Obesity, Inflammation, and Clinical Outcomes in COVID-19: A Multicenter Prospective Cohort Study.

CONTEXT: Obesity is a risk factor for coronavirus disease 2019 (COVID-19)-related outcomes; however, the mechanism remains unclear. OBJECTIVE: The objective of this analysis was to determine whether inflammation mediates the association between obesity and COVID-19 outcomes. DESIGN: The International Study of Inflammation in Covid-19 (ISIC): A Prospective Multi-Center Observational Study Examining the Role of Biomarkers of Inflammation in Predicting Covid-19 Related Outcomes in Hospitalized Patients. SETTING: Ten hospitals in the United States and Europe. PARTICIPANTS: Adults hospitalized specifically for COVID-19 between February 1, 2020, through October 19, 2022. MAIN OUTCOME MEASURES: Inflammatory biomarkers, including soluble urokinase plasminogen activator receptor (suPAR), were measured at admission. Associations were examined between body-mass index (BMI, kg/m2) and a composite of death, need for mechanical ventilation, and renal replacement therapy, stratified by pre- and post-Omicron variants. The contribution of inflammation to the relationship between obesity and outcomes was assessed. RESULTS: Among 4644 participants (mean age 59.3, 45.6% male, 21.8% BMI≥35), those with BMI>40 (n=485) had 55% higher odds of the composite outcome (95% CI[1.21 to 1.98]) compared to non-obese individuals (BMI<30, n=2358) in multivariable analysis. In multiple mediation analysis, only suPAR remained a significant mediator between BMI and composite outcome. Associations were amplified for participants younger than 65 years and with pre-Omicron variants. CONCLUSION: Obesity is associated with worse outcomes in COVID-19, notably in younger participants and in the pre-Omicron era. Inflammation, as measured by suPAR, is a significant mediator of the association between obesity and COVID-19 outcomes.

Effect of Centhaquine on the Coagulation Cascade in Normal State and Uncontrolled Hemorrhage: A Multiphase Study Combining Ex Vivo and In Vivo Experiments in Different Species.

Centhaquine is a novel vasopressor acting on α2A- and α2B-adrenoreceptors, increasing venous return and improving tissue perfusion. We investigated the effects of centhaquine on blood coagulation in normal state and uncontrolled hemorrhage using ex vivo and in vivo experiments in different species. Thromboelastography (TEG) parameters included clotting time (R), clot kinetics [K and angle (α)], clot strength (MA), and percent lysis 30 min post-MA (LY30). In normal rat blood, centhaquine did not alter R, K, α, MA, or LY30 values of the normal vehicle group or the antithrombotic effects of aspirin and heparin. Subsequently, New Zealand white rabbits with uncontrolled hemorrhage were assigned to three resuscitation groups: Sal-MAP 45 group (normal saline to maintain a mean arterial pressure, MAP, of 45 mmHg), Centh-MAP 45 group (0.05 mg kg-1 centhaquine plus normal saline to maintain a MAP of 45 mmHg), and Sal-MAP 60 group (normal saline to maintain a MAP of 60 mmHg). The Sal-MAP 45 group was characterized by no change in R, reduced K and MA, and increased α. In the Centh-MAP 45 group, TEG showed no change in R, K, and α compared to saline; however, MA increased significantly (p = 0.018). In the Sal-MAP 60 group, TEG showed no change in R, an increase in α (p < 0.001), a decrease in K (p < 0.01), and a decrease in MA (p = 0.029) compared to the Centh-MAP 45 group. In conclusion, centhaquine does not impair coagulation and facilitates hemostatic resuscitation.

Evaluating the diagnostic and prognostic ability of ischemia modified albumin in COVID-19.

