Purpose
Corticosteroids are now recommended for patients with severe COVID-19 including those with COVID-related ARDS. This has generated renewed interest regarding whether corticosteroids should be ...used in non-COVID ARDS as well. The objective of this study was to summarize all RCTs examining the use of corticosteroids in ARDS.
Methods
The protocol of this study was pre-registered on PROSPERO (CRD42020200659). We searched online databases including MEDLINE, EMBASE, CDC library of COVID research, CINAHL, and COCHRANE. We included RCTs that compared the effect of corticosteroids to placebo or usual care in adult patients with ARDS, including patients with COVID-19. Three reviewers abstracted data independently and in duplicate using a pre-specified standardized form. We assessed individual study risk of bias using the revised Cochrane ROB-2 tool and rated certainty in outcomes using GRADE methodology. We pooled data using a random effects model. The main outcome for this review was 28-day-mortality.
Results
We included 18 RCTs enrolling 2826 patients. The use of corticosteroids probably reduced mortality in patients with ARDS of any etiology (2740 patients in 16 trials, RR 0.82, 95% CI 0.72–0.95, ARR 8.0%, 95% CI 2.2–12.5%, moderate certainty). Patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course.
Conclusion
The use of corticosteroids probably reduces mortality in patients with ARDS. This effect was consistent between patients with COVID-19 and non-COVID-19 ARDS, corticosteroid types, and dosage.
Mitochondrial calcium (Ca(2+)) import is a well-described phenomenon regulating cell survival and ATP production. Of multiple pathways allowing such entry, the mitochondrial Ca(2+) uniporter is a ...highly Ca(2+)-selective channel complex encoded by several recently-discovered genes. However, the identity of the pore-forming subunit remains to be established, since knockdown of all the candidate uniporter genes inhibit Ca(2+) uptake in imaging assays, and reconstitution experiments have been equivocal. To definitively identify the channel, we use whole-mitoplast voltage-clamping, the technique that originally established the uniporter as a Ca(2+) channel. We show that RNAi-mediated knockdown of the mitochondrial calcium uniporter (MCU) gene reduces mitochondrial Ca(2+) current (I MiCa ), whereas overexpression increases it. Additionally, a classic feature of I MiCa , its sensitivity to ruthenium red inhibition, can be abolished by a point mutation in the putative pore domain without altering current magnitude. These analyses establish that MCU encodes the pore-forming subunit of the uniporter channel. DOI:http://dx.doi.org/10.7554/eLife.00704.001.
Purpose
High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. ...Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings.
Methods
We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions.
Results
The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty).
Conclusions
This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians.
The mitochondrial uniporter is a highly selective calcium channel in the organelle's inner membrane. Its molecular components include the EF-hand-containing calcium-binding proteins mitochondrial ...calcium uptake 1 (MICU1) and MICU2 and the pore-forming subunit mitochondrial calcium uniporter (MCU). We sought to achieve a full molecular characterization of the uniporter holocomplex (uniplex). Quantitative mass spectrometry of affinity-purified uniplex recovered MICU1 and MICU2, MCU and its paralog MCUb, and essential MCU regulator (EMRE), a previously uncharacterized protein. EMRE is a 10-ki loda Ito n, m etazoa ç-specific protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and additionally bridges the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU.
Up to 12% of the 800,000 patients who undergo mechanical ventilation in the United States every year require tracheostomies. A recent systematic review showed that early tracheostomy was associated ...with better outcomes: more ventilator-free days, shorter ICU stays, less sedation and reduced long-term mortality. However, the financial impact of early tracheostomies remain unknown.
To conduct a cost-analysis on the timing of tracheostomy in mechanically ventilated patients.
We extracted individual length of hospital stay and length of ICU stay data from the studies included in the systematic review from Hosokawa et al. We also searched for any recent randomized control trials on the topic that were published after this review. The weighted length of stay was estimated using a random effects model. Average daily hospital and ICU costs per patients were obtained from a cost study by Kahn et al. We estimated hospital and ICU costs by multiplying LOS with respective average daily cost per patient. We calculated difference in costs by subtracting hospital costs, ICU costs and total direct variable costs from early tracheotomy to late tracheotomy. 95% confidence intervals were estimated using bootstrap re-sampling procedures with 1000 iterations.
