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Supplemental Digital Content is available in the text., OBJECTIVES: Cardiopulmonary bypass triggers systemic inflammation, resulting in lung injury, and frequently leads to prolonged mechanical ventilation. Biomarkers of systemic inflammation are required to predict the risk of such complications. We hypothesize that specific serum proteins can be used as biomarkers to predict the severity of lung injury following cardiac surgery. DESIGN: Retrospective chart review study. SETTING: Clinical variables were collected and used in conjuncture with unbiased proteomic analysis using mass spectrometry that was performed on frozen plasma samples from a study group (patients with mechanical ventilation > 48 hr post surgery) and a control group (patients with mechanical ventilation < 48 hr post surgery). SUBJECTS: Subjects included were infants who underwent cardiac surgery with similar complexity (Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery 3 or 4) using cardiopulmonary bypass. Patients in both groups were matched for their weight, age, and duration of cardiopulmonary bypass. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Four-hundred eighty-three proteins were identified (99% minimum confidence and two peptides minimum, protein false discovery rate 0.1%) on proteomic analysis of four control and four study patients at precardiopulmonary bypass, 0, and 48 hours postcardiopulmonary bypass samples. Thirty-six of 178 proteins were significantly different (≥ 1.5-fold; p < 0.05) at precardiopulmonary bypass (top increased: tenascin; top decreased: tetranectin), 18 of 140 proteins at 0 hour (top increased: hemoglobin beta; top decreased: C8 beta), and 25 of 166 proteins at 48 hours post surgery (top increased: proteoglycan 4; top decreased: galectin-3–binding protein). The top pathway involved cytoskeleton remodeling. Other pathways involved immune response and blood coagulation. Proteoglycan 4 was validated by enzyme-linked immunosorbent assay in a different set of samples (n = 20/group; mean ± sd: 128 ± 67 vs 195 ± 160 ng/mL) (p = 0.037). CONCLUSIONS: Multiple proteomic biomarkers were associated with worse respiratory outcomes. Precardiopulmonary bypass biomarkers might indicate risk factors (e.g., abnormalities of coagulation), whereas those identified at 0 hour and post cardiopulmonary bypass may reflect mechanisms of ongoing pathobiology.

Supplemental Digital Content is available in the text., OBJECTIVES: Acute spinal cord injury is a devastating injury that may lead to loss of independent function. Stem-cell therapies have shown promise; however, a clinically efficacious stem-cell therapy has yet to be developed. Functionally, endothelial progenitor cells induce angiogenesis, and neural stem cells induce neurogenesis. In this study, we explored using a multimodal therapy combining endothelial progenitor cells with neural stem cells encapsulated in a bioactive biomimetic hydrogel matrix to facilitate stem cell–induced neurogenesis and angiogenesis in a rat hemisection spinal cord injury model. DESIGN: Laboratory experimentation. SETTING: University laboratory. SUBJECTS: Female Fischer 344 rats. INTERVENTIONS: Three groups of rats: 1) control, 2) biomimetic hydrogel therapy, and 3) combined neural stem cell, endothelial progenitor cell, biomimetic hydrogel therapy underwent right-sided spinal cord hemisection at T9–T10. The blinded Basso, Beattie, and Bresnahan motor score was obtained weekly; after 4 weeks, observational histologic analysis of the injured spinal cords was completed. MEASUREMENTS AND MAIN RESULTS: Blinded Basso, Beattie, and Bresnahan motor score of the hind limb revealed significantly improved motor function in rats treated with combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy (p < 0.05) compared with the control group. The acellular biomimetic hydrogel group did not demonstrate a significant improvement in motor function compared with the control group. Immunohistochemistry evaluation of the injured spinal cords demonstrated de novo neurogenesis and angiogenesis in the combined neural stem cell, endothelial progenitor cell, and biomimetic hydrogel therapy group, whereas, in the control group, a gap or scar was found in the injured spinal cord. CONCLUSIONS: This study demonstrates proof of concept that multimodal therapy with endothelial progenitor cells and neural stem cells combined with a bioactive biomimetic hydrogel can be used to induce de novo CNS tissue in an injured rat spinal cord.

