A new perspective in sepsis treatment: could RGD-dependent integrins be novel targets?

Sepsis is a life-threatening condition caused by the response of the body to an infection, and has recently been regarded as a global health priority because of the lack of effective treatments available. Vascular endothelial cells have a crucial role in sepsis and are believed to be a major target of pathogens during the early stages of infection. Accumulating evidence suggests that common sepsis pathogens, including bacteria, fungi, and viruses, all contain a critical integrin recognition motif, Arg-Gly-Asp (RGD), in their major cell wall-exposed proteins that might act as ligands to crosslink to vascular endothelial cells, triggering systemic dysregulation resulting in sepsis. In this review, we discuss the potential of anti-integrin therapy in the treatment of sepsis and septic shock

Can nebulised heparin reduce acute lung injury in patients with SARS‑CoV‑2 requiring advanced respiratory support in Ireland: the CHARTER‑Ireland phase Ib/IIa, randomised, parallel-group, open-label study

Background: Nebulised unfractionated heparin may attenuate COVID-19 ARDS by reducing pulmonary microvascular thrombosis, blocking SARS-CoV-2 entry into cells, and decreasing lung inflammation. COVID-19 patients with a raised D-dimer have areas of pulmonary hypoperfusion on CT perfusion scans of the lung and have increased mortality risk.Methods: This was a phase Ib/IIa open-label multi-centre, randomised controlled trial. The study was designed to evaluate whether nebulised unfractionated heparin decreased D-dimer concentrations, with safety as a co-primary outcome.Results: Forty patients were recruited, with 20 patients into each group. Mean age was 56.6 (SD 11.5) in the heparin group and 51.3 (SD 14.7) in the standard care group, while 60% of participants were male. There was no change in D-dimers from baseline to day 10 (heparin group mean change - 316.5, [SD 1840.3] and control group mean change - 321.7 [SD 3589.4]; p = 0.996). Fourteen patients suffered at least one serious adverse event, 9 patients the Heparin group and 5 in the control group. Eight patients had one or more bleeding events, 5 in the heparin group and 3 in the control group, but were no cases of pulmonary bleeding, of severe haemorrhage or of heparin-induced thrombocytopenia. Patients receiving heparin therapy had lower PaO2/FiO2 ratios, increased oxygenation indices, and decreased ROX index profiles, up to day 10. The time to separation from respiratory support, and the time to ICU or hospital discharge was similar in both groups. There were 3 deaths in the Heparin group and 2 in the control group.Conclusions: Nebulised unfractionated heparin was safe and well tolerated, but did not reduce D-dimer concentrations, and worsened oxygenation indices in patients with COVID-19 ARDS.</p

Pressure ulcer risk assessment in the ICU. is it time for a more objective measure?

Background: The Braden scale, one of the most widely used risk assessment tools is often criticized when used in the Intensive Care Unit. Most patients in the Intensive Care Unit are at risk of pressure ulcer development meaning that the Braden score will usually indicate high risk for these patients. This study set out to determine the correlation between Sub-Epidermal Moisture measurements and Braden scores among Intensive Care Unit patients. Methods: This study employed an observational research design. Braden score was assessed on all study days (1-5), in addition to visual skin assessment and Sub-Epidermal Moisture measurements at the sacrum and heels. Sub-Epidermal Moisture measurements were categorised as low ( Results: A total of 53 participants were recruited. The median (interquartile range) baseline Braden score was 9 (9-10) and 81 % (n = 43) of participants were at very high/high risk of pressure ulcer development. Braden scores remained relatively constant over time with little fluctuation in scores. 19 % (n = 10) of patients had normal ( Conclusion: Although this was not its original intention, a missing link with the Braden scale is that it does not provide information on how patients are responding to the adverse effects of pressure and shear forces. Furthermore, in patients who are critically unwell, most patients are classified as being "at risk" of pressure ulcer development. Therefore, an objective measure of how patients are responding to pressure and shear forces at different anatomical areas is needed. Implications to clinical practice: Sub-Epidermal Moisture measurements can offer more information, not only on identifying those who are at risk, but also how those patients are tolerating this risk at different anatomical sites.</p

Pressure ulcer risk assessment in the ICU. is it time for a more objective measure?

Background: The Braden scale, one of the most widely used risk assessment tools is often criticized when used in the Intensive Care Unit. Most patients in the Intensive Care Unit are at risk of pressure ulcer development meaning that the Braden score will usually indicate high risk for these patients. This study set out to determine the correlation between Sub-Epidermal Moisture measurements and Braden scores among Intensive Care Unit patients. Methods: This study employed an observational research design. Braden score was assessed on all study days (1-5), in addition to visual skin assessment and Sub-Epidermal Moisture measurements at the sacrum and heels. Sub-Epidermal Moisture measurements were categorised as low ( Results: A total of 53 participants were recruited. The median (interquartile range) baseline Braden score was 9 (9-10) and 81 % (n = 43) of participants were at very high/high risk of pressure ulcer development. Braden scores remained relatively constant over time with little fluctuation in scores. 19 % (n = 10) of patients had normal ( Conclusion: Although this was not its original intention, a missing link with the Braden scale is that it does not provide information on how patients are responding to the adverse effects of pressure and shear forces. Furthermore, in patients who are critically unwell, most patients are classified as being "at risk" of pressure ulcer development. Therefore, an objective measure of how patients are responding to pressure and shear forces at different anatomical areas is needed. Implications to clinical practice: Sub-Epidermal Moisture measurements can offer more information, not only on identifying those who are at risk, but also how those patients are tolerating this risk at different anatomical sites.</p