BACKGROUND: Patients with COVID-19 can rapidly deteriorate and develop acute hypoxic respiratory failure. Prominent features of the disease include severe inflammation, endotheliitis, and thrombosis. OBJECTIVES: The aim of the study was to evaluate the diagnostic and prognostic effectiveness of ischemia modified albumin (ΙΜΑ) in a cohort of COVID-19 patients. METHODS: This prospective observational study included adults with SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction test, who were hospitalized specifically for COVID-19. The outcomes of interest were progression to severe acute respiratory failure during the index hospitalization defined as partial pressure of oxygen/fraction of inspired oxygen lower or equal to 150, admission to the intensive care unit (ICU) and in-hospital mortality. Admission IMA levels were determined using the commercially available "IMA Assay Kit" method (Abbexa LTD, Cambridge, UK). Adults without SARS-CoV-2 infection were used as controls. RESULTS: 135 COVID-19 patients and 64 controls were included. Admission IMA levels were significantly higher in COVID-19 patients compared to controls [[24.38 (11.94) ng/ml vs. 14.69 (3.52) ng/ml, p < 0.01]. Receiver operating characteristic analysis of admission IMA showed an area under the curve (AUC) of 94% (p < 0.0001) for COVID-19 diagnosis (cut-off value: 17.5 ng/ml; sensitivity: 90.37%; specificity: 87.5%). Admission IMA was also associated with mortality (AUC: 68%, p = 0.01). However, it was not associated with severe acute respiratory failure (AUC: 47%, p = 0.53) or ICU admission (AUC: 58%, p = 0.41). CONCLUSION: Admission IMA was significantly increased in COVID-19 patients and was associated with in-hospital mortality.

Continuous vs intermittent Non-Invasive blood pressure MONitoring in preventing postoperative organ failure (niMON): study protocol for an open-label, multicenter randomized trial.

BACKGROUND: Blood pressure has become one of the most important vital signs to monitor in the perioperative setting. Recently, the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) recommended, with low level of evidence, continuous monitoring of blood pressure during the intraoperative period. Continuous monitoring allows for early detection of hypotension, which may potentially lead to a timely treatment. Whether the ability to detect more hypotension events by continuous noninvasive blood pressure (C-NiBP) monitoring can improve patient outcomes is still unclear. Here, we report the rationale, study design, and statistical analysis plan of the niMON trial, which aims to evaluate the effect of intraoperative C-NiBP compared with intermittent (I-NiBP) monitoring on postoperative myocardial and renal injury. METHODS: The niMon trial is an investigator-initiated, multicenter, international, open-label, parallel-group, randomized clinical trial. Eligible patients will be randomized in a 1:1 ratio to receive C-NiBP or I-NiBP as an intraoperative monitoring strategy. The proportion of patients who develop myocardial injury in the first postoperative week is the primary outcome; the secondary outcomes are the proportions of patients who develop postoperative AKI, in-hospital mortality rate, and 30 and 90 postoperative days events. A sample size of 1265 patients will provide a power of 80% to detect a 4% absolute reduction in the rate of the primary outcome. CONCLUSIONS: The niMON data will provide evidence to guide the choice of the most appropriate intraoperative blood pressure monitoring strategy. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: NCT05496322, registered on the 5th of August 2023.

Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke.

Perioperative stroke is a devastating complication that occurs during surgery or within 30 days following the surgical procedure. Its prevalence ranges from 0.08 to 10% although it is most likely an underestimation, as sedatives and narcotics can substantially mask symptomatology and clinical presentation. Understanding the underlying pathophysiology and identifying potential therapeutic targets are of paramount importance. Protease-activated receptors (PARs), a unique family of G-protein-coupled receptors, are widely expressed throughout the human body and play essential roles in various physiological and pathological processes. This review elucidates the biology and significance of PARs, outlining their diverse functions in health and disease, and their intricate involvement in cerebrovascular (patho)physiology and neuroprotection. PARs exhibit a dual role in cerebral ischemia, which underscores their potential as therapeutic targets to mitigate the devastating effects of stroke in surgical patients.

Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pao2/Fio2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pao2/Fio2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group (p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Novel insights into voltage-gated ion channels: Translational breakthroughs in medical oncology.

Preclinical evidence suggests that voltage gradients can act as a kind of top-down master regulator during embryogenesis and orchestrate downstream molecular-genetic pathways during organ regeneration or repair. Moreover, electrical stimulation shifts response to injury toward regeneration instead of healing or scarring. Cancer and embryogenesis not only share common phenotypical features but also commonly upregulated molecular pathways. Voltage-gated ion channel activity is directly or indirectly linked to the pathogenesis of cancer hallmarks, while experimental and clinical studies suggest that their modulation, e.g., by anesthetic agents, may exert antitumor effects. A large recent clinical trial served as a proof-of-principle for the benefit of preoperative use of topical sodium channel blockade as a potential anticancer strategy against early human breast cancers. Regardless of whether ion channel aberrations are primary or secondary cancer drivers, understanding the functional consequences of these events may guide us toward the development of novel therapeutic approaches.

