Early Fluid Is Less Fluid: Comparing Early Versus Late ICU Resuscitation in Severely Injured Trauma Patients.

OBJECTIVES: The temporal trends of crystalloid resuscitation in severely injured trauma patients after ICU admission are not well characterized. We hypothesized early crystalloid resuscitation was associated with less volume and better outcomes than delaying crystalloid. DESIGN: Retrospective, observational. SETTING: High-volume level 1 academic trauma center. PATIENTS: Adult trauma patients admitted to the ICU with emergency department serum lactate greater than or equal to 4 mmol/dL, elevated lactate (≥ 2 mmol/L) at ICU admission, and normal lactate by 48 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For the 333 subjects, we analyzed patient and injury characteristics and the first 48 hours of ICU course. Receipt of greater than or equal to 500 mL/hr of crystalloid in the first 6 hours of ICU admission was used to distinguish early vs. late resuscitation. Outcomes included ICU length of stay (LOS), ventilator days, and acute kidney injury (AKI). Unadjusted and multivariable regression methods were used to compare early resuscitation vs. late resuscitation. Compared with the early resuscitation group, the late resuscitation group received more volume by 48 hours (5.5 vs. 4.1 L; p ≤ 0.001), had longer ICU LOS (9 vs. 5 d; p ≤ 0.001), more ventilator days (5 vs. 2 d; p ≤ 0.001), and higher occurrence rate of AKI (38% vs. 11%; p ≤ 0.001). On multivariable regression, late resuscitation remained associated with longer ICU LOS and ventilator days and higher odds of AKI. CONCLUSIONS: Delaying resuscitation is associated with both higher volumes of crystalloid by 48 hours and worse outcomes compared with early resuscitation. Judicious crystalloid given early in ICU admission could improve outcomes in the severely injured.

A Rare Case of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Associated With Hemophagocytic Lymphohistiocytosis in a Patient With Recurrent Sinusitis.

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to nasal-type extranodal natural killer/T-cell lymphoma (ENKL). Nasal-type ENKL is a rare subtype of non-Hodgkin's lymphoma usually associated with Epstein-Barr virus (EBV). The patient was a 19-year-old woman who presented with facial numbness, diminished hearing, and dysgeusia. She was febrile with palatal necrosis, loss of gag reflex, and cranial nerve palsies. Labs revealed neutropenia. Broad-spectrum antimicrobials, including amphotericin, were started. Given concern for invasive fungal disease, she underwent surgical debridement, which revealed inflamed fibrous tissue and extensive necrosis. Pathology showed no fungal elements or malignancy. Lack of clinical improvement and worsening palatal necrosis prompted additional debridement. Histology identified an atypical CD3+/CD56+ cellular infiltrate. Bone marrow biopsy showed prominent hemophagocytosis, but no malignancy. She met the criteria for HLH and high-dose dexamethasone was started. Her fevers resolved. Additional labs and nasal tissue sampling with EBV-encoded RNA staining were recommended. Flow cytometry was negative, but histology revealed ENKL nasal-type, with positive EBV-encoded RNA in situ hybridization. Plasma EBV DNA level was 11,518 IU/mL. The M-SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) regimen was initiated; one cycle led to marked improvement. EBV level returned to zero. Subsequent radiation and chemotherapy, followed by autologous stem cell transplant consolidation, led to complete remission. We conclude that ENKL may mimic invasive sinusitis clinically. Fibrinoid necrosis in vessels and surrounding tissues often leads to diagnostic delay. It is important to have a high degree of clinical suspicion for malignancy in cases of HLH and sinusitis unresponsive to appropriate therapy. Obtaining proper tissue, communication with the pathologist, and prompt initiation of therapy are crucial.

The Sensitivity of Limited-Sequence MRI in Identifying Pediatric Cervical Spine Injury: A Western Pediatric Surgery Research Consortium Multicenter Retrospective Cohort Study.

