Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study.

BACKGROUND: Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma. METHODS: Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays. RESULTS: We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t1/2) was 1.4 h (95% CI 1.2-1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points. CONCLUSIONS: We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.

Increased complement activation 3 to 6 h after trauma is a predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome: a prospective observational study.

BACKGROUND: Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome. METHODS: In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC3-6). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients' admission TCC, TCC-AUC3-6, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures. RESULTS: TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC3-6 correlated positively with New Injury Severity Score (Spearman's rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (- 0.21, 0.02 and - 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC3-6 were negatively associated with ventilator-free days. TCC-AUC3-6 outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4. CONCLUSIONS: Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males. CONCLUSION: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.

HMGB1 concentration measurements in trauma patients: assessment of pre-analytical conditions and sample material.

BACKGROUND: HMGB1 is a mediator of systemic inflammation in sepsis and trauma, and a promising biomarker in many diseases. There is currently no standard operating procedure for pre-analytical handling of HMGB1 samples, despite that pre-analytical conditions account for a substantial part of the overall error rate in laboratory testing. We hypothesized that the considerable variations in reported HMGB1 concentrations and kinetics in trauma patients could be partly explained by differences in pre-analytical conditions and choice of sample material. METHODS: Trauma patients (n = 21) admitted to a Norwegian Level I trauma center were prospectively included. Blood was drawn in K2EDTA coated tubes and serum tubes. The effects of delayed centrifugation were evaluated in samples stored at room temperature for 15 min, 3, 6, 12, and 24 h respectively. Plasma samples subjected to long-term storage in - 80 °C and to repeated freeze/thaw cycles were compared with previously analyzed samples. HMGB1 concentrations in simultaneously acquired arterial and venous samples were also compared. HMGB1 was assessed by standard ELISA technique, additionally we investigated the suitability of western blot in both serum and plasma samples. RESULTS: Arterial HMGB1 concentrations were consistently lower than venous concentrations in simultaneously obtained samples (arterial = 0.60 x venous; 95% CI 0.30-0.90). Concentrations in plasma and serum showed a strong linear correlation, however wide limits of agreement. Storage of blood samples at room temperature prior to centrifugation resulted in an exponential increase in plasma concentrations after ≈6 h. HMGB1 concentrations were fairly stable in centrifuged plasma samples subjected to long-term storage and freeze/thaw cycles. We were not able to detect HMGB1 in either serum or plasma from our trauma patients using western blotting. CONCLUSIONS: Arterial and venous HMGB1 concentrations cannot be directly compared, and concentration values in plasma and serum must be compared with caution due to wide limits of agreement. Although HMGB1 levels in clinical samples from trauma patients are fairly stable, strict adherence to a pre-analytical protocol is advisable in order to protect sample integrity. Surprisingly, we were unable to detect HMGB1 utilizing standard western blot analysis.

Biphasic Release of the Alarmin High Mobility Group Box 1 Protein Early After Trauma Predicts Poor Clinical Outcome.

OBJECTIVES: The causal role of the prototype alarmin high mobility group box 1 protein in systemic inflammation and remote organ injury after trauma and shock is established in animal models but not in humans. Our aim was therefore to determine high mobility group box 1 protein concentration kinetics with high time resolution during the first hours after trauma in individual patients and investigate the association with outcome. DESIGN: Prospective single-center observational study. SETTING: University hospital Level I trauma center. PATIENTS: Convenience recruitment of 136 trauma patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total plasma high mobility group box 1 protein levels were analyzed with enzyme-linked immunosorbent assay in repeated samples. Relationships between predefined predictor variables and outcome were examined in multivariable linear regression models. Ventilator-free days was used as primary outcome measure. Two distinct high mobility group box 1 protein release phases were identified. An initial exponential decay phase with half-life 26 minutes was not correlated with outcome. In contrast, a second high mobility group box 1 protein wave peaking 3-6 hours after trauma in the most severely injured and physiologically deranged patients was consistently the most important predictor of outcome in our multivariable models, rendering all other predictor variables insignificant except for smaller contributions from age and sex, and of admission base excess for maximal creatinine concentration. CONCLUSIONS: High mobility group box 1 protein was released in two consecutive phases. Only the second high mobility group box 1 protein wave was a significant predictor of outcome. Patients with a high high mobility group box 1 protein concentration between 3 and 6 hours after trauma might hypothetically benefit from high mobility group box 1 protein-specific antagonist therapy.

COVID-19 with silent hypoxemia. / Covid-19 med stille hypoksemi.

Some COVID-19 patients deteriorate rapidly and seemingly without warning. This is also true for relatively young patients who were previously healthy or who had only minor underlying conditions. We describe one such case, in which a man in his sixties developed rapidly progressive respiratory failure with severe hypoxia.

Hypobaric Decompression and White Matter Hyperintensities: An Evaluation of the NATO Standard.