Peri-operative night-time work of anaesthesiologists: A qualitative study of critical issues and proposals.

BACKGROUND: Qualitative data on the opinions of anaesthesiologists regarding the impact of peri-operative night-time working conditions on patient safety are lacking. OBJECTIVES: This study aimed to achieve in-depth understanding of anaesthesiologists' perceptions regarding the impact of night-time working conditions on peri-operative patient safety and actions that may be undertaken to mitigate perceived risks. DESIGN: Qualitative analysis of responses to two open-ended questions. SETTING: Online platform questionnaire promoted by the European Society of Anaesthesiology and Intensive Care (ESAIC). PARTICIPANTS: The survey sample consisted of an international cohort of anaesthesiologists. MAIN OUTCOME MEASURES: We identified and classified recurrent themes in the responses to questions addressing perceptions regarding (Q1) peri-operative night-time working conditions, which may affect patient safety and (Q2) potential solutions. RESULTS: We analysed 2112 and 2113 responses to Q1 and Q2, respectively. The most frequently reported themes in relation to Q1 were a perceived reduction in professional performance accompanied by concerns regarding the possible consequences of work with fatigue (27%), and poor working conditions at night-time (35%). The most frequently proposed solutions in response to Q2 were a reduction of working hours and avoidance of 24-h shifts (21%), an increase in human resources (14%) and performance of only urgent or emergency surgeries at night (14%). CONCLUSION: Overall, the surveyed anaesthesiologists believe that workload-to-staff imbalance and excessive working hours were potential bases for increased peri-operative risk for their patients, partly because of fatigue-related medical errors during night-time work. The performance of nonemergency elective surgical cases at night and lack of facilities were among the reported issues and potential targets for improvement measures. Further studies should investigate whether countermeasures can improve patient safety as well as the quality of life of anaesthesia professionals. Regulations to improve homogeneity, safety, and quality of anaesthesia practice at night seem to be urgently needed.

Shear Stress and Endothelial Mechanotransduction in Trauma Patients with Hemorrhagic Shock: Hidden Coagulopathy Pathways and Novel Therapeutic Strategies.

Massive trauma remains a leading cause of death and a global public health burden. Post-traumatic coagulopathy may be present even before the onset of resuscitation, and correlates with severity of trauma. Several mechanisms have been proposed to explain the development of abnormal coagulation processes, but the heterogeneity in injuries and patient profiles makes it difficult to define a dominant mechanism. Regardless of the pattern of death, a significant role in the pathophysiology and pathogenesis of coagulopathy may be attributed to the exposure of endothelial cells to abnormal physical forces and mechanical stimuli in their local environment. In these conditions, the cellular responses are translated into biochemical signals that induce/aggravate oxidative stress, inflammation, and coagulopathy. Microvascular shear stress-induced alterations could be treated or prevented by the development and use of innovative pharmacologic strategies that effectively target shear-mediated endothelial dysfunction, including shear-responsive drug delivery systems and novel antioxidants, and by targeting the venous side of the circulation to exploit the beneficial antithrombogenic profile of venous endothelial cells.

Mechanisms of landiolol-mediated positive inotropy in critical care settings.

PURPOSE: To present the potential mechanisms by which landiolol enhances a positive inotropic response in critically ill patients. METHODS: Analysis of preclinical, animal, and clinical data to provide novel knowledge and translate research findings into potential clinical application. RESULTS: The super-selective ß1-antagonist landiolol may increase inotropy and may be associated with positive outcomes in critically ill patients with acute decompensated heart failure or sepsis. CONCLUSION: This review sheds light on the potential mechanisms by which landiolol enhances a positive inotropic response, potentially alleviating the long-held concern over possible negative hemodynamic effects in critically ill patients.

The Relation of Calculated Plasma Volume Status to Sublingual Microcirculatory Blood Flow and Organ Injury.

