Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury.

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

Effect of invasive mechanical ventilation on the diversity of the pulmonary microbiota.

Pulmonary microbial diversity may be influenced by biotic or abiotic conditions (e.g., disease, smoking, invasive mechanical ventilation (MV), etc.). Specially, invasive MV may trigger structural and physiological changes in both tissue and microbiota of lung, due to gastric and oral microaspiration, altered body posture, high O2 inhalation-induced O2 toxicity in hypoxemic patients, impaired airway clearance and ventilator-induced lung injury (VILI), which in turn reduce the diversity of the pulmonary microbiota and may ultimately lead to poor prognosis. Furthermore, changes in (local) O2 concentration can reduce the diversity of the pulmonary microbiota by affecting the local immune microenvironment of lung. In conclusion, systematic literature studies have found that invasive MV reduces pulmonary microbiota diversity, and future rational regulation of pulmonary microbiota diversity by existing or novel clinical tools (e.g., lung probiotics, drugs) may improve the prognosis of invasive MV treatment and lead to more effective treatment of lung diseases with precision.

Imaging the acute respiratory distress syndrome: past, present and future.

In patients with the acute respiratory distress syndrome (ARDS), lung imaging is a fundamental tool in the study of the morphological and mechanistic features of the lungs. Chest computed tomography studies led to major advances in the understanding of ARDS physiology. They allowed the in vivo study of the syndrome's lung features in relation with its impact on respiratory physiology and physiology, but also explored the lungs' response to mechanical ventilation, be it alveolar recruitment or ventilator-induced lung injuries. Coupled with positron emission tomography, morphological findings were put in relation with ventilation, perfusion or acute lung inflammation. Lung imaging has always been central in the care of patients with ARDS, with modern point-of-care tools such as electrical impedance tomography or lung ultrasounds guiding clinical reasoning beyond macro-respiratory mechanics. Finally, artificial intelligence and machine learning now assist imaging post-processing software, which allows real-time analysis of quantitative parameters that describe the syndrome's complexity. This narrative review aims to draw a didactic and comprehensive picture of how modern imaging techniques improved our understanding of the syndrome, and have the potential to help the clinician guide ventilatory treatment and refine patient prognostication.

Invasive mechanical ventilation in patients with acute respiratory distress syndrome receiving extracorporeal support: a narrative review of strategies to mitigate lung injury.

Veno-venous extracorporeal membrane oxygenation is indicated in patients with acute respiratory distress syndrome and severely impaired gas exchange despite evidence-based lung protective ventilation, prone positioning and other parts of the standard algorithm for treating such patients. Extracorporeal support can facilitate ultra-lung-protective ventilation, meaning even lower volumes and pressures than standard lung-protective ventilation, by directly removing carbon dioxide in patients needing injurious ventilator settings to maintain sufficient gas exchange. Injurious ventilation results in ventilator-induced lung injury, which is one of the main determinants of mortality in acute respiratory distress syndrome. Marked reductions in the intensity of ventilation to the lowest tolerable levels under extracorporeal support may be achieved and could thereby potentially mitigate ventilator-induced lung injury and theoretically patient self-inflicted lung injury in spontaneously breathing patients with high respiratory drive. However, the benefits of this strategy may be counterbalanced by the use of continuous deep sedation and even neuromuscular blocking drugs, which may impair physical rehabilitation and impact long-term outcomes. There are currently a lack of large-scale prospective data to inform optimal invasive ventilation practices and how to best apply a holistic approach to patients receiving veno-venous extracorporeal membrane oxygenation, while minimising ventilator-induced and patient self-inflicted lung injury. We aimed to review the literature relating to invasive ventilation strategies in patients with acute respiratory distress syndrome receiving extracorporeal support and discuss personalised ventilation approaches and the potential role of adjunctive therapies in facilitating lung protection.

Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma.

Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.

Positive end-expiratory pressure in COVID-19 acute respiratory distress syndrome: the heterogeneous effects.