INTRODUCTION: In their seminal work, McGuire and colleagues reported an increased incidence of white matter hyperintensities (WMH) in a cohort of U2 pilots and hypobaric chamber personnel. WMH burden was higher in U2 pilots with previous reports of decompression sickness (DCS), and McGuire's reports have raised concerns regarding adverse outcomes in the aftermath of hypobaric exposures. Accordingly, a NATO working group has recently revised its standard recommendations regarding hypobaric exposures, including measures to mitigate the risk of WMH. Mandatory recovery time for up to 72 h between repeated exposures has been suggested on the basis of experimental evidence. However, we argue that the evidence is scarce which supports restricting repeated exposures to mitigate WMH. It is plausible that WMH is correlated with DCS and emphasis should be made on limiting the duration of exposures rather than restricting short and repeated exposures. The profiles in the NATO recommendations are meant to mitigate the risk of DCS. Still, they will potentially expose NATO Air Force and Special Operations personnel to flight profiles that can give rise to DCS incidence above 35%. Awaiting reliable data, we recommend limiting the duration of exposures and allowing for short repeated exposures.Ottestad W, Hansen TA, Ksin JI. Hypobaric decompression and white matter hyperintensities: an evaluation of the NATO standard. Aerosp Med Hum Perform. 2021; 92(1):3942.

Pre-hospital critical care management of severe hypoxemia in victims of Covid-19: a case series.

OBJECTIVE: Despite critical hypoxemia, Covid-19 patients may present without proportional signs of respiratory distress. We report three patients with critical respiratory failure due to Covid-19, in which all presented with severe hypoxemia refractory to supplemental oxygen therapy. We discuss possible strategies for ventilatory support in the emergency pre-hospital setting, and point out some pitfalls regarding the management of these patients. Guidelines for pre-hospital care of critically ill Covid-19 patients cannot be established based on the current evidence base, and we have to apply our understanding of respiratory physiology and mechanics in order to optimize respiratory support. METHODS: Three cases with similar clinical presentation were identified within the Norwegian national helicopter emergency medical service (HEMS) system. The HEMS units are manned by a consultant anaesthesiologist. Patient's next of kin and the Regional committee for medical and health research ethics approved the publication of this report. CONCLUSION: Patients with Covid-19 and severe hypoxemia may pose a considerable challenge for the pre-hospital emergency medical services. Intubation may be associated with a high risk of complications in these patients and should be carried out with diligence when considered necessary. The following interventions are worth considering in Covid-19 patients with refractory hypoxemia before proceeding to intubation. First, administering oxygen via a tight fitting BVM with an oxygen flow rate that exceeds the patient's ventilatory minute volume. Second, applying continuous positive airway pressure, while simultaneously maintaining a high FiO2. Finally, assuming the patient is cooperative, repositioning to prone position.

Extracellular vesicle-associated procoagulant activity is highest the first 3 hours after trauma and thereafter declines substantially: A prospective observational pilot study.

BACKGROUND: Trauma patients have high concentrations of circulating extracellular vesicles (EVs) following injury, but the functional role of EVs in this setting is only partly deciphered. We aimed to describe in detail EV-associated procoagulant activity in individual trauma patients during the first 12 hours after injury to explore their putative function and relate findings to relevant trauma characteristics and outcome. METHODS: In a prospective observational study of 33 convenience recruited trauma patients, citrated plasma samples were obtained at trauma center admission and 2, 4, 6, and 8 hours thereafter. We measured thrombin generation from isolated EVs and the procoagulant activity of phosphatidylserine (PS)-exposing EVs. Correlation and multivariable linear regression analyses were used to explore associations between EV-associated procoagulant activity and trauma characteristics as well as outcome measures. RESULTS: EV-associated procoagulant activity was highest in the first 3 hours after injury. EV-associated thrombin generation normalized within 7 to 12 hours of injury, whereas the procoagulant activity of PS-exposing EVs declined to a level right above that of healthy volunteers. Increased EV-associated procoagulant activity at admission was associated with higher New Injury Severity Score, lower admission base excess, higher admission international normalized ratio, prolonged admission activated partial thromboplastin time, higher Sequential Organ Failure Assessment score at day 0, and fewer ventilator-free days. CONCLUSION: Our data suggest that EVs have a transient hypercoagulable function and may play a role in the early phase of hemostasis after injury. The role of EVs in trauma-induced coagulopathy and posttraumatic thrombosis should be studied bearing in mind this novel temporal pattern. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level V.

Oculometric Feature Changes During Acute Hypoxia in a Simulated High-Altitude Airdrop Scenario.