INTRODUCTION: Clinical clearance of a child's cervical spine after trauma is often challenging due to impaired mental status or an unreliable neurologic examination. Magnetic resonance imaging (MRI) is the gold standard for excluding ligamentous injury in children but is constrained by long image acquisition times and frequent need for anesthesia. Limited-sequence MRI (LSMRI) is used in evaluating the evolution of traumatic brain injury and may also be useful for cervical spine clearance while potentially avoiding the need for anesthesia. The purpose of this study was to assess the sensitivity and negative predictive value of LSMRI as compared to gold standard full-sequence MRI as a screening tool to rule out clinically significant ligamentous cervical spine injury. METHODS: We conducted a ten-center, five-year retrospective cohort study (2017-2021) of all children (0-18y) with a cervical spine MRI after blunt trauma. MRI images were re-reviewed by a study pediatric radiologist at each site to determine if the presence of an injury could be identified on limited sequences alone. Unstable cervical spine injury was determined by study neurosurgeon review at each site. RESULTS: We identified 2,663 children less than 18 years of age who underwent an MRI of the cervical spine with 1,008 injuries detected on full-sequence studies. The sensitivity and negative predictive value of LSMRI were both >99% for detecting any injury and 100% for detecting any unstable injury. Young children (age < 5 years) were more likely to be electively intubated or sedated for cervical spine MRI. CONCLUSION: LSMRI is reliably detects clinically significant ligamentous injury in children after blunt trauma. To decrease anesthesia use and minimize MRI time, trauma centers should develop LSMRI screening protocols for children without a reliable neurologic exam. LEVEL OF EVIDENCE: 2 (Diagnostic Tests or Criteria).

A core outcome set for acute necrotizing pancreatitis: An Eastern Association for the Surgery of Trauma modified Delphi method consensus study.

BACKGROUND: The management of acute necrotizing pancreatitis (ANP) has changed dramatically over the past 20 years including the use of less invasive techniques, the timing of interventions, nutritional management, and antimicrobial management. This study sought to create a core outcome set (COS) to help shape future research by establishing a minimal set of essential outcomes that will facilitate future comparisons and pooling of data while minimizing reporting bias. METHODS: A modified Delphi process was performed through involvement of ANP content experts. Each expert proposed a list of outcomes for consideration, and the panel anonymously scored the outcomes on a 9-point Likert scale. Core outcome consensus defined a priori as >70% of scores receiving 7 to 9 points and <15% of scores receiving 1 to 3 points. Feedback and aggregate data were shared between rounds with interclass correlation trends used to determine the end of the study. RESULTS: A total of 19 experts agreed to participate in the study with 16 (84%) participating through study completion. Forty-three outcomes were initially considered with 16 reaching consensuses after four rounds of the modified Delphi process. The final COS included outcomes related to mortality, organ failure, complications, interventions/management, and social factors. CONCLUSION: Through an iterative consensus process, content experts agreed on a COS for the management of ANP. This will help shape future research to generate data suitable for pooling and other statistical analyses that may guide clinical practice. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Massive transfusion protocol reactivation as a novel marker of physician team under-triage after injury.

BACKGROUND: Large trauma centers have protocols for the assessment of injury and triaging of care with attempts to over-triage to ensure adequate care for all patients. We noted that a significant number of patients undergo a second massive transfusion protocol (MTP) activation in the first 24 h of care and conducted a retrospective cohort study of patients involved over a 3-year period. METHODS: Transfusion service records of MTP activations 2019-2021 were linked to Trauma Registry records and divided into cohorts receiving a single versus a reactivation of the MTP. Time of activation and amounts of blood products issued were linked to demographic, injury severity, and outcome data. Categorical and continuous data were compared between cohorts with chi-squared, Fisher's, and Wilcoxan tests as appropriate, and multivariable regression models were used to seek interactions (p < .05). RESULTS: MTP activation was recorded for 1884 acute trauma patients over our 3-year study period, 142 of whom (7.5%) had reactivation. Factors associated with reactivation included older age (46 vs. 40 years), higher injury severity score (ISS, 27 vs. 22), leg injuries, and presentation during morning shift change (5-7 a.m., 3.3% vs. 7.7%). Patients undergoing MTP reactivation used more RBCs (5 U vs. 2 U) and had more ICU days (3 vs. 2). CONCLUSIONS: Older patients and those presenting during shift change are at risk for failure to recognize their complex injury patterns and under-triage for trauma care. The fidelity and granularity of transfusion service records can provide unique opportunities for quality assessment and improvement in trauma care.