Objectives:. Andexanet alfa is the first approved antidote in the management of life-threatening bleeds in patients treated with Xa inhibitors. The ANNEXA-4 study was successful in reducing factor Xa levels during time of administration but lacked correlation to improved patient outcomes. Given its novel mechanism of action, U.S. boxed warning, cost of up to $58,000 per dose, and limited efficacy data compared with standard of care, hospitals are faced with a dilemma with its addition to formulary and process for ensuring optimized use. The objective of this study was to evaluate adherence to institution restriction criteria and the clinical outcomes of treatment for patients for whom andexanet alfa is requested. Design:. Retrospective cohort study of andexanet alfa requests within a 12-month time period. Setting:. A 600-bed community teaching hospital. Patients:. Patients whom pharmacists received request for dispensing andexanet alfa. Interventions:. None. MEASUREMENTS AND MAIN RESULTS:. Quality outcomes reviewed compliance to restriction criteria. Clinical outcomes evaluated use of adjunctive blood products, ICU length of stay, hospital length of stay, and hospital mortality. Safety outcomes evaluated incidence of thrombotic events. Andexanet alfa was requested for 16 patients from November 2018 to November 2019. It was administered in nine patients, with compliance to restriction criteria of 66.6%, average ICU length of stay 5.6 days, hospital length of stay 8.6 days, hospital mortality in 44.4%, and thrombotic events in 33.3%. Orders were rejected in seven patients with compliance to restriction criteria of 100%, ICU length of stay 3.2 days, hospital length of stay 5.5 days, hospital mortality in 14%, and thrombotic events in 14%. Conclusions:. A greater rate of adverse effects and mortality was identified with the use of andexanet alfa compared with clinical trials. This is potentially due to its use in a more severely ill patient population and lack of adherence to restriction criteria.

Objectives:. Prolonged cardiac arrest is known to cause global ischemic brain injury and functional impairment. Upon resuscitation, electroencephalographic recordings of brain activity begin to resume and can potentially be used to monitor neurologic recovery. We have previously shown that intrathecal orexin shows promise as a restorative drug and arousal agent in rodents. Our goal is to determine the electrophysiology effects of orexin in a rodent model of asphyxial cardiac arrest, focusing on the electroencephalographic activity in the gamma and super-gamma bands (indicative of return of higher brain function). Design:. Experimental animal study. Setting:. University-based animal research laboratory. Subjects:. Adult male Wistar rats. Interventions:. In an established model of asphyxial cardiac arrest (n = 24), we treated half of Wistar rats with orexin administered intranasally by atomizer 30 minutes post return of spontaneous circulation in one of two dose levels (10 and 50 µM); the rest were treated with saline as control. Continuous electroencephalographic recording was obtained and quantitatively analyzed for the gamma fraction. Gamma and high-frequency super-gamma band measures were compared against clinical recovery according to Neuro-Deficit Score. Measurements and Main Results:. Compared with the control cohort, the high-dose orexin cohort showed significantly better Neuro-Deficit Score 4 hours after return of spontaneous circulation (55.17 vs 47.58; p < 0.02) and significantly higher mean gamma fraction (0.251 vs 0.177; p < 0.02) in cerebral regions surveyed by rostral electrodes for the first 170 minutes after administration of orexin. Conclusions:. Our findings support early and continuous monitoring of electroencephalography-based gamma activity as a marker of better functional recovery after intranasal administration of orexin as measured by Neuro-Deficit Score in an established animal model of asphyxial cardiac arrest.