BACKGROUND: We hypothesized that as CARDS may present different pathophysiological features than classic ARDS, the application of high levels of end-expiratory pressure is questionable. Our first aim was to investigate the effects of 5-15 cmH2O of PEEP on partitioned respiratory mechanics, gas exchange and dead space; secondly, we investigated whether respiratory system compliance and severity of hypoxemia could affect the response to PEEP on partitioned respiratory mechanics, gas exchange and dead space, dividing the population according to the median value of respiratory system compliance and oxygenation. Thirdly, we explored the effects of an additional PEEP selected according to the Empirical PEEP-FiO2 table of the EPVent-2 study on partitioned respiratory mechanics and gas exchange in a subgroup of patients. METHODS: Sixty-one paralyzed mechanically ventilated patients with a confirmed diagnosis of SARS-CoV-2 were enrolled (age 60 [54-67] years, PaO2/FiO2 113 [79-158] mmHg and PEEP 10 [10-10] cmH2O). Keeping constant tidal volume, respiratory rate and oxygen fraction, two PEEP levels (5 and 15 cmH2O) were selected. In a subgroup of patients an additional PEEP level was applied according to an Empirical PEEP-FiO2 table (empirical PEEP). At each PEEP level gas exchange, partitioned lung mechanics and hemodynamic were collected. RESULTS: At 15 cmH2O of PEEP the lung elastance, lung stress and mechanical power were higher compared to 5 cmH2O. The PaO2/FiO2, arterial carbon dioxide and ventilatory ratio increased at 15 cmH2O of PEEP. The arterial-venous oxygen difference and central venous saturation were higher at 15 cmH2O of PEEP. Both the mechanics and gas exchange variables significantly increased although with high heterogeneity. By increasing the PEEP from 5 to 15 cmH2O, the changes in partitioned respiratory mechanics and mechanical power were not related to hypoxemia or respiratory compliance. The empirical PEEP was 18 ± 1 cmH2O. The empirical PEEP significantly increased the PaO2/FiO2 but also driving pressure, lung elastance, lung stress and mechanical power compared to 15 cmH2O of PEEP. CONCLUSIONS: In COVID-19 ARDS during the early phase the effects of raising PEEP are highly variable and cannot easily be predicted by respiratory system characteristics, because of the heterogeneity of the disease.

Validation of at-the-bedside formulae for estimating ventilator driving pressure during airway pressure release ventilation using computer simulation.

BACKGROUND: Airway pressure release ventilation (APRV) is widely available on mechanical ventilators and has been proposed as an early intervention to prevent lung injury or as a rescue therapy in the management of refractory hypoxemia. Driving pressure ([Formula: see text]) has been identified in numerous studies as a key indicator of ventilator-induced-lung-injury that needs to be carefully controlled. [Formula: see text] delivered by the ventilator in APRV is not directly measurable in dynamic conditions, and there is no "gold standard" method for its estimation. METHODS: We used a computational simulator matched to data from 90 patients with acute respiratory distress syndrome (ARDS) to evaluate the accuracy of three "at-the-bedside" methods for estimating ventilator [Formula: see text] during APRV. RESULTS: Levels of [Formula: see text] delivered by the ventilator in APRV were generally within safe limits, but in some cases exceeded levels specified by protective ventilation strategies. A formula based on estimating the intrinsic positive end expiratory pressure present at the end of the APRV release provided the most accurate estimates of [Formula: see text]. A second formula based on assuming that expiratory flow, volume and pressure decay mono-exponentially, and a third method that requires temporarily switching to volume-controlled ventilation, also provided accurate estimates of true [Formula: see text]. CONCLUSIONS: Levels of [Formula: see text] delivered by the ventilator during APRV can potentially exceed levels specified by standard protective ventilation strategies, highlighting the need for careful monitoring. Our results show that [Formula: see text] delivered by the ventilator during APRV can be accurately estimated at the bedside using simple formulae that are based on readily available measurements.

Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury.