Predicting high-intensity resuscitation needs in injured patients in the post-hemostasis phase of care following intervention.

BACKGROUND: Best resuscitation practices in the posthemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this posthemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at intensive care unit (ICU) admission. METHODS: Clinical data were extracted for consecutive injured patients (2016-2019) admitted to the ICU following an immediate procedure in the operating room or angiography suite. High-intensity resuscitation thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 L) use in the initial 12 hours of ICU care and/or vasoactive medication use between ICU hours 2 and 12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six hundred five patients were included. Patients were 79% male, young (median age, 39 years), severely injured (median Injury Severity Score, 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSION: Intensive care unit admission data can identify subsequent HIR in the posthemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Characteristics of victims of trauma requiring invasive mechanical ventilation with a short stay in critical care.

BACKGROUND: Many patients who are admitted to the intensive care unit (ICU) have needs which rapidly resolve and are discharged alive within 24 h. We sought to characterize the outcomes of critically ill trauma victims at our institution with a short stay in the ICU. METHODS: We conducted a retrospective cohort study of all critically ill adult trauma victims presenting to our ED between January 1st, 2011 and December 31st, 2019. We included patients who were endotracheally intubated in either the prehospital setting or the ED and were admitted either to the operating room (OR), angiography suite, or ICU. Our primary outcome was the proportion of patients who were discharged alive from the ICU within 24 h. RESULTS: We included 3869 patients meeting the criteria above who were alive at 24 h. This population was 78% male with a median age of 40 and 76% of patients suffered from blunt trauma. The median injury severity score (ISS) of the group was 21 [inter-quartile range (IQR) 11-30]. In-hospital mortality amongst the group was 12%. 17% of the group were discharged alive from the ICU within 24 h. Thirty-four percent of the group had an ISS ≤ 15. Of the group which left the ICU alive within 24 h, six patients (0.9%) died in the hospital, 2 % of patients were re-admitted to an ICU, and 0.6% of patients required re-intubation. CONCLUSIONS: We found that 17% of patients who were intubated in the prehospital setting or emergency department and subsequently hospitalized were discharged alive from the ICU within 24 h.

Early Fluid is Less Fluid: Comparing Early Versus Late Resuscitation in Severely Injured Trauma Patients.

Background: We aimed to characterize the temporal trends of crystalloid resuscitation in severely injured trauma patients after intensive care unit (ICU) admission. Using 500 mL/hr of crystalloid in the first 6 hours of ICU admission to distinguish early versus late resuscitation, we hypothesized early resuscitation was associated with less volume by 48 hours and better outcomes compared with late resuscitation. Methods: We performed a retrospective review of the trauma registry of a high-volume level 1 academic trauma center to examine adult trauma patients admitted to the ICU (2016-2019) with: with initial serum lactate ≥ 4 mmol/dL, elevated lactate (≥ 2 mmol/L) at ICU admission, and lactate normalization within 48 hours. We analyzed patient and injury characteristics, and the first 48 hours of ICU course. The primary outcome was ICU length of stay (LOS); secondary outcomes included ventilator days, acute kidney injury (AKI), and in-hospital death. We compared subjects who received early resuscitation to those received late resuscitation using unadjusted methods and multivariable regression models. Results: We analyzed 333 subjects. The late resuscitation group received less volume over the first 24 hours, but surpassed the early group by 48 hours (5.5 vs 4.1L, p ≤ 0.001). The late group had longer ICU LOS (9 vs 5 days, p ≤ 0.001) and ventilator days (5 vs 2 days, p ≤ 0.001), and higher incidence of AKI (38% vs 11%, p ≤ 0.001). On multivariable regression, late resuscitation remained associated with longer ICU LOS and ventilator days, and higher odds of AKI after adjusting for important confounders. Conclusions: After hemostasis, crystalloid can play an important role in restoration of organ perfusion. Delaying resuscitation is associated with both receipt of higher volumes of crystalloid by 48 hours and worse outcomes compared to early resuscitation. Judicious crystalloid given early in ICU admission could improve outcomes in the severely injured.

Defining the Optimal Antibiotic Duration in Necrotizing Skin and Soft Tissue Infections: Clinical Experience from a Quaternary Referral Center.