Supplemental Digital Content is available in the text., Objectives: To provide an objective characterization of acute neurologic injury in critically ill patients with coronavirus disease 2019. Design: Prospective observational study. Demographics, comorbidities, and daily clinical physiologic and laboratory data were collected. Plasma levels of neurofilament-light chain, total tau, ubiquitin carboxy-terminal hydrolase L1, and glial fibrillary acidic protein were measured. The primary neurologic outcome was delirium defined by the Intensive Care Delirium Screening Checklist (scale 1–8). Associations among plasma biomarkers, respiratory failure, and inflammation were analyzed. Setting: Multicenter study in ICUs. Patients: Critically ill patients with respiratory failure, with coronavirus disease 2019, or without (ICU control). Measurements and Main Results: A total of 27 patients with coronavirus disease 2019 and 19 ICU controls were enrolled. Compared with ICU controls with pneumonia of other etiology, patients with coronavirus disease 2019 had significantly higher glial fibrillary acidic protein (272 pg/mL [150–555 pg/mL] vs 118 pg/mL [78.5–168 pg/mL]; p = 0.0009). In coronavirus disease 2019 patients, glial fibrillary acidic protein (rho = 0.5115, p = 0.0064), ubiquitin carboxy-terminal hydrolase L1 (rho = 0.4056, p = 0.0358), and neurofilament-light chain (rho = 0.6223, p = 0.0005) positively correlated with Intensive Care Delirium Screening Checklist score and were increased in patients with delirium (Intensive Care Delirium Screening Checklist ≥ 4) in the coronavirus disease 2019 group but not in ICU controls. There were no associations between the measures of respiratory function or cytokines with glial fibrillary acidic protein, total tau, ubiquitin carboxy-terminal hydrolase L1, or neurofilament-light chain levels in patients with coronavirus disease 2019. Conclusions: Plasma glial fibrillary acidic protein is two-fold higher in critically ill patients with coronavirus disease 2019 compared with ICU controls. Higher levels of glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain associate with delirium in patients with coronavirus disease 2019. Elevated plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neurofilament-light chain are independent of respiratory function and peripheral cytokines.

Supplemental Digital Content is available in the text., Objectives: The amount of tissue damage and the amplitude of the immune response after trauma are related to the development of infectious complications later on. Changes in the neutrophil compartment can be used as read out of the amplitude of the immune response after trauma. The study aim was to test whether 24/7 point-of-care analysis of neutrophil marker expression by automated flow cytometry can be achieved after trauma. Design: A prospective cohort study was performed. Polytrauma patients who developed infectious complications were compared with polytrauma patients who did not develop infectious complications. Setting: The study was performed in a level 1 trauma center. Patients: All trauma patients presented in the trauma bay were included. Interventions: An extra blood tube was drawn from all patients. Thereafter, a member of the trauma team placed the blood tube in the fully automated flow cytometer, which was located in the corner of the trauma room. Next, a modified and tailored protocol for this study was automatically performed. Main Results: The trauma team was able to successfully start the point-of-care automated flow cytometry analysis in 156 of 164 patients, resulting in a 95% success rate. Polytrauma patients who developed infectious complications had a significantly higher %CD16dim/CD62Lbright neutrophils compared with polytrauma patients who did not develop infectious complications (p = 0.002). Area under the curve value for %CD16dim/CD62Lbright neutrophils is 0.90 (0.83–0.97). Conclusions: This study showed the feasibility of the implementation of a fully automated point-of-care flow cytometry system for the characterization of the cellular innate immune response in trauma patients. This study supports the concept that the assessment of CD16dim/CD62Lbright neutrophils can be used for early detection of patients at risk for infectious complications. Furthermore, this can be used as first step toward immuno-based precision medicine of polytrauma patients at the ICU.

Although do-not-resuscitate orders only prohibit cardiopulmonary resuscitation in the case of cardiac arrest, the common initiation of this code status in the context of end-of-life care may lead providers to draw premature conclusions about other goals of care. The aim of this study is to identify concerns regarding care quality in the setting of do-not-resuscitate orders within the Department of Defense and compare differences in perceptions between members of the critical care team. Design A cross sectional observational study was conducted. Setting This study took place in the setting of critical care within the Department of Defense. Subjects All members of the Uniformed Services Section of the Society of Critical Care Medicine were invited to participate. Interventions A validated 31-question survey exploring the perceptions of care quality in the setting of do-not-resuscitate status was distributed. Measurements and main results Exploratory factor analysis was used to categorically group survey questions, and average factor scores were compared between respondent groups using t tests. Responses to individual questions were also analyzed between comparison groups using Fisher exact tests. Factor analysis revealed no significant differences between respondents of different training backgrounds; however, those with do-not-resuscitate training were more likely to agree that active treatment would be pursued (p = 0.024) and that trust and communication would be maintained (p = 0.005). Although 38% of all respondents worry that quality of care will decrease, 93% agree that life-prolonging treatments should be offered. About a third of providers wrongly believed that a do-not-resuscitate order must be reversed prior to an operation. Conclusions Although providers across training backgrounds held similar concerns about decreased care quality in the ICU, there is wide belief that the routine and noninvasive interventions are offered as indicated. Those with do-not-resuscitate training were more likely to believe that standards of care continued to be met after code status change.