BACKGROUND: Severe acute hypoxia results in a rapid deterioration of cognitive functioning and thus poses a risk for human operations in high altitude environments. This study aimed at investigating the effects of oxygen system failure during a high-altitude high-opening (HAHO) parachute jump scenario from 30,000 ft (9144 m) on human physiology and cognitive performance using a noncontact eye-tracking task.METHODS: Nine healthy male volunteers (ages 27-48) were recruited from the Norwegian Special Operations Commandos. Eye-tracking data were collected to derive information on cognitive performance in the context of rapid dynamic changes in pressure altitude while performing a modified King-Devick test. The baseline data was collected at 8000 ft (2438 m) while breathing 100% oxygen during decompression. For every test, the corresponding arterial blood gas analysis was performed.RESULTS: The study subjects endured severe hypoxia, which resulted in significant prolongations of fixation time (range: 284.1-245.6 ms) until 23,397 ft (131 m) and fixation size (range: 34.6-32.4 mm) until 25,389 ft (7739 m) as compared to the baseline (217.6 ± 17.8 ms and 27.2 ± 4.5 mm, respectively). The increase in the saccadic movement and decrease in the saccadic velocity was observed until 28,998 ft and 27,360 ft (8839 and 8339 m), respectively.DISCUSSION: This is the first study to investigate cognitive performance from measured oculometric variables during severe hypobaric hypoxia in a simulated high-altitude airdrop mission scenario. The measurement of altered oculometric variables under hypoxic conditions represents a potential avenue to study altered cognitive performance using noncontact sensors that can derive information and serve to provide the individual with a warning from impending incapacitation.Pradhan GN, Ottestad W, Meland A, Kåsin JI, Høiseth LØ, Cevette MJ, Stepanek J. Oculometric feature changes during acute hypoxia in a simulated high-altitude airdrop scenario. Aerosp Med Hum Perform. 2021; 92(12):928-936.

Arterial Oxygen Saturation, Pulse Oximetry, and Cerebral and Tissue Oximetry in Hypobaric Hypoxia.

INTRODUCTION: Clinical accuracy of pulse oximeters (giving Spo2) is routinely tested down to an Sao2 of 70%, but lower oxygen saturations are often experienced during hypobaric hypoxia. Cerebral (Sco2) and peripheral tissue (Sto2) oxygen saturations can be measured using near infra-red spectroscopy. In a project simulating oxygen system failure during high altitude-high opening parachuting (HAHO), Sao2, Spo2, Sco2, and forearm Sto2 were measured. The aim of the present analysis was to explore the agreement between Sao2 and the three noninvasive measurements of hypoxemia (Spo2, Sco2, and Sto2).METHODS: Healthy volunteers from the Norwegian Special Operations Commando were studied in a hypobaric chamber as supplemental oxygen was removed at 301 hPa ambient pressure (30,000 ft) and recompressed at 25 hPa · min-1 (1000 ft · min-1) to ground level simulating a HAHO parachute flight. Sao2 was compared with Spo2, Sco2, and Sto2 in scatterplots and Bland-Altman plots, calculating bias and limits of agreement (LOA).RESULTS: The bias ± LOA were: Sao2 vs. Spo2: -5.8% ± 16, Sao2 vs. Sco2: -3.4% ± 11, and Sao2 vs. Sto2: 17% ± 30. The bias for Sao2 vs. Spo2 was dependent on the range of values, and correcting for this with a sloped bias line reduced the LOA to ± 8.2%.DISCUSSION: There were wide limits of agreement between Sao2 and Spo2. Sao2 and Sco2 agreed better, whereas Sao2 and forearm Sto2 had wide LOA. The agreement between Sao2 and Spo2 improved when correcting for the underestimation of Spo2 at low values. There is a poor agreement between Spo2 and the gold standard Sao2 during extreme hypobaric hypoxemia.Ottestad W, Kåsin JI, Høiseth LØ. Arterial oxygen saturation, pulse oximetery, and cerebral and tissue oximetry in hypobaric hypoxia. Aerospace Med Hum Perform. 2018; 89(12):1045-1049.

Acute hypoxia in a simulated high-altitude airdrop scenario due to oxygen system failure.

High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. PaO2 decreased from baseline 18.4 (17.3-19.1) kPa, 138.0 (133.5-143.3) mmHg, to a minimum value of 3.3 (2.9-3.7) kPa, 24.8 (21.6-27.8) mmHg, after 180 (60-210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals.NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia.

Radiation-induced effects on gene expression: an in vivo study on breast cancer.

BACKGROUND AND PURPOSE: Breast cancer is diagnosed worldwide in approximately one million women annually and radiation therapy is an integral part of treatment. The purpose of this study was to investigate the molecular basis underlying response to radiotherapy in breast cancer tissue. MATERIAL AND METHODS: Tumour biopsies were sampled before radiation and after 10 treatments (of 2 Gray (Gy) each) from 19 patients with breast cancer receiving radiation therapy. Gene expression microarray analyses were performed to identify in vivo radiation-responsive genes in tumours from patients diagnosed with breast cancer. The mutation status of the TP53 gene was determined by using direct sequencing. RESULTS AND CONCLUSION: Several genes involved in cell cycle regulation and DNA repair were found to be significantly induced by radiation treatment. Mutations were found in the TP53 gene in 39% of the tumours and the gene expression profiles observed seemed to be influenced by the TP53 mutation status.