Background: Early initiation of broad-spectrum antibiotic agents is a cornerstone of the care of necrotizing skin and soft tissue infections (NSTI). However, the optimal duration of antibiotic agents is unclear. We sought to characterize antibiotic prescribing patterns for patients with NSTI, as well as associated complications. Patients and Methods: Using an NSTI registry, we characterized antibiotic use at a quaternary referral center. Kaplan-Meier analyses were used to describe overall antibiotic duration and relative to operative source control, stratified by presence of other infections that independently influenced antibiotic duration. Factors associated with successful antibiotic discontinuation were identified using logistic regression. Results: Between 2015 and 2018, 441 patients received antibiotic agents for NSTI with 18% experiencing a complicating secondary infection. Among those without a complicating infection, the median duration of antibiotic administration was 9.8 days (95% confidence interval [CI], 9.2-10.5) overall, and 7.0 days after the final debridement. Perineal NSTI received fewer days of antibiotic agents (8.3 vs. 10.6) compared with NSTI without perineal involvement. White blood cell (WBC) count and fever were not associated with failure of antibiotic discontinuation, however, a chronic wound as the underlying infection etiology was associated with greater odds of antibiotic discontinuation failure (odds ratio [OR], 4.33; 95% CI, 1.24-15.1). Conclusions: A seven-day course of antibiotic agents after final operative debridement may be sufficient for NSTI without any secondary complicating infections, because clinical characteristics do not appear to be associated with differences in successful antibiotic discontinuation.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

A Description of Mechanically Ventilated Patients Admitted From the Emergency Department With a Short Critical Care Stay.

BACKGROUND: Patients admitted to an intensive care unit (ICU) requiring invasive mechanical ventilation who are discharged alive from the ICU within 24 h are poorly characterized in the literature. OBJECTIVE: Our aim was to characterize a cohort of intubated emergency department (ED) patients who are extubated and discharged from the ICU within 24 h. METHODS: We conducted a retrospective, observational cohort study at a single level I trauma center from January 2017 to December 2019. We included adults who were admitted to an ICU from the ED requiring invasive mechanical ventilation. Our primary outcome was the proportion of patients who were discharged from the ICU alive within 24 h. RESULTS: Of 13,374 ED patients admitted to an ICU during the study period, 2871 patients were intubated and ventilated in the prehospital or ED settings. Of these, 14% were discharged alive from the ICU within 24 h of admission. Only 21% of these patients were intubated in the ED. We identified the following two distinct subpopulations comprising 62% of this short-stay group: patients with a primary discharge diagnosis of intoxication (47%) and minimally injured trauma patients (53%), with 4% of patients in both subgroups. CONCLUSIONS: A total of 14% of patients receiving intubation with mechanical ventilation in the prehospital environment or in the ED were discharged alive from the ICU within 24 h. We identified two distinct subgroups of patients with a short stay in intensive care who may be candidates for ED extubation, including patients with intoxication and minimally injured trauma patients.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Long-term health-related quality of life and independence among older survivors of serious injury.

BACKGROUND: Little is known about the recovery experiences of older trauma intensive care unit (TICU) survivors and the relationship between geriatric trauma care and long-term functional ability and health-related quality of life (HRQOL). METHODS: We conducted a prospective cohort study of 218 patients (age, ≥65 years) admitted to a Level 1 regional trauma center TICU before versus after implementation of a geriatric care bundle with protocolized geriatrics consultations (Geri-T). Survivors or their proxies were interviewed approximately 1 year after hospitalization. Outcomes included the Katz Index of Independence in Activities of Daily Living (ADLs), Lawton Instrumental Activities of Daily Living (IADLs), and EQ-5D-5L HRQOL survey. Two investigator-developed questions regarding recovery experiences were included. Differences in outcomes among survivors admitted before versus after Geri-T were analyzed using multivariable linear regression. Responses to questions about recovery experiences were qualitatively assessed using content analysis. RESULTS: We reached 67% (146/218) of hospital survivors or their proxies across both groups; 126 patients were still alive and completed the survey. Mean age was 76 (SD, 8), 36% were female, and 90% were independent with ADLs preinjury. At follow-up, independence with ADLs was 76% and IADLs was 63%. The mean EQ-5D-5L index score was 0.78 (SD, 0.18). Most patients (65%) reported having not returned to preinjury functional status. Neither functional ability or HRQOL differed significantly among patients admitted before versus after Geri-T. Content analysis of open-ended questions revealed themes of activity limitations, persistent pain, and cognitive dysfunction. CONCLUSION: Nearly one-fifth of TICU survivors experienced loss of ADL function 1 year after injury, and most reported having not returned to preinjury functional status. Nonetheless, patient-reported HRQOL was comparable to age-adjusted norms. Geri-T was not associated with differences in HRQOL or functional ability. Survivors reported persistent difficulty with activities beyond those of daily living, pain, and cognition. LEVEL OF EVIDENCE: Prognostic and Epidemiologic, Level III.