Supplemental Digital Content is available in the text., Objectives: To determine whether time-series analysis and Shannon information entropy of facial expressions predict acute clinical deterioration in patients on general hospital wards. Design: Post hoc analysis of a prospective observational feasibility study (Visual Early Warning Score study). Setting: General ward patients in a community hospital. Patients: Thirty-four patients at risk of clinical deterioration. Interventions: A 3-minute video (153,000 frames) for each of the patients enrolled into the Visual Early Warning Score study database was analyzed by a trained psychologist for facial expressions measured as action units using the Facial Action Coding System. Measurements and Main Results: Three-thousand six-hundred eighty-eight action unit were analyzed over the 34 3-minute study periods. The action unit time variables considered were onset, apex, offset, and total time duration. A generalized linear regression model and time-series analyses were performed. Shannon information entropy (Hn) and diversity (Dn) were calculated from the frequency and repertoire of facial expressions. Patients subsequently admitted to critical care displayed a reduced frequency rate (95% CI moving average of the mean: 9.5–10.9 vs 26.1–28.9 in those not admitted), a higher Shannon information entropy (0.30 ± 0.06 vs 0.26 ± 0.05; p = 0.019) and diversity index (1.36 ± 0.08 vs 1.30 ± 0.07; p = 0.020) and a prolonged action unit reaction time (23.5 vs 9.4 s) compared with patients not admitted to ICU. The number of action unit identified per window within the time-series analysis predicted admission to critical care with an area under the curve of 0.88. The area under the curve for National Early Warning Score alone, Hn alone, National Early Warning Score plus Hn, and National Early Warning Score plus Hn plus Dn were 0.53, 0.75, 0.76, and 0.81, respectively. Conclusions: Patients who will be admitted to intensive care have a decrease in the number of facial expressions per unit of time and an increase in their diversity.

Supplemental Digital Content is available in the text., Objectives: Arginine is a conditionally essential amino acid, the precursor for nitric oxide and a key factor in cell proliferation, protein synthesis, and energy metabolism. When there is increased demand in the setting of inflammation, ischemia-reperfusion injury, and organ dysfunction, endogenous arginine production falls short, and external supplementation may be necessary. The goal of this study was to assess changes in concentrations of plasma arginine, citrulline, ornithine, glutamine, and plasma arginase in infants and children undergoing surgery for congenital heart disease with cardiopulmonary bypass. Design: Prospective observational study. Setting: The study was conducted in the Heart Center at Texas Children’s Hospital. Subjects: Children undergoing surgery for congenital heart disease with cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Serial perioperative blood samples were collected for quantification of amino acids, arginase, nitric oxide metabolites, and markers of organ function (lactate, Pao2/Fio2 ratio, and creatinine clearance). Thirty children (18 males) were included in the study; median (interquartile range) age 0.5 years (0.3–0.9 yr). The mean ± sd for plasma amino acid concentrations before cardiopulmonary bypass: arginine 62 ± 20 µmol/L, citrulline 24 ± 6 µmol/L, ornithine 53 ± 32 µmol/L, and glutamine 591 ± 126 µmol/L. Arginine concentration was decreased within the first 24 hours (43 ± 15 µmol/L; p = 0.004), citrulline and glutamine concentrations decreased over the first 48 hours (11 ± 4 µmol/L; p < 0.001 and 493 ± 131 µmol/L; p = 0.019, respectively) and were associated with an increase in arginase (3.8 ± 3 µg/mL; p < 0.05). There was an increase in Vasoactive-Inotropic Score (5.9 ± 19 vs 0.5 ± 2; p < 0.001), decrease in creatinine clearance (76 ± 24 vs 93 ± 31; p = 0.002), and Pao2/Fio2 ratio (243 ± 138 vs 374 ± 200; p = 0.007) comparing to baseline. Conclusions: A widely variable degree of arginine, citrulline, and glutamine depletion occurs in children after surgery for congenital heart disease. These findings were associated with increased arginase and coincide with some of the markers of organ perfusion.

