Organizational factors are associated with outcome of critically ill patients and may vary by time of day and day of week. We aimed to identify the association between out-of-hours admission to ...critical care and mortality.
MEDLINE (via Ovid) and EMBASE (via Ovid).
We performed a systematic search of the literature for studies on out-of-hours adult general ICU admission on patient mortality.
Meta-analyses were performed and Forest plots drawn using RevMan software. Data are presented as odds ratios (95% CIs, p values).
A total of 16 studies with 902,551 patients were included in the analysis with a crude mortality of 18.2%. Fourteen studies with 717,331 patients reported mortality rates by time of admission and 11 studies with 835,032 patients by day of admission. Admission to ICU at night was not associated with an increased odds of mortality compared with admissions during the day (odds ratio, 1.04 0.98-1.11; p = 0.18). However, admissions during the weekend were associated with an increased odds of death compared with ICU admissions during weekdays (1.05 1.01-1.09; p = 0.006). Increased mortality associated with weekend ICU admissions compared with weekday ICU admissions was limited to North American countries (1.08 1.03-1.12; p = 0.0004). The absence of a routine overnight on-site intensivist was associated with increased mortality among weekend ICU admissions compared with weekday ICU admissions (1.11 1.00-1.22; p = 0.04) and nighttime admissions compared with daytime ICU admissions (1.11 1.00-1.23; p = 0.05).
Adjusted risk of death for ICU admission was greater over the weekends compared with weekdays. The absence of a dedicated intensivist on-site overnight may be associated with increased mortality for acute admissions. These results need to be interpreted in context of the organization of local healthcare resources before changes to healthcare policy are implemented.
Abstract
COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific ...outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female patients. We conducted a retrospective cohort study assessing the interaction between biological sex and anti-IL-6 receptor antibody treatment with respect to hospital mortality or progression of respiratory failure. We used a Cox proportional hazards regression model to adjust for age, ethnicity, steroid use, baseline C-reactive protein, and COVID-19 variant. We included 1274 patients, of which 58% were male and 15% received anti-IL-6 receptor antibodies. There was a significant interaction between sex and anti-IL-6 receptor antibody use on progression to respiratory failure or death (
p
= 0.05). For patients who did not receive anti-IL-6 receptor antibodies, the risk of death was slightly higher in males (HR = 1.13 (0.72–1.79)), whereas in patients who did receive anti-IL-6 receptor antibodies, the risk was lower in males (HR = 0.65 (0.32–1.33)). There was a heterogenous treatment effect with anti-IL-6 receptor antibodies between males and females; with anti-IL-6 receptor antibody use having a greater benefit in preventing progression to respiratory failure or death in males (
p
= 0.05).
Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form ...of selenium, hydrogen selenide (HSe
/H
Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O
consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H
O
), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.
Diffuse alveolar haemorrhage (DAH) is a serious complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A literature review was performed to ascertain the diagnostic ...features, treatment, and outcome of this rare but serious condition. Haemoptysis and dyspnoea are common but non-specific features. Chest radiography is usually abnormal, and high-resolution computerised tomographic scanning is more sensitive. Increased uptake of inhaled carbon monoxide and reduced clearance of C15O on lung function testing is suggestive of intra-alveolar blood. Fiberoptic bronchoscopy and bronchoalveolar lavage are useful when a super-added infection is suspected. Concurrent renal disease is common and contributes to the morbidity and mortality. Treatment should be individualised, and it is based on glucocorticoid and cyclophosphamide induction with azathioprine maintenance. The role of plasmapheresis is unclear, and is currently being evaluated. Patients are at risk of disease and treatment-related long-term complications. Ongoing research into the most efficacious therapeutic regimens associated with the least side effects is especially important.
Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between ...different macrolides, and synergistic effects with other antibiotics have not been explored.
We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients.
Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076).
Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.
