Mechanical ventilation is a life-saving therapy that catalyzed the development of modern intensive care units. The origins of modern mechanical ventilation can be traced back about five centuries to ...the seminal work of Andreas Vesalius. This article is a short history of mechanical ventilation, tracing its origins over the centuries to the present day. One of the great advances in ventilatory support over the past few decades has been the development of lung-protective ventilatory strategies, based on our understanding of the iatrogenic consequences of mechanical ventilation such as ventilator-induced lung injury. These strategies have markedly improved clinical outcomes in patients with respiratory failure.
Cardiogenic shock can occur due to acute ischaemic or non-ischaemic cardiac events, or from progression of long-standing underlying heart disease. When addressing the cause of underlying disease, the ...management of cardiogenic shock consists of vasopressors and inotropes; however, these agents can increase myocardial oxygen consumption, impair tissue perfusion, and are frequently ineffective. An alternative approach is to temporarily augment cardiac output using mechanical devices. The use of these devices—known as temporary circulatory support systems—has increased substantially in recent years, despite being expensive, resource intensive, associated with major complications, and lacking high-quality evidence to support their use. This Review summarises the physiological basis underlying the use of temporary circulatory support for cardiogenic shock, reviews the evidence informing indications and contraindications, addresses ethical considerations, and highlights the need for further research.
We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 ...protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000–5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
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•Soluble human ACE2 can inhibit SARS-CoV-2 infections•SARS-CoV-2 can directly infect human blood vessel and kidney organoids•Human organoids as model systems to study SARS-CoV-2 infections/COVID-19
Clinical-grade recombinant human ACE2 can reduce SARS-CoV-2 infection in cells and in multiple human organoid models.
IMPORTANCE: Bayesian analysis of clinical trial data may provide useful information to aid in study interpretation, especially when trial evidence suggests that the benefits of an intervention are ...uncertain, such as in a trial that evaluated early extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS). OBJECTIVE: To demonstrate the potential utility of Bayesian analyses by estimating the posterior probability, under various assumptions, that early ECMO was associated with reduced mortality in patients with very severe ARDS in a randomized clinical trial (RCT). DESIGN AND EVIDENCE: A post hoc Bayesian analysis of data from an RCT (ECMO to Rescue Lung Injury in Severe ARDS EOLIA) that included 249 patients with very severe ARDS who had been randomized to receive early ECMO (n = 124; mortality at 60 days, 35%) vs initial conventional lung-protective ventilation with the option for rescue ECMO (n = 125, mortality at 60 days, 46%). The trial was designed to detect an absolute risk reduction (ARR) of 20%, relative risk (RR) of 0.67. Statistical prior distributions were specified to represent varying levels of preexisting enthusiasm or skepticism for ECMO and by Bayesian meta-analysis of previously published studies (with downweighting to account for differences and quality between studies). The RR, credible interval (CrI), ARR, and probability of clinically important mortality benefit (varying from RR less than 1 to RR less than 0.67 and ARR from 2% or more to 20% or more) were estimated with Bayesian modeling. FINDINGS: Combining a minimally informative prior distribution with the findings of the EOLIA trial, the posterior probability of RR less than 1 for mortality at 60 days after randomization was 96% (RR, 0.78 95% CrI, 0.56-1.04); the posterior probability of RR less than 0.67 was 18%, the probability of ARR of 2% or more was 92%, and the probability of ARR of 20% or more was 2%. With a moderately enthusiastic prior, equivalent to information from a trial of 264 patients with an RR of 0.78, the estimated RR was 0.78 (95% CrI, 0.63-0.96), the probability of RR less than 1 was 99%, the probability of RR less than 0.67 was 8%, the probability of ARR of 2% or more was 97%, and the probability of ARR of 20% or more was 0%. With a strongly skeptical prior, equivalent to information from a trial of 264 patients with an RR of 1.0, the estimated RR was 0.88 (95% CrI, 0.71-1.09), the probability of RR less than 1 was 88%, the probability of RR less than 0.67 was 0%, the probability of ARR of 2% or more was 78%, and the probability of ARR of 20% or more was 0%. If the prior was informed by previous studies, the estimated RR was 0.71 (95% CrI, 0.55-0.94), the probability of RR less than 1 was 99%, the probability of RR less than 0.67 was 48%, the probability of ARR of 2% or more was 98%, and the probability of ARR of 20% or more was 4%. CONCLUSIONS AND RELEVANCE: Post hoc Bayesian analysis of data from a randomized clinical trial of early extracorporeal membrane oxygenation compared with conventional lung-protective ventilation with the option for rescue extracorporeal membrane oxygenation among patients with very severe acute respiratory distress syndrome provides information about the posterior probability of mortality benefit under a broad set of assumptions that may help inform interpretation of the study findings.
This trial compared extracorporeal membrane oxygenation with non-ECMO ventilator care in patients with severe ARDS. There was no significant between-group difference in 60-day mortality. ...Interpretation was made difficult by crossovers from control to ECMO treatment.