Mechanical ventilation may cause ventilator-induced lung injury (VILI) in patients requiring ventilator support. Inhibition of autophagy is an important approach to ameliorate VILI as it always enhances lung injury after exposure to various stress agents. This study aimed to further reveal the potential mechanisms underlying the effects of geranylgeranyl diphosphate synthase large subunit 1 (GGPPS1) knockout and autophagy in VILI using C57BL/6 mice with lung-specific GGPPS1 knockout that were subjected to mechanical ventilation. The results demonstrate that GGPPS1 knockout mice exhibit significantly attenuated VILI based on the histologic score, the lung wet-to-dry ratio, total protein levels, neutrophils in bronchoalveolar lavage fluid, and reduced levels of inflammatory cytokines. Importantly, the expression levels of autophagy markers were obviously decreased in GGPPS1 knockout mice compared with wild-type mice. The inhibitory effects of GGPPS1 knockout on autophagy were further confirmed by measuring the ultrastructural change of lung tissues under transmission electron microscopy. In addition, knockdown of GGPPS1 in RAW264.7 cells reduced cyclic stretch-induced inflammation and autophagy. The benefits of GGPPS1 knockout for VILI can be partially eliminated through treatment with rapamycin. Further analysis revealed that Rab37 was significantly downregulated in GGPPS1 knockout mice after mechanical ventilation, while it was highly expressed in the control group. Simultaneously, Rab37 overexpression significantly enhances autophagy in cells that are treated with cyclin stretch, including GGPPS1 knockout cells. Collectively, our results indicate that GGPPS1 knockout results in reduced expression of Rab37 proteins, further restraining autophagy and VILI.

An Extracorporeal Membrane Oxygenation First Strategy in COVID-19 Acute Respiratory Distress Syndrome.

COVID-19 can be associated with acute respiratory distress syndrome, which increases the likelihood of morbidity and mortality. Ventilator-induced lung injury is a known complication of mechanical ventilation (MV) and can further compound lung injury and recovery. Escalation to extracorporeal membrane oxygenation can be required in patients who deteriorate on MV. We report our experience with complete avoidance of MV using an ECMO First strategy deployed in an awake nonintubated COVID-19 patient with severe pneumonia.

Noninvasive respiratory support and patient self-inflicted lung injury in COVID-19: a narrative review.

COVID-19 pneumonia is associated with hypoxaemic respiratory failure, ranging from mild to severe. Because of the worldwide shortage of ICU beds, a relatively high number of patients with respiratory failure are receiving prolonged noninvasive respiratory support, even when their clinical status would have required invasive mechanical ventilation. There are few experimental and clinical data reporting that vigorous breathing effort during spontaneous ventilation can worsen lung injury and cause a phenomenon that has been termed patient self-inflicted lung injury (P-SILI). The aim of this narrative review is to provide an overview of P-SILI pathophysiology and the role of noninvasive respiratory support in COVID-19 pneumonia. Respiratory mechanics, vascular compromise, viscoelastic properties, lung inhomogeneity, work of breathing, and oesophageal pressure swings are discussed. The concept of P-SILI has been widely investigated in recent years, but controversies persist regarding its mechanisms. To minimise the risk of P-SILI, intensivists should better understand its underlying pathophysiology to optimise the type of noninvasive respiratory support provided to patients with COVID-19 pneumonia, and decide on the optimal timing of intubation for these patients.

Barotrauma during non-invasive ventilation for acute respiratory distress syndrome caused by COVID-19: a balance between risks and benefits.

Ventilatory support is vital for the management of severe forms of COVID-19. Non-invasive ventilation is often used in patients who do not meet criteria for intubation or when invasive ventilation is not available, especially in a pandemic when resources are limited. Despite non-invasive ventilation providing effective respiratory support for some forms of acute respiratory failure, data about its effectiveness in patients with viral-related pneumonia are inconclusive. Acute respiratory distress syndrome caused by severe acute respiratory syndrome-coronavirus 2 infection causes life-threatening respiratory failure, weakening the lung parenchyma and increasing the risk of barotrauma. Pulmonary barotrauma results from positive pressure ventilation leading to elevated transalveolar pressure, and in turn to alveolar rupture and leakage of air into the extra-alveolar tissue. This article reviews the literature regarding the use of non-invasive ventilation in patients with acute respiratory failure associated with COVID-19 and other epidemic or pandemic viral infections and the related risk of barotrauma.

Oesophageal balloon positioning by echocardiography to guide positive pressure ventilation.

Understanding the respiratory mechanics of ARDS patients is crucial to avoid ventilator-induced lung injury (VILI), and this is much more challenging if not only lung compliance is altered but the whole compliance of the respiratory system is abnormal, as in obese patients. We face this problem daily in the ICU, and to optimize ventilation, we estimate respiratory mechanics using an oesophageal balloon. The balloon position is crucial to assess reliable values. In the present technical note, we describe the use of echocardiography to confirm the correct position of this instrument.

IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Targeted lateral positioning decreases lung collapse and overdistension in COVID-19-associated ARDS.

BACKGROUND: Among the challenges for personalizing the management of mechanically ventilated patients with coronavirus disease (COVID-19)-associated acute respiratory distress syndrome (ARDS) are the effects of different positive end-expiratory pressure (PEEP) levels and body positions in regional lung mechanics. Right-left lung aeration asymmetry and poorly recruitable lungs with increased recruitability with alternating body position between supine and prone have been reported. However, real-time effects of changing body position and PEEP on regional overdistension and collapse, in individual patients, remain largely unknown and not timely monitored. The aim of this study was to individualize PEEP and body positioning in order to reduce the mechanisms of ventilator-induced lung injury: collapse and overdistension. METHODS: We here report a series of five consecutive mechanically ventilated patients with COVID-19-associated ARDS in which sixteen decremental PEEP titrations were performed in the first days of mechanical ventilation (8 titration pairs: supine position immediately followed by 30° targeted lateral position). The choice of lateral tilt was based on X-Ray. This targeted lateral position strategy was defined by selecting the less aerated lung to be positioned up and the more aerated lung to be positioned down. For each PEEP level, global and regional collapse and overdistension maps and percentages were measured by electrical impedance tomography. Additionally, we present the incidence of lateral asymmetry in a cohort of forty-four patients. RESULTS: The targeted lateral position strategy resulted in significantly smaller amounts of overdistension and collapse when compared with the supine one: less collapse along the PEEP titration was found within the left lung in targeted lateral (P = 0.014); and less overdistension along the PEEP titration was found within the right lung in targeted lateral (P = 0.005). Regarding collapse within the right lung and overdistension within the left lung: no differences were found for position. In the cohort of forty-four patients, ventilation inequality of > 65/35% was observed in 15% of cases. CONCLUSIONS: Targeted lateral positioning with bedside personalized PEEP provided a selective attenuation of overdistension and collapse in mechanically ventilated patients with COVID-19-associated ARDS and right-left lung aeration/ventilation asymmetry. TRIAL REGISTRATION: Trial registration number: NCT04460859.

Secreted Extracellular Cyclophilin A Is a Novel Mediator of Ventilator-induced Lung Injury.

Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator-induced lung injury. eCypA (extracellular CypA [cyclophilin A]) is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to coronavirus disease (COVID-19). Objectives: To explore the involvement of eCypA in the pathophysiology of ventilator-induced lung injury. Methods: Mice were ventilated with a low or high Vt for up to 3 hours, with or without blockade of eCypA signaling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretching to explore the cellular source of eCypA, and CypA concentrations were measured in BAL fluid from patients with acute respiratory distress syndrome to evaluate the clinical relevance. Measurements and Main Results: High-Vt ventilation in mice provoked a rapid increase in soluble CypA concentration in the alveolar space but not in plasma. In vivo ventilation and in vitro stretching experiments indicated the alveolar epithelium as the likely major source. In vivo blockade of eCypA signaling substantially attenuated physiological dysfunction, macrophage activation, and MMPs (matrix metalloproteinases). Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated concentrations of eCypA within BAL fluid. Conclusions: CypA is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. eCypA represents an exciting novel target for pharmacological intervention.

Virtual patients for mechanical ventilation in the intensive care unit.

BACKGROUND: Mechanical ventilation (MV) is a core intensive care unit (ICU) therapy. Significant inter- and intra- patient variability in lung mechanics and condition makes managing MV difficult. Accurate prediction of patient-specific response to changes in MV settings would enable optimised, personalised, and more productive care, improving outcomes and reducing cost. This study develops a generalised digital clone model, or in-silico virtual patient, to accurately predict lung mechanics in response to changes in MV. METHODS: An identifiable, nonlinear hysteresis loop model (HLM) captures patient-specific lung dynamics identified from measured ventilator data. Identification and creation of the virtual patient model is fully automated using the hysteresis loop analysis (HLA) method to identify lung elastances from clinical data. Performance is evaluated using clinical data from 18 volume-control (VC) and 14 pressure-control (PC) ventilated patients who underwent step-wise recruitment maneuvers. RESULTS: Patient-specific virtual patient models accurately predict lung response for changes in PEEP up to 12 cmH2O for both volume and pressure control cohorts. R2 values for predicting peak inspiration pressure (PIP) and additional retained lung volume, Vfrc in VC, are R2=0.86 and R2=0.90 for 106 predictions over 18 patients. For 14 PC patients and 84 predictions, predicting peak inspiratory volume (PIV) and Vfrc yield R2=0.86 and R2=0.83. Absolute PIP, PIV and Vfrc errors are relatively small. CONCLUSIONS: Overall results validate the accuracy and versatility of the virtual patient model for capturing and predicting nonlinear changes in patient-specific lung mechanics. Accurate response prediction enables mechanically and physiologically relevant virtual patients to guide personalised and optimised MV therapy.