Post-operative infections are a common cause of morbidity following major surgery. Little is understood about how major surgery perturbs immune function leading to heightened risk of subsequent ...infection. Through analysis of paired blood samples obtained immediately before and 24 h following surgery, we evaluated changes in circulating immune cell phenotype and function across the first 24 h, to identify early immune changes associated with subsequent infection.
We conducted a prospective observational study of adult patients undergoing major elective gastrointestinal, gynecological, or maxillofacial surgery requiring planned admission to the post-anesthetic care unit. Patients were followed up to hospital discharge or death. Outcome data collected included mortality, length of stay, unplanned intensive care unit admission, and post-operative infections (using the standardized endpoints in perioperative medicine-core outcome measures for perioperative and anesthetic care criteria). Peripheral blood mononuclear cells were isolated prior to and 24 h following surgery from which cellular immune traits including activation and functional status were assessed by multi-parameter flow cytometry and serum immune analytes compared by enzyme-linked immunosorbent assay (ELISA).
Forty-eight patients were recruited, 26 (54%) of whom developed a post-operative infection. We observed reduced baseline pre- and post-operative monocyte CXCR4 and CD80 expression (chemokine receptors and co-stimulation markers, respectively) in patients who subsequently developed an infection as well as a profound and selective post-operative increase in CD4
lymphocyte IL-7 receptor expression in the infection group only. Higher post-operative monocyte count was significantly associated with the development of post-operative infection (false discovery rate < 1%; adjusted p-value = 0.001) with an area under the receiver operating characteristic curve of 0.84 (p < 0.0001).
Lower monocyte chemotaxis markers, higher post-operative circulating monocyte counts, and reduced co-stimulatory signals are associated with subsequent post-operative infections. Identifying the underlying mechanisms and therapeutics to reverse defects in immune cell function requires further exploration.
The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane ...bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1β and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to a lesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases. The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia, glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis may also be responsible for development of CKD itself and its related complications, including vascular calcification and sepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3 inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractive potential therapeutic target in a variety of renal diseases.
Mitochondrial dysfunction and immune cell dysfunction are commonplace in sepsis and are associated with increased mortality risk. The short chain fatty acid, butyrate, is known to have ...anti-inflammatory effects and promote mitochondrial biogenesis. We therefore explored the immunometabolic effects of butyrate in an animal model of sepsis. Isolated healthy human volunteer peripheral mononuclear cells were stimulated with LPS in the presence of absence of butyrate, and released cytokines measured. Male Wistar rats housed in metabolic cages received either intravenous butyrate infusion or placebo commencing 6 h following faecal peritonitis induction. At 24 h, splenocytes were isolated for high-resolution respirometry, and measurement of mitochondrial membrane potential (MMP), reactive oxygen species (mtROS), and intracellular cytokines (TNF alpha, IL-10) using flow cytometry. Isolated splenocytes from septic and septic butyrate treated rats were stimulated with LPS for 18 h and the effects of butyrate on cytokine release assessed. Ex vivo, butyrate (1.8 mM) reduced LPS-induced TNF alpha (p = 0.019) and IL-10 (p = 0.001) release by human PBMCs. In septic animals butyrate infusion reduced the respiratory exchange ratio (p < 0.001), consistent with increased fat metabolism. This was associated with a reduction in cardiac output (p = 0.001), and increased lactate (p = 0.031) compared to placebo-treated septic animals (p < 0.05). Butyrate treatment was associated with a reduction in splenocyte basal respiration (p = 0.077), proton leak (p = 0.022), and non-mitochondrial respiration (p = 0.055), and an increase in MMP (p = 0.007) and mtROS (p = 0.027) compared to untreated septic animals. Splenocyte intracellular cytokines were unaffected by butyrate, although LPS-induced IL-10 release was impaired (p = 0.039). In summary, butyrate supplementation exacerbates myocardial and immune cell mitochondrial dysfunction in a rat model of faecal peritonitis.
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