More men than women have died from COVID-19. Genes encoded on X chromosomes, and sex hormones may explain the decreased fatality of COVID-19 in women. The angiotensin-converting enzyme 2 gene is ...located on X chromosomes. Men, with a single X chromosome, may lack the alternative mechanism for cellular protection after exposure to SARS-CoV-2. Some Toll-like receptors encoded on the X chromosomes can sense SARS-CoV-2 nucleic acids, leading to a stronger innate immunity response in women. Both estrogen and estrogen receptor-α contribute to T cell activation. Interventional approaches including estrogen-related compounds and androgen receptor antagonists may be considered in patients with COVID-19.
The COVID-19 pandemic has seen a surge of patients with acute respiratory distress syndrome (ARDS) in intensive care units across the globe. As experience of managing patients with ...COVID-19-associated ARDS has grown, so too have efforts to classify patients according to respiratory system mechanics, with a view to optimising ventilatory management. Personalised lung-protective mechanical ventilation reduces mortality and has become the mainstay of treatment in ARDS. In this Viewpoint, we address ventilatory strategies in the context of recent discussions on phenotypic heterogeneity in patients with COVID-19-associated ARDS. Although early reports suggested that COVID-19-associated ARDS has distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics of patients with ARDS, with or without COVID-19, are broadly similar. In the absence of evidence to support a shift away from the current paradigm of ventilatory management, we strongly recommend adherence to evidence-based management, informed by bedside physiology, as resources permit.
Diaphragm dysfunction worsens outcomes in mechanically ventilated patients, but the clinical impact of potentially preventable changes in diaphragm structure and function caused by mechanical ...ventilation is unknown.
To determine whether diaphragm atrophy developing during mechanical ventilation leads to prolonged ventilation.
Diaphragm thickness was measured daily by ultrasound in adults requiring invasive mechanical ventilation; inspiratory effort was assessed by thickening fraction. The primary outcome was time to liberation from ventilation. Secondary outcomes included complications (reintubation, tracheostomy, prolonged ventilation, or death). Associations were adjusted for age, severity of illness, sepsis, sedation, neuromuscular blockade, and comorbidity.
Of 211 patients enrolled, 191 had two or more diaphragm thickness measurements. Thickness decreased more than 10% in 78 patients (41%) by median Day 4 (interquartile range, 3-5). Development of decreased thickness was associated with a lower daily probability of liberation from ventilation (adjusted hazard ratio, 0.69; 95% confidence interval CI, 0.54-0.87; per 10% decrease), prolonged ICU admission (adjusted duration ratio, 1.71; 95% CI, 1.29-2.27), and a higher risk of complications (adjusted odds ratio, 3.00; 95% CI, 1.34-6.72). Development of increased thickness (n = 47; 24%) also predicted prolonged ventilation (adjusted duration ratio, 1.38; 95% CI, 1.00-1.90). Decreasing thickness was related to abnormally low inspiratory effort; increasing thickness was related to excessive effort. Patients with thickening fraction between 15% and 30% (similar to breathing at rest) during the first 3 days had the shortest duration of ventilation.
Diaphragm atrophy developing during mechanical ventilation strongly impacts clinical outcomes. Targeting an inspiratory effort level similar to that of healthy subjects at rest might accelerate liberation from ventilation.
It is unclear whether seasonal changes, school closures or other public health interventions will result in a slowdown of the current coronavirus disease 2019 (COVID-19) pandemic. We aimed to ...determine whether epidemic growth is globally associated with climate or public health interventions intended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
We performed a prospective cohort study of all 144 geopolitical areas worldwide (375 609 cases) with at least 10 COVID-19 cases and local transmission by Mar. 20, 2020, excluding China, South Korea, Iran and Italy. Using weighted random-effects regression, we determined the association between epidemic growth (expressed as ratios of rate ratios RRR comparing cumulative counts of COVID-19 cases on Mar. 27, 2020, with cumulative counts on Mar. 20, 2020) and latitude, temperature, humidity, school closures, restrictions of mass gatherings, and measures of social distancing during an exposure period 14 days previously (Mar. 7 to 13, 2020).
In univariate analyses, there were no associations of epidemic growth with latitude and temperature, but weak negative associations with relative humidity (RRR per 10% 0.91, 95% confidence interval CI 0.85-0.96) and absolute humidity (RRR per 5 g/m
0.92, 95% CI 0.85-0.99). Strong associations were found for restrictions of mass gatherings (RRR 0.65, 95% CI 0.53-0.79), school closures (RRR 0.63, 95% CI 0.52-0.78) and measures of social distancing (RRR 0.62, 95% CI 0.45-0.85). In a multivariable model, there was a strong association with the number of implemented public health interventions (
for trend = 0.001), whereas the association with absolute humidity was no longer significant.
Epidemic growth of COVID-19 was not associated with latitude and temperature, but may be associated weakly with relative or absolute humidity. Conversely, public health interventions were strongly associated with reduced epidemic growth.
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