LMWF5A, which contains NAK, is potentially a useful therapeutic in medical conditions where inflammation is prevalent such as trauma, sepsis, and wound healing.