Objectives: Sedatives are suspected contributors to neurologic dysfunction in PICU patients, to whom they are administered during sensitive neurodevelopment. Relevant preclinical modeling has largely used comparatively brief anesthesia in infant age-approximate animals, with insufficient study of repetitive combined drug administration during childhood. We hypothesized that childhood neurodevelopment is selectively vulnerable to repeated treatment with benzodiazepine and opioid. We report a preclinical model of combined midazolam and morphine in early childhood age-approximate rats. Design: Animal model. Setting: Basic science laboratory. Subjects: Male and female Long-Evans rats. Interventions: Injections of morphine + midazolam were administered twice daily from postnatal days 18–22, tapering on postnatal days 23 and 24. Control groups included saline, morphine, or midazolam. To screen for acute neurodevelopmental effects, brain homogenates were analyzed by western blot for synaptophysin, drebrin, glial fibrillary acidic protein, S100 calcium-binding protein B, ionized calcium-binding adaptor molecule 1, and myelin basic proteins. Data analysis used Kruskal-Wallis with Dunn posttest, with a p value of less than 0.05 significance. Measurements and Main Results: Morphine + midazolam and morphine animals gained less weight than saline or midazolam (p ≤ 0.01). Compared with saline, morphine + midazolam expressed significantly higher drebrin levels (p = 0.01), with numerically but not statistically decreased glial fibrillary acidic protein. Similarly, morphine animals exhibited less glial fibrillary acidic protein and more S100 calcium-binding protein B and synaptophysin. Midazolam animals expressed significantly more S100 calcium-binding protein B (p < 0.001) and 17–18.5 kDa myelin basic protein splicing isoform (p = 0.01), with numerically increased synaptophysin, ionized calcium-binding adaptor molecule 1, and 21.5 kDa myelin basic protein, and decreased glial fibrillary acidic protein. Conclusions: Analysis of brain tissue in this novel rodent model of repetitive morphine and midazolam administration showed effects on synaptic, astrocytic, microglial, and myelin proteins. These findings warrant further investigation because they may have implications for critically ill children requiring sedation and analgesia.

Supplemental Digital Content is available in the text., Objectives: The furosemide stress test measures the volume of urine produced after a furosemide challenge. Furosemide stress test has previously demonstrated sensitive and specific prediction of progression to Kidney Disease: Improving Global Outcomes guideline defined acute kidney injury stage III in the ICU. Furosemide is actively excreted into the nephron lumen where it inhibits the sodium-potassium-chloride cotransporter, causing diuresis. We hypothesize that furosemide excretion is a more direct measure of tubule health than diuresis. Design: We developed a furosemide excretion stress test to evaluate this hypothesis in a murine model of septic-acute kidney injury. Setting: Basic science laboratory. Subjects: Male and female 8-week old CD-1 mice. Interventions: Sepsis was induced by cecal ligation and puncture in male and female mice. Furosemide stress test/furosemide excretion stress test started 42 hours post-cecal ligation and puncture with a 1 mg/kg furosemide bolus and urine was collected for 12 hours. The mice were then euthanized or monitored until 7 days post-cecal ligation and puncture. In another cohort, mice were treated with vasopressin, which decreases urine volume. Furosemide concentration was determined by high performance liquid chromatography. Measurements and Main Results: Urine production during the 12-hour collection varied from 0.08 to 2.62 mL. Both urine production (furosemide stress test) and furosemide excretion (furosemide excretion stress test) predicted mortality (area under the receiver operating characteristic curve = 0.925 and 0.916) and time of death (R2 = 0.26 and 0.74). Male and female mice demonstrated consistent results. Following vasopressin treatment, furosemide stress test specificity fell to 33% (p = 0.016) but furosemide excretion stress test specificity was maintained. Conclusions: The furosemide stress test and furosemide excretion stress test performed similarly in predicting mortality; however, furosemide excretion stress test was superior in predicting time to death and maintained performance when challenged with vasopressin treatment in a mouse sepsis model.

