The belief that, for the individual patient, the benefit of prompt and continued use of antimicrobials outweighs any potential harm is a significant barrier to improved stewardship of these vital ...agents. Antimicrobial stewardship may be perceived as utilitarian rationing, seeking to preserve the availability of effective antimicrobials by limiting the development of resistance in a manner which could conflict with the immediate treatment of the patient in need. This view does not account for the growing evidence of antimicrobial-associated harm to individual patients. This review sets out the evidence for antimicrobial-associated harm and how this should be balanced with the need for prompt and appropriate therapy in infection. It describes the mechanisms by which antimicrobials may harm patients including: mitochondrial toxicity; immune cell toxicity; adverse drug reactions; selection of resistant organisms within a given patient; and disruption of the microbiome. Finally, the article indicates how the harms of antimicrobials may be mitigated and identifies areas for research and development in this field.
Purpose
Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, ...meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19.
Methods
We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28–30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite.
Results
We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 0.74–1.01;
p
= 0.07;
I
2
= 10%; TSA adjusted CI 0.66–1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = −0.018 −0.037 to −0.002;
p
= 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission.
Conclusions
For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation.
Building synthetic protocells and prototissues hinges on the formation of biomimetic skeletal frameworks. Recreating the complexity of cytoskeletal and exoskeletal fibers, with their widely varying ...dimensions, cellular locations and functions, represents a major material hurdle and intellectual challenge which is compounded by the additional demand of using simple building blocks to ease fabrication and control. Here we harness simplicity to create complexity by assembling structural frameworks from subunits that can support membrane-based protocells and prototissues. We show that five oligonucleotides can anneal into nanotubes or fibers whose tunable thicknesses and lengths spans four orders of magnitude. We demonstrate that the assemblies' location inside protocells is controllable to enhance their mechanical, functional and osmolar stability. Furthermore, the macrostructures can coat the outside of protocells to mimic exoskeletons and support the formation of millimeter-scale prototissues. Our strategy could be exploited in the bottom-up design of synthetic cells and tissues, to the generation of smart material devices in medicine.
Patients with limited cardiac reserve are less likely to survive and develop more complications following major surgery. By augmenting oxygen delivery index (DO2I) with a combination of intravenous ...fluids and inotropes (goal directed therapy (GDT)), postoperative mortality and morbidity of high-risk patients may be reduced. However, although most studies suggest that GDT may improve outcome in high-risk surgical patients, it is still not widely practiced. We set out to test the hypothesis that GDT results in greatest benefit in terms of mortality and morbidity in patients with the highest risk of mortality and have undertaken a systematic review of the current literature to see if this is correct. We performed a systematic search of Medline, Embase and CENTRAL databases for randomized controlled trials (RCTs) and reviews of GDT in surgical patients. To minimize heterogeneity we excluded studies involving cardiac, trauma, and paediatric surgery. Extremely high risk, high risk and intermediate risks of mortality were defined as >20%, 5 to 20% and <5% mortality rates in the control arms of the trials, respectively. Meta analyses were performed and Forest plots drawn using RevMan software. Data are presented as odd ratios (OR; 95% confidence intervals (CI), and P-values). A total of 32 RCTs including 2,808 patients were reviewed. All studies reported mortality. Five studies (including 300 patients) were excluded from assessment of complication rates as the number of patients with complications was not reported. The mortality benefit of GDT was confined to the extremely high-risk group (OR = 0.20, 95% CI 0.09 to 0.41; P < 0.0001). Complication rates were reduced in all subgroups (OR = 0.45, 95% CI 0.34 to 0.60; P < 0.00001). The morbidity benefit was greatest amongst patients in the extremely high-risk subgroup (OR = 0.27, 95% CI 0.15 to 0.51; P < 0.0001), followed by the intermediate risk subgroup (OR = 0.43, 95% CI 0.27 to 0.67; P = 0.0002), and the high-risk subgroup (OR 0.56, 95% CI 0.36 to 0.89; P = 0.01). Despite heterogeneity in trial quality and design, we found GDT to be beneficial in all high-risk patients undergoing major surgery. The mortality benefit of GDT was confined to the subgroup of patients at extremely high risk of death. The reduction of complication rates was seen across all subgroups of GDT patients.
Purpose
The integration of palliative care into intensive care units (ICUs) is advocated to mitigate physical and psychological burdens for patients and their families, and to improve end-of-life ...care. The most efficacious palliative care interventions, the optimal model of their delivery and the most appropriate outcome measures in ICU are not clear.
Methods
We conducted a systematic review of randomised clinical trials and observational studies to evaluate the number and types of palliative care interventions implemented within the ICU setting, to assess their impact on ICU practice and to evaluate differences in palliative care approaches across different countries.
Results
Fifty-eight full articles were identified, including 9 randomised trials and 49 cohort studies; all but 4 were conducted within North America. Interventions were categorised into five themes: communication (14, 24.6%), ethics consultations (5, 8.8%), educational (18, 31.6%), involvement of a palliative care team (28, 49.1%) and advance care planning or goals-of-care discussions (7, 12.3%). Thirty studies (51.7%) proposed an integrative model, whilst 28 (48.3%) reported a consultative one. The most frequently reported outcomes were ICU or hospital length of stay (33/55, 60%), limitation of life-sustaining treatment decisions (22/55, 40%) and mortality (15/55, 27.2%). Quantitative assessment of pooled data was not performed due to heterogeneity in interventions and outcomes between studies.
Conclusion
Beneficial effects on the most common outcomes were associated with strategies to enhance palliative care involvement, either with an integrative or a consultative approach. Few studies reported functional outcomes for ICU patients. Almost all studies were from North America, limiting the generalisability to other healthcare systems.
Steroids in ARDS: more light is being shed Arulkumaran, Nishkantha; Snow, Timothy Arthur Chandos; Longobardo, Alessia ...
Intensive care medicine,
11/2020, Letnik:
46, Številka:
11
Journal Article
While the primary objective, 28-day mortality, was unaffected by addition of clarithromycin to a beta-lactam in the management of community-acquired pneumonia, the authors report a significant ...reduction in sepsis recurrence associated with increased monocyte HLA-DR. ...it is worth commenting on antimicrobial resistance issues. The authors report that the pathogens identified in their patient population were already highly resistant (multi-drug resistant 24.4%; extremely drug-resistant 47.4%; pan-drug resistant 7.7%) on study enrollment, but do not provide data on macrolide resistance.
The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R ...knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases.
We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered.
Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage and development of a functional assay for P2X7R that would help to guide treatment.
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