The average weighted cost of ICU stay in patients with an early tracheostomy was $4316 less when compared to patients with late tracheostomy (95% CI: 403–8229). Subgroup analysis revealed that very early tracheostomies (<4days) cost on average $3672 USD less than late tracheostomies (95% CI: –1309, 10,294) and that early tracheostomies (<10days but >4) cost on average $6385 USD less than late tracheostomies (95% CI: –4396–17,165).
This study shows that early tracheostomy can significantly reduce direct variable and likely total hospital costs in the intensive care unit based on length of stay alone. This is in addition to the already shown benefits of early tracheostomy in terms of ventilator dependent days, reduced length of stays, decreased pain, and improved communication. Further prospective studies on this topic are needed to prove the cost-effectiveness of early tracheostomy in the critically ill population.
•Early tracheostomy reduces ICU & hospital costs.•Early tracheostomy reduces ICU length of stay.•Findings are consistent after sensitivity analysis.
During the mitochondrial permeability transition, a large channel in the inner mitochondrial membrane opens, leading to the loss of multiple mitochondrial solutes and cell death. Key triggers include ...excessive reactive oxygen species and mitochondrial calcium overload, factors implicated in neuronal and cardiac pathophysiology. Examining the differential behavior of mitochondrial Ca2+ overload in Drosophila versus human cells allowed us to identify a gene, MCUR1, which, when expressed in Drosophila cells, conferred permeability transition sensitive to electrophoretic Ca2+ uptake. Conversely, inhibiting MCUR1 in mammalian cells increased the Ca2+ threshold for inducing permeability transition. The effect was specific to the permeability transition induced by Ca2+, and such resistance to overload translated into improved cell survival. Thus, MCUR1 expression regulates the Ca2+ threshold required for permeability transition.
Purpose
We conducted two World Health Organization-commissioned reviews to inform use of high-flow nasal cannula (HFNC) in patients with coronavirus disease (COVID-19). We synthesized the evidence ...regarding efficacy and safety (review 1), as well as risks of droplet dispersion, aerosol generation, and associated transmission (review 2) of viral products.
Source
Literature searches were performed in Ovid MEDLINE, Embase, Web of Science, Chinese databases, and medRxiv.
Review 1
: we synthesized results from randomized-controlled trials (RCTs) comparing HFNC to conventional oxygen therapy (COT) in critically ill patients with acute hypoxemic respiratory failure.
Review 2:
we narratively summarized findings from studies evaluating droplet dispersion, aerosol generation, or infection transmission associated with HFNC. For both reviews, paired reviewers independently conducted screening, data extraction, and risk of bias assessment. We evaluated certainty of evidence using GRADE methodology.
Principal findings
No eligible studies included COVID-19 patients.
Review 1:
12 RCTs (
n
= 1,989 patients) provided low-certainty evidence that HFNC may reduce invasive ventilation (relative risk RR, 0.85; 95% confidence interval CI, 0.74 to 0.99) and escalation of oxygen therapy (RR, 0.71; 95% CI, 0.51 to 0.98) in patients with respiratory failure. Results provided no support for differences in mortality (moderate certainty), or in-hospital or intensive care length of stay (moderate and low certainty, respectively).
Review 2
: four studies evaluating droplet dispersion and three evaluating aerosol generation and dispersion provided very low certainty evidence. Two simulation studies and a crossover study showed mixed findings regarding the effect of HFNC on droplet dispersion. Although two simulation studies reported no associated increase in aerosol dispersion, one reported that higher flow rates were associated with increased regions of aerosol density.
Conclusions
High-flow nasal cannula may reduce the need for invasive ventilation and escalation of therapy compared with COT in COVID-19 patients with acute hypoxemic respiratory failure. This benefit must be balanced against the unknown risk of airborne transmission.
TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. ...Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. M7Vs accumulate Zn2+ in a glutathione-enriched, reduced lumen when cytosolic Zn2+ concentrations are elevated. Treatments that increase reactive oxygen species (ROS) trigger TRPM7-dependent Zn2+ release from the vesicles, whereas reduced glutathione prevents TRPM7-dependent cytosolic Zn2+ influx. These observations strongly support the notion that ROS-mediated TRPM7 activation releases Zn2+ from intracellular vesicles after Zn2+ overload. Like the endoplasmic reticulum, these vesicles are a distributed system for divalent cation uptake and release, but in this case the primary divalent ion is Zn2+ rather than Ca2+.
Populations such as healthcare workers (HCW) that are unable to practice physical distancing are at high risk of acquiring Coronavirus disease-2019 (COVID-19). In these cases pharmacological ...prophylaxis would be a solution to reduce severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) transmission. Hydroxychloroquine has in vitro antiviral properties against SARS CoV-2. We therefore sought to determine the efficacy and safety of hydroxychloroquine as prophylaxis for COVID-19.
We electronically searched EMBASE, MEDLINE, the Cochrane COVID-19 Register of Controlled Trials, Epistemonikos COVID-19, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform up to September 28th, 2020 for randomized controlled trials (RCTs). We calculated pooled relative risks (RRs) for dichotomous outcomes with the corresponding 95% confidence intervals (CIs) using a random-effect model. We identified four RCTs (n = 4921) that met our eligibility criteria. The use of hydroxychloroquine, compared to placebo, did not reduce the risks of developing COVID-19 (RR 0.82, 95% CI 0.65 to 1.04, moderate certainty), hospitalization (RR 0.72, 95% CI 0.34 to 1.50, moderate certainty), or mortality (RR 3.26, 95% CI 0.13 to 79.74, low certainty), however, hydroxychloroquine use increased the risk of adverse events (RR 2.76, 95% CI 1.38 to 5.55, moderate certainty).
Although pharmacologic prophylaxis is an attractive preventive strategy against COVID-19, the current body of evidence failed to show clinical benefit for prophylactic hydroxychloroquine and showed a higher risk of adverse events when compared to placebo or no prophylaxis.
Post-cardiac arrest, outcomes for most patients are poor, regardless of setting. Many patients who do achieve spontaneous return of circulation require vasopressor therapy to maintain organ ...perfusion. There is some evidence to support the use of corticosteroids in cardiac arrest.
Assess the efficacy and safety of corticosteroids in patients following in- and out-of-hospital cardiac arrest.
We searched databases CINAHL, EMBASE, LILACS, MEDLINE, Web of Science, CENTRAL, ClinicalTrails.gov, and ICTRP. We included randomized controlled trials (RCTs) that examined the efficacy and safety of corticosteroids, as compared to placebo or usual care in patients post-cardiac arrest. We pooled estimates of effect size using random effects meta-analysis and report relative risk (RR) with 95% confidence intervals (CIs). We assessed risk of bias (ROB) for the included trials using the modified Cochrane ROB tool and rated the certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation methodology.
We included 8 RCTs (n = 2213 patients). Corticosteroids administered post-cardiac arrest had an uncertain effect on mortality measured at the longest point of follow-up (RR 0.96, 95% CI 0.90-1.02, very low certainty, required information size not met using trial sequential analysis). Corticosteroids probably increase return of spontaneous circulation (ROSC) (RR 1.32, 95% CI 1.18-1.47, moderate certainty) and may increase the likelihood of survival with good functional outcome (RR 1.49, 95% CI 0.87-2.54, low certainty). Corticosteroids may decrease the risk of ventilator associated pneumonia (RR 0.76, 95% CI 0.46-1.09, low certainty), may increase renal failure (RR 1.29, 95% CI 0.84-1.99, low certainty), and have an uncertain effect on bleeding (RR 2.04, 95% CI 0.53-7.84, very low certainty) and peritonitis (RR 10.54, 95% CI 2.99-37.19, very low certainty).
In patients during or after cardiac arrest, corticosteroids have an uncertain effect on mortality but probably increase ROSC and may increase the likelihood of survival with good functional outcome at hospital discharge. Corticosteroids may decrease ventilator associated pneumonia, may increase renal failure, and have an uncertain effect on bleeding and peritonitis. However, the pooled evidence examining these outcomes was sparse and imprecision contributed to low or very low certainty of evidence.
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