Complication Rates in Patients With Classic and Radiographic Variants of Seymour Fractures.

BACKGROUND: At a tertiary-care, level 1 pediatric trauma center, we have observed fractures of the distal phalanx involving the physis, with associated nail bed injuries, that are distinct from the classic description of the Seymour fracture. We investigated the time to definitive management and the associated morbidity of these Seymour fracture variants compared with classically described Seymour fractures. We hypothesize that these Seymour variants are similarly problematic in terms of complications and delays to the definitive treatment and thus warrant increased awareness. METHODS: A retrospective chart review was performed of all patients with distal phalanx fractures involving the physis and associated nail bed injuries that were treated with operative intervention at a single pediatric specialty institution over a 9-year period. Radiographs and clinical photographs were reviewed to determine if the patient presented with a classic Seymour fracture or variant. Primary outcomes included time from injury to definitive treatment and complication rate. RESULTS: Of the 66 Seymour fractures identified in the chart review, 36 (55%) were identified as classic Seymour fractures and 30 (45%) were identified as variants. The mean time to operative intervention in the classic and variant groups was 7.3 versus 12.7 days (P=0.216). The complication rates in the classic and variant groups were 11.1% versus 23.3% (P=0.185), with infections accounting for nearly all complications identified. Overall infection rates for the classic and variant cohorts were 8.3% and 20.0% (P=0.169), respectively, with the majority presenting preoperatively (5.6% vs. 13.3%, P=0.274). CONCLUSIONS: We found that patients with classic Seymour fractures or radiographic variants had statistically similar incidence rates, complication rates, and delays in treatment, with a trend towards higher complication rates and delayed time to treatment in patients with variant-type injuries. We propose a minor expansion of the definition of Seymour fractures to include common variants to increase awareness of these problematic injuries, minimize delays in treatment, and decrease complications. LEVEL OF EVIDENCE: Level III; Retrospective Comparative Study.

PREHOSPITAL CRYSTALLOID RESUSCITATION: PRACTICE VARIATION AND ASSOCIATIONS WITH CLINICAL OUTCOMES.

ABSTRACT: Introduction: Although resuscitation guidelines for injured patients favor blood products, crystalloid resuscitation remains a mainstay in prehospital care. Our understanding of contemporary prehospital crystalloid (PHC) practices and their relationship with clinical outcomes is limited. Methods: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial data set was used for this investigation. We sought to identify factors associated with PHC volume variation and hypothesized that higher PHC volume is associated with worse coagulopathy and a higher risk of acute respiratory distress syndrome (ARDS) but a lower risk of acute kidney injury (AKI). Subjects were divided into groups that received <1,000 mL PHC (PHC<1,000) and ≥1,000 mL PHC (PHC≥1,000); initial laboratory values and outcomes (ARDS and AKI risk) were summarized with medians and interquartile ranges or percentages and compared using Wilcoxon rank-sum tests and chi-square tests. The primary outcome was ARDS risk. Multivariable regression was used to characterize the association of each 500 mL aliquot of PHC with initial laboratory values and clinical outcomes. Results: PHC volume among study subjects (n = 680) varied (median, 0.3 L; interquartile range, 0-0.9 L) with weak associations demonstrated among prehospital hemodynamics, intubation, Glasgow Coma Score, and Injury Severity Score (0.008 ≤ R2 ≤ 0.09); prehospital time and enrollment site explained more variation in PHC volume with R2 values of 0.2 and 0.54, respectively. Compared with PHC<1,000, PHC≥1,000 had higher INR, PT, PTT, and base deficit and lower hematocrit and platelets. The proportion of ARDS in the PHC≥1,000 group was higher than PHC<1,000 (21% vs. 12%, P < 0.01), whereas the rate of AKI was similar between groups (23% vs. 23%, P = 0.9). In regression analyses, each 500 mL of PHC was associated with increased INR and PTT, and decreased hematocrit and platelet count (P < 0.05). Each 500 mL of PHC was associated with increased ARDS risk and decreased AKI risk (P < 0.05). Conclusion: PHC administration correlates poorly with prehospital hemodynamics and injury characteristics. Increased PHC volume is associated with greater anemia, coagulopathy, and increased risk of ARDS, although it may be protective against AKI.