Supplemental Digital Content is available in the text., Objectives: To identify mechanisms associated with sepsis-acute kidney injury based on the expression levels of renal injury biomarkers, neutrophil gelatinase–associated lipocalin, and kidney injury molecule-1 in renal biopsies which may allow the identification of sepsis-acute kidney injury patient subtypes. Design: Prospective, clinical laboratory study using “warm” human postmortem sepsis-acute kidney injury kidney biopsies. Setting: Research laboratory at university teaching hospital. Subjects: Adult patients who died of sepsis in the ICU and control patients undergoing tumor nephrectomy. Measurements and Main Results: Reverse transcription quantitative polymerase chain reaction and immunohistochemical staining were used to quantify messenger RNA and protein expression levels of neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 in the kidney of sepsis-acute kidney injury patients and control subjects. Morphometric analysis was used to quantify renal and glomerular neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 protein levels. Neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 messenger RNA and protein levels were increased in kidneys of sepsis-acute kidney injury patients compared with control kidney tissue. Neutrophil gelatinase–associated lipocalin was localized in the distal tubules, collecting ducts, the adventitia of the renal arterioles, and in the glomerular tufts of renal biopsies from sepsis-acute kidney injury patients. In contrast, kidney injury molecule-1 was localized at the brush border of the proximal tubules. There was no correlation between neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 levels. Furthermore, renal neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 levels were not associated with the extent of renal injury, the severity of critical illness, or serum creatinine levels at either ICU admission or day of expiration. By laser microdissecting glomeruli, followed by reverse transcription quantitative polymerase chain reaction, we identified heterogenous glomerular neutrophil gelatinase–associated lipocalin production in the kidney of sepsis-acute kidney injury patients. Conclusion: We found differences in the expression of neutrophil gelatinase–associated lipocalin and kidney injury molecule-1 in patients with the same syndrome “sepsis-acute kidney injury” meaning there is no single pathway leading to sepsis-acute kidney injury. This underscores the beliefs that there are many/different pathophysiological pathways that can cause sepsis-acute kidney injury. Hence, patients with criteria that meet the definitions of both acute kidney injury and sepsis can be divided into subtypes based on pathophysiological features.

Supplemental Digital Content is available in the text., Objectives: We hypothesize that knowledge of a stable personalized baseline state and increased data sampling frequency would markedly improve the ability to detect progressive hypovolemia during hemorrhage earlier and with a lower false positive rate than when using less granular data. Design: Prospective temporal challenge. Setting: Large animal research laboratory, University Medical Center. Subjects: Fifty-one anesthetized Yorkshire pigs. Interventions: Pigs were instrumented with arterial, pulmonary arterial, and central venous catheters and allowed to stabilize for 30 minutes then bled at a constant rate of either 5 mL·min–1 (n = 13) or 20 (n = 38) until mean arterial pressure decreased to 40 or 30 mm Hg in the 5 and 20 mL·min–1 pigs, respectively. Measurements and Main Results: Data during the stabilization period served as baseline. Hemodynamic variables collected at 250 Hz were used to create predictive models of “bleeding” using featurized beat-to-beat and waveform data and compared with models using mean unfeaturized hemodynamic variables averaged over 1-minute as simple hemodynamic metrics using random forest classifiers to identify bleeding with or without baseline data. The robustness of the prediction was evaluated in a leave-one-pig-out cross-validation. Predictive performance of models was compared by their activity monitoring operating characteristic and receiver operating characteristic profiles. Primary hemodynamic threshold data poorly identified bleed onset unless very stable initial baseline reference data were available. When referenced to baseline, bleed detection at a false positive rates of 10–2 with time to detect 80% of pigs bleeding was similar for simple hemodynamic metrics, beat-to-beat, and waveform at about 3–4 minutes. Whereas when universally baselined, increasing sampling frequency reduced latency of bleed detection from 10 to 8 to 6 minutes, for simple hemodynamic metrics, beat-to-beat, and waveform, respectively. Some informative features differed between simple hemodynamic metrics, beat-to-beat, and waveform models. Conclusions: Knowledge of personal stable baseline data allows for early detection of new-onset bleeding, whereas if no personal baseline exists increasing sampling frequency of hemodynamic monitoring data improves bleeding detection earlier and with lower false positive rate.