Predictors of early ICU re-admission, a retrospective observational case control study

Aim: This study aimed to identify predictors of early ICU re-admission following discharge, considering the multifaceted nature of this phenomenon.Methods: This retrospective observational case-control study was conducted, involving 51 patients (27 cases, 24 controls). The study assessed various parameters, including admission source, specialty, APACHE II scores, mechanical ventilation, vasopressor support, and CRRT. Data were collected at primary admission, discharge, and re-admission.Results: The analysis revealed statistically significant associations between early re-admission and mechanical ventilation [71.4% of cases (n=20) versus 45.8% of controls (n=11), p = 0.039], vasopressor support [77.8% of cases (n=22) versus 50% of controls (n=12), p = 0.038], predicted mortality [Median predicted mortality was 25.5 for cases and only 7 for controls, p = 0.038], and length of stay [Median length of stay was 9.5 days for cases and 4 days for controls, p = 0.028]. Discharging patients on enteral nutrition significantly increased the likelihood of early re-admission [70.4% of cases (n=19) were discharged on enteral nutrition while only 20.8% of controls (n=5) were discharged on enteral nutrition, pDiscussion: These findings underscore the importance of considering multiple clinical and physiological parameters in assessing and managing patients at risk for early ICU re-admission. The study contributes valuable insights for enhancing patient care and optimising discharge decision-making processes. However, this study is preliminary, highlighting the necessity for a larger case cohort and recommending a multicentre approach to validate and broaden the findings.</p

SARS-CoV-2 uses major endothelial integrin αvβ3 to cause vascular dysregulation in-vitro during COVID-19

The unprecedented global COVID-19 pandemic has prompted a desperate international effort to accelerate the development of anti-viral candidates. For unknown reasons, COVID-19 infections are associated with adverse cardiovascular complications, implicating that vascular endothelial cells are essential in viral propagation. The etiological pathogen, SARS-CoV-2, has a higher reproductive number and infection rate than its predecessors, indicating it possesses novel characteristics that infers enhanced transmissibility. A unique K403R spike protein substitution encodes an Arg-Gly-Asp (RGD) motif, introducing a potential role for RGD-binding host integrins. Integrin αVβ3 is widely expressed across the host, particularly in the endothelium, which acts as the final barrier before microbial entry into the bloodstream. This mutagenesis creates an additional binding site, which may be sufficient to increase SARS-CoV-2 pathogenicity. Here, we investigate how SARS-CoV-2 passes from the epithelium to endothelium, the effects of αVβ3 antagonist, Cilengitide, on viral adhesion, vasculature permeability and leakage, and also report on a simulated interaction between the viral and host protein in-silico

Enhancing safety in intrahospital transport of critically ill patients: developing an intrahospital transport tool

The transport of critically ill patients is a high-risk procedure. The overall incidence of adverse events (AEs) during the intra-hospital transfer (IHT) of critically ill patients reportedly ranges from 1.7 % to 75.7 %. It is crucial to record the physiological parameters, ventilatory requirements and hemodynamic support of all critically ill patients undergoing transfer. NICE guidelines recommend using standardized care systems (e.g., checklists, staffing and equipment) when transferring critically ill patients within or between hospitals. However, we found a lack of practical and clinically acceptable evidence-based tools that could be used to document the intrahospital transfer of critically ill patients in our hospital.</p

Reply to Blot et al. and to Inoue et al.

We thank Blot and colleagues for their interest in our article and for raising an important question regarding the suitability of IL-6 as a therapeutic target in coronavirus disease (COVID-19).In their correspondence, Blot and colleagues provide data on IL-6 levels measured in patients with a diagnosis of COVID-19 versus non–COVID-19 pneumonia. Although we believe the data presented by Blot and colleagues are valid, we suggest that the IL-6 levels depicted are, by virtue of sample timing, processing methodology, and patient severity of disease, not comparable to ours and should be interpreted in context.</p

Reply to Blot et al. and to Inoue et al.

We thank Blot and colleagues for their interest in our article and for raising an important question regarding the suitability of IL-6 as a therapeutic target in coronavirus disease (COVID-19).In their correspondence, Blot and colleagues provide data on IL-6 levels measured in patients with a diagnosis of COVID-19 versus non–COVID-19 pneumonia. Although we believe the data presented by Blot and colleagues are valid, we suggest that the IL-6 levels depicted are, by virtue of sample timing, processing methodology, and patient severity of disease, not comparable to ours and should be interpreted in context.</p

Human endothelial cell-derived exosomal microRNA-99a/b drives a sustained inflammatory response during sepsis by inhibiting mTOR expression

The pathophysiology of sepsis and its accompanying hyper-inflammatory response are key events that lead to multi-organ failure and death. A growing body of literature now suggests that the vascular endothelium plays a critical role in driving early events of sepsis progression. In this study, we demonstrate how endothelial-derived exosomes contribute to a successive pro-inflammatory phenotype of monocytes. Exosomes isolated from S. aureus infected endothelial cells drive both CD11b and MHCII expression in monocytes and contribute dysregulated cytokine production. Conversely, healthy endothelial exosomes had no major effect. microRNA (miRNA) profiling of exosomes identified miR-99 upregulation which we hypothesised as driving this phenotypic change through mechanistic target of rapamycin (mTOR). Knockdown of mTOR with miR-99a and miR-99b mimetics in S. aureus infected monocytes increased IL-6 and decreased IL-10 production. Interestingly, inhibition of miRNAs with antagomirs has the opposing effect. Collectively, endothelial exosomes are driving a pro-inflammatory phenotype in monocytes through dysregulated expression of miR-99a and miR-99b