Neuroimaging, wearable sensors, and blood-based biomarkers reveal hyperacute changes in the brain after sub-concussive impacts.

Impacts in mixed martial arts (MMA) have been studied mainly in regard to the long-term effects of concussions. However, repetitive sub-concussive head impacts at the hyperacute phase (minutes after impact), are not understood. The head experiences rapid acceleration similar to a concussion, but without clinical symptoms. We utilize portable neuroimaging technology - transcranial Doppler (TCD) ultrasound and functional near infrared spectroscopy (fNIRS) - to estimate the extent of pre- and post-differences following contact and non-contact sparring sessions in nine MMA athletes. In addition, the extent of changes in neurofilament light (NfL) protein biomarker concentrations, and neurocognitive/balance parameters were determined following impacts. Athletes were instrumented with sensor-based mouth guards to record head kinematics. TCD and fNIRS results demonstrated significantly increased blood flow velocity (p = 0.01) as well as prefrontal (p = 0.01) and motor cortex (p = 0.04) oxygenation, only following the contact sparring sessions. This increase after contact was correlated with the cumulative angular acceleration experienced during impacts (p = 0.01). In addition, the NfL biomarker demonstrated positive correlations with angular acceleration (p = 0.03), and maximum principal and fiber strain (p = 0.01). On average athletes experienced 23.9 ± 2.9 g peak linear acceleration, 10.29 ± 1.1 rad/s peak angular velocity, and 1,502.3 ± 532.3 rad/s2 angular acceleration. Balance parameters were significantly increased following contact sparring for medial-lateral (ML) center of mass (COM) sway, and ML ankle angle (p = 0.01), illustrating worsened balance. These combined results reveal significant changes in brain hemodynamics and neurophysiological parameters that occur immediately after sub-concussive impacts and suggest that the physical impact to the head plays an important role in these changes.

A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis.

Accumulating evidence suggests that protein S-nitrosylation is enzymatically regulated and that specificity in S-nitrosylation derives from dedicated S-nitrosylases and denitrosylases that conjugate and remove S-nitrosothiols, respectively. Here, we report that mice deficient in the protein denitrosylase SCoR2 (S-nitroso-Coenzyme A Reductase 2; AKR1A1) exhibit marked reductions in serum cholesterol due to reduced secretion of the cholesterol-regulating protein PCSK9. SCoR2 associates with endoplasmic reticulum (ER) secretory machinery to control an S-nitrosylation cascade involving ER cargo-selection proteins SAR1 and SURF4, which moonlight as S-nitrosylases. SAR1 acts as a SURF4 nitrosylase and SURF4 as a PCSK9 nitrosylase to inhibit PCSK9 secretion, while SCoR2 counteracts nitrosylase activity by promoting PCSK9 denitrosylation. Inhibition of PCSK9 by an NO-based drug requires nitrosylase activity, and small-molecule inhibition of SCoR2 phenocopies the PCSK9-mediated reductions in cholesterol observed in SCoR2-deficient mice. Our results reveal enzymatic machinery controlling cholesterol levels through S-nitrosylation and suggest a distinct treatment paradigm for cardiovascular disease.

Diagnostic Accuracy of Ultrasound in Predicting Extrathyroidal Extension and Its Relation to Body Mass Index in a North American Population.