BACKGROUND: The calculated plasma volume status (cPVS) was validated as a surrogate of intravascular filling. The aim of this study is to assess the cPVS in relation to sublingual perfusion and organ injury. METHODS: Pre- and postoperative cPVS were obtained by determining the actual and ideal plasma volume levels in surgical patients. The sublingual microcirculation was assessed using SDF imaging, and we determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the assessment of the distribution of cPVS and its association with intraoperative sublingual microcirculation and postoperative complications. RESULTS: The median pre- and postoperative cPVS were -7.25% (IQR -14.29--1.88) and -0.4% (IQR -5.43-6.06), respectively (p < 0.001). The mean intraoperative administered fluid volume was 2.5 ± 2.5 L (1.14 L h-1). No statistically significant correlation was observed between the pre- or postoperative cPVS and sublingual microcirculation variables. Higher preoperative (OR = 1.04, p = 0.098) and postoperative cPVS (OR = 1.057, p = 0.029) were associated with postoperative organ injury and complications (sepsis (30%), anemia (24%), respiratory failure (13%), acute kidney injury (6%), hypotension (6%), stroke (3%)). CONCLUSIONS: The calculated PVS was associated with an increased risk of organ injury and complications in this cohort.

A Hypertonic Seawater Nasal Irrigation Solution Containing Algal and Herbal Natural Ingredients Reduces Viral Load and SARS-CoV-2 Detection Time in the Nasal Cavity.

Nasal irrigation is thought to decrease the viral load present in the nasal cavity. Our aim was to assess the effect of a hypertonic seawater solution [with algal and herbal natural ingredients (Sinomarin®)] on the viral load of nasopharynx in patients hospitalized with severe COVID-19 pneumonia. We conducted a prospective, randomized, controlled trial from June 2022 to December 2022. We allocated 56 patients with COVID-19 pneumonia into two groups (28 in each group)-the hypertonic seawater group [nasal irrigations with a hypertonic seawater solution (Sinomarin®) every 4 h for 16 h per day, for two consecutive days] and the control group (no nasal irrigations). A second nasopharyngeal swab was collected 48 h after the baseline nasopharyngeal swab (8 h after the last wash in the hypertonic seawater group) to estimate the SARS-CoV-2 viral load as determined by cycle threshold (Ct) values. In the hypertonic seawater group, the mean Ct values significantly increased two days after the initial measurement [ΔCt 48-0 h = 3.86 ± 3.03 cycles, p < 0.001 (95%CI: 2.69 to 5.04)]. No significant differences in the Ct values were observed in the control group [ΔCt 48-0 h = -0.14 ± 4.29, p = 0.866 (95%CI: -1.80 to -1.52)]. At follow-up, 17 patients from the hypertonic seawater group had negative test results compared to only 9 patients from the control group (p = 0.03). Nasal irrigations with a hypertonic seawater solution containing algal and herbal natural ingredients significantly decreased nasopharyngeal viral load and the detection time of SARS-CoV-2 in the nasal cavity.

Effects of Vasopressin Receptor Agonists during the Resuscitation of Hemorrhagic Shock: A Systematic Review and Meta-Analysis of Experimental and Clinical Studies.

BACKGROUND: The clinical impact of vasopressin in hemorrhagic shock remains largely unknown. OBJECTIVE: This systematic review and meta-analysis was designed to investigate the effects of vasopressin receptor agonists during the resuscitation of hemorrhagic shock. METHODS: A systematic search of PubMed (MEDLINE), Scopus, and PubMed Central was conducted for relevant articles. Experimental (animal) and clinical studies were included. The primary objective was to investigate the correlation of vasopressin receptor agonist use with mortality and various hemodynamic parameters. RESULTS: Data extraction was possible in thirteen animal studies and two clinical studies. Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents [RR (95% CI): 1.17 (0.67, 2.08); p = 0.562; I2 = 50%]. The available data were insufficient to conduct a meta-analysis assessing the effect of vasopressin receptor agonists on hemodynamics. Drawing safe conclusions from animal studies was challenging, due to significant heterogeneity in terms of species and dosage of vasopressin receptor agonists among studies. CONCLUSIONS: Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents after hemorrhagic shock. More data are needed to deduce certain conclusions.