Supplemental Digital Content is available in the text., Objectives: Healthcare surfaces contribute to nosocomial disease transmission. Studies show that despite standard guidelines and practices for cleaning and disinfection, secondary infection spread among healthcare workers and patients is common in ICUs. Manual terminal cleaning practices in healthcare are subject to highly variable results due to differences in training, compliance, and other inherent complexities. Standard cleaning practices combined with no-touch disinfecting technologies, however, may significantly lower nosocomial infection rates. The objective of this study was to evaluate the efficacy of a whole-room, no-touch disinfection intervention to reduce the concentration and cross-contamination of surface bacteria when used in tandem with manual cleaning protocols. Design: Bacterial tracers were seeded onto hospital room surfaces to quantitatively evaluate the efficacy of manual terminal cleaning practices alone and in tandem with a no-touch, whole-room atomization system. Cross-contamination potentials and labor efficiency were also evaluated. Subjects and Intervention: Environmental service personnel cleaning efficacy was evaluated pre and post application of manual terminal cleaning protocols alone and in tandem with a whole-room atomization system with an United States Environmental Protection Agency-registered hospital-grade hypochlorous acid disinfectant. Setting: The study was conducted in an unoccupied patient room at Banner University Medical Center in Tucson, AZ. The room was located in a newly constructed ICU suite. Measurements and Main Results: Manual terminal cleaning averaged a 2.4 log10 reduction in seeded bacterial counts compared with a 4.9 average and up to a 6 log10 reduction with tandem cleaning. Cross-contamination among surfaces following terminal cleaning alone was documented in 50% of the samples compared with 0% with tandem cleaning, with the latter achieving a 64% improvement in manual labor efficiency. Conclusions: The use of whole-room atomized disinfection with terminal cleaning protocols lowered manual labor times, improved disinfection outcomes, and eliminated the transfer of bacterial pathogens in healthcare environments.

Supplemental Digital Content is available in the text., Objectives: Effective treatment options for surfactant therapy in acute respiratory distress syndrome and coronavirus disease 2019 have not been established. To conduct preclinical studies in vitro and in vivo to evaluate efficiency, particle size, dosing, safety, and efficacy of inhaled surfactant using a breath-synchronized, nebulized delivery system in an established acute respiratory distress syndrome model. Design: Preclinical study. Setting: Research laboratory. Subjects: Anesthetized pigs. Intervention: In vitro analysis included particle size distribution and inhaled dose during simulated ventilation using a novel breath-synchronized nebulizer. Physiologic effects of inhaled aerosolized surfactant (treatment) were compared with aerosolized normal saline (control) in an adult porcine model (weight of 34.3 ± 0.6 kg) of severe acute respiratory distress syndrome (Pao2/Fio2

Objective We performed these studies to learn how iodine in the form of free iodide behaves during stress. Design Prospective observational trial using samples obtained from human trauma patients and retrospective observational study using remnant samples from human sepsis patients and arctic ground squirrels. Preclinical interventional study using hind-limb ischemia and reperfusion injury in mice. Setting Level I trauma center emergency room and ICU and animal research laboratories. Subjects Adult human sepsis and trauma patients, wild-caught adult arctic ground squirrels, and sexually mature laboratory mice. Interventions Ischemia and reperfusion injury was induced in mice by temporary application of tourniquet to one hind-limb. Iodide was administered IV just prior to reperfusion. Measurements and main results Free iodide was measured using ion chromatography. Relative to iodide in plasma from normal donors, iodide was increased 17-fold in plasma from trauma patients and 26-fold in plasma from sepsis patients. In arctic ground squirrels, iodide increases over three-fold during hibernation. And during ischemia/reperfusion injury in mice, iodide accumulates in ischemic tissue and reduces both local and systemic tissue damage. Conclusions Iodide redistributes during stress and improves outcome after injury. Essential functions of iodide may have contributed to its evolutionary selection and be useful as a therapeutic intervention for human patients.