Detection of extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) influences treatment plan and surgical aggressiveness. Ultrasound (US) is the long-standing preoperative imaging method of choice. Recent literature from Asia suggests US accuracy to be influenced by patient characteristics, such as body mass index (BMI). Here, we examine the effect of BMI on the accuracy of US at a North American tertiary referral center. A total of 204 PTC-confirmed patients were retrospectively read by a radiologist blinded to surgical pathology findings. The radiologist recorded multiple sonographic features, including ETE, loss of echogenic capsule, nodule vascularity, capsular abutment, and bulging of contour. When considering all patients, the ultrasonographic feature with the best overall performance was loss of echogenic capsule (diagnostic odds ratio (DOR) = 4.48, 95% confidence interval (CI) = 1.86-10.78). Sub-group analysis by patient BMI found that area under the curve (AUC) for sonographic features was greater in non-obese BMI patients (0.71 ± 0.06) when compared with obese patients (0.43 ± 0.05; p = 0.001). Overall, US diagnostic performance was significantly better in non-obese (DOR = 3.70, 95%CI = 1.53-8.94) patients when compared to those who were obese (DOR = 1.12, 95%CI = 0.62-2.03; p = 0.03). Loss of the echogenic capsule did not differ between the two cohorts with respect to DOR (p = 0.51), specificity (p = 0.52), or sensitivity (p = 0.09). Our work suggests that the diagnostic value of ETE detection by US is impaired in obese patients. Considering that loss of the echogenic capsule did not differ with respect to diagnostic performance, specificity, nor sensitivity between non-obese and obese patients, it could be considered the most important predictor of US-determined ETE.

Inflammatory Mediators in Atherosclerotic Vascular Remodeling.

Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.

Neuroendocrine Carcinoma as a Cause of Humoral Hypercalcemia of Malignancy: A Case of a Patient With Elevated Parathyroid Hormone-Related Protein.

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome caused by elevations in parathyroid hormone-related protein (PTH-rP). HHM often presents in patients with squamous cell carcinomas of the lung, head, and neck, as well as breast, ovarian, renal, and bladder carcinomas. HHM associated with neuroendocrine carcinoma (NEC) is rarely observed. Here, we report a case of NEC-associated HHM refractory to standard calcium-reducing therapies but improved with the off-label addition of cinacalcet. A 31-year-old male with metastatic NEC presented to the emergency department (ED) with symptoms of nausea, emesis, constipation, and progressive weakness. He was being treated via a clinical trial at a tertiary referral center after failing standard therapies. He had recently been admitted at an outside facility for hypercalcemia, which had been managed with denosumab (120 mg subcutaneously) over the previous four weeks. He was admitted from the ED with a serum calcium of 14.6 mg/dL, potassium of 2.9 mmol/L, and phosphate of 1.2 mg/dL; ionized calcium was elevated at 8.0 mg/dL. Despite hydration and aggressive electrolyte replacement, his calcium increased to 15.5 mg/dL. Further laboratory evaluation revealed parathyroid hormone (PTH) of 6 pg/mL (10-65 pg/mL), 25-hydroxyvitamin D of 25 ng/mL (25-80 ng/mL), 1,25-dihydroxyvitamin D of 513 pg/mL (18-64 pg/mL), and PTH-rP of 25 pmol/L (<2.5 pmol/L), consistent with HHM. Calcitonin was avoided due to a prior hypersensitivity reaction. He received prednisone 10 mg daily and pamidronate 90 mg IV, and his calcium improved to 11.5 mg/dL. He was discharged and investigational therapy was resumed. This therapy failed, and he did not qualify for additional cancer therapy due to refractory hypercalcemia. He was started on cinacalcet, and his calcium decreased enough to permit further cancer treatment. He had multiple hospitalizations with fluctuating calcium levels and ultimately died several months later after sustaining a subarachnoid hemorrhage from a fall. In conclusion, we report a rare case of HHM associated with NEC. While many cases of HHM are effectively managed with hydration, calcitonin, antiresorptive therapies, and glucocorticoids, some are refractory. Our patient was refractory and differed from most patients with HHM in at least two ways. As mentioned previously, NEC causing HHM is quite uncommon (~2% of cases); it is unclear, but this malignancy might predispose to refractory hypercalcemia. Our patient's elevated vitamin D may also have made his HHM more resistant to treatment. Ultimately, while not first line, cinacalcet was an effective treatment in our patient. This provides additional evidence that cinacalcet may be considered for refractory hypercalcemia secondary to malignancy.