Supplemental Digital Content is available in the text., Objectives: Sepsis is a leading cause of death in the United States. Putative targets to prevent systemic inflammatory response syndrome include antagonism of toll-like receptors 2 and 4 and CD44 receptors in vascular endothelial cells. Proteoglycan-4 is a mucinous glycoprotein that interacts with CD44 and toll-like receptor 4 resulting in a blockade of the NOD-like receptor pyrin domain-containing-3 pathway. We hypothesized that endothelial cells induced into a sepsis phenotype would have less interleukin-6 expression after recombinant human proteoglycan 4 treatment in vitro. Design: Enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction to measure interleukin-6 protein and gene expression. Setting: Research laboratory. Subjects: Human umbilical vascular endothelial cells, human lung microvascular endothelial cells, and transgenic mouse (wild type) (Cd44+/+/Prg4+/+), Cd44–/– (Cd44tm1HbgPrg4+/+), Prg4GT/GT (Cd44+/+ Prg4tm2Mawa/J), and double knockout (Cd44tm1Hbg Prg4tm2Mawa/J) lung microvascular endothelial cells. Interventions: Cells were treated with 100 or 250 ng/mL lipopolysaccharide-Escherichia coli K12 and subsequently treated with recombinant human proteoglycan 4 after 30 minutes. Interleukin-6 levels in conditioned media were measured via enzyme-linked immunosorbent assay and gene expression was measured via reverse transcriptase-quantitative polymerase chain reaction with ΔΔ–Ct analysis. Additionally, human umbilical vascular endothelial cells and human lung microvascular endothelial cells were treated with 1:10 diluted plasma from 15 patients with sepsis in culture media. After 30 minutes, either 50 or 100 µg/mL recombinant human proteoglycan 4 was administered. Interleukin-6 protein and gene expression were assayed. Proteoglycan 4 levels were also compared between control and sepsis patient plasma. Measurements and Main Results: Human umbilical vascular endothelial cell, human lung microvascular endothelial cell, and mouse lung microvascular endothelial cell treated with lipopolysaccharide had significantly increased interleukin-6 protein compared with controls. Recombinant human proteoglycan-4 significantly reduced interleukin-6 in human and mouse endothelial cells. Interleukin-6 gene expression was significantly increased after lipopolysaccharide treatment compared with controls. This response was reversed by 50 or 100 µg/mL recombinant human proteoglycan-4 in 80% of sepsis samples in human umbilical vascular endothelial cells and in 60–73% in human lung microvascular endothelial cells. In Cd44–/– genotypes of the mouse lung microvascular endothelial cells, recombinant human proteoglycan-4 significantly reduced interleukin-6 protein levels after lipopolysaccharide treatment, indicating that Cd44 is not needed for recombinant human proteoglycan-4 to have an effect in a toll-like receptor 4 agonist inflammation model. Patient sepsis samples had higher plasma levels of native proteoglycan-4 than controls. Interpretation and Conclusions: Recombinant human proteoglycan-4 is a potential adjunct therapy for sepsis patients and warrants future in vivo model studies.

Objectives: Children represent a unique patient population treated by military personnel during wartime, as seen in the recent conflicts in Iraq and Afghanistan. We sought to describe ICU resource utilization by U.S. military personnel treating pediatric trauma patients in Iraq and Afghanistan. Design: This is a retrospective review of prospectively collected data within Department of Defense Trauma Registry. Setting: We studied pediatric casualties treated in U.S. and coalition military hospitals in Iraq and Afghanistan between January 2007 and January 2016. Patients: We queried the Department of Defense Trauma Registry for patients less than 18 years with one documented day within an ICU. Interventions: We used descriptive statistics to analyze injuries patterns and interventions. We defined prolonged length of stay as ICU stay four days or greater. Regression methodology was utilized to identify factors associated with prolonged length of stay. Measurements and Main Results: There were 1955 (56.8%) pediatric patients that met our inclusion criteria. The most common mechanism of injury was explosive (45.2%) followed by gunshot wounds (20.8%). The median composite ISS was 14. The median length of stay was 3 days with 90.2% surviving to hospital discharge. Mechanical ventilation was the most frequent intervention (67.6%) followed by arterial access (21.8%). Prolonged length of stay was associated with all serious injuries, ventilator management, blood product administration, wound dressing, bronchoscopy, imaging, and central venous access. Conclusions: Pediatric casualties accounted for nearly one in 10 admissions with the majority requiring intensive care. The most commonly performed interventions were mechanical ventilation, vascular access, and imaging, each of which requires a specialized skill set to provide optimal patient management. All serious injuries by body region except facial were associated with a prolonged length of ICU stay, as well as blood product administration, ventilator management, intracranial pressure monitoring, wound care, bronchoscopy, imaging, and central venous access. The epidemiology of this unique population may be useful in planning future pre-deployment training and resource management in ICUs in deployed environments.