Challenges for the development of alternative low-cost ventilators during COVID-19 pandemic in Brazil. / Desafios para o desenvolvimento de ventiladores alternativos de baixo custo durante a pandemia de COVID-19 no Brasil.

The COVID-19 pandemic has brought concerns to managers, healthcare professionals, and the general population related to the potential mechanical ventilators' shortage for severely ill patients. In Brazil, there are several initiatives aimed at producing alternative ventilators to cover this gap. To assist the teams that work in these initiatives, we provide a discussion of some basic concepts on physiology and respiratory mechanics, commonly used mechanical ventilation terms, the differences between triggering and cycling, the basic ventilation modes and other relevant aspects, such as mechanisms of ventilator-induced lung injury, respiratory drive, airway heating and humidification, cross-contamination risks, and aerosol dissemination. After the prototype development phase, preclinical bench-tests and animal model trials are needed to determine the safety and performance of the ventilator, following the minimum technical requirements. Next, it is mandatory going through the regulatory procedures as required by the Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária - ANVISA). The manufacturing company should be appropriately registered by ANVISA, which also must be notified about the conduction of clinical trials, following the research protocol approval by the Research Ethics Committee. The registration requisition of the ventilator with ANVISA should include a dossier containing the information described in this paper, which is not intended to cover all related matters but to provide guidance on the required procedures.

A pandemia por COVID-19 tem deixado os gestores, os profissionais de saúde e a população preocupados com a potencial escassez de ventiladores pulmonares para suporte de pacientes graves. No Brasil, há diversas iniciativas com o intuito de produzir ventiladores alternativos para ajudar a suprir essa demanda. Para auxiliar as equipes que atuam nessas iniciativas, são expostos alguns conceitos básicos sobre fisiologia e mecânica respiratória, os termos comumente utilizados no contexto da ventilação mecânica, as fases do ciclo ventilatório, as diferenças entre disparo e ciclagem, os modos ventilatórios básicos e outros aspectos relevantes, como mecanismos de lesão pulmonar induzida pela ventilação mecânica, pacientes com drive respiratório, necessidade de umidificação de vias aéreas, risco de contaminação cruzada e disseminação de aerossóis. Após a fase de desenvolvimento de protótipo, são necessários testes pré-clínicos de bancada e em modelos animais, a fim de determinar a segurança e o desempenho dos equipamentos, seguindo requisitos técnicos mínimos exigidos. Então, é imprescindível passar pelo processo regulatório exigido pela Agência Nacional de Vigilância Sanitária (ANVISA). A empresa responsável pela fabricação do equipamento deve estar regularizada junto à ANVISA, que também deve ser notificada da condução dos testes clínicos em humanos, seguindo protocolo de pesquisa aprovado pelo Comitê de Ética em Pesquisa. O registro do ventilador junto à ANVISA deve ser acompanhado de um dossiê, composto por documentos e informações detalhadas neste artigo, que não tem o propósito de esgotar o assunto, mas de nortear os procedimentos necessários.

Case Report of Patients with Acute Respiratory Distress Syndrome Caused by COVID-19: Successfully Treated by Venovenous Extracorporeal Membrane Oxygenation and an Ultra-Protective Ventilation.

Coronavirus disease (COVID-19) started in Wuhan (China) at the end of 2019, and then increased rapidly. In patients with severe acute respiratory distress syndrome (ARDS) caused by COVID-19, venovenous extracorporeal membrane oxygenation (VV-ECMO) is considered a rescue therapy that provides adequate gas exchange. The way in which mechanical ventilation is applied during VV-ECMO is not clear, however it is associated with prognosis. Currently, the mortality rate of COVID-19 patients that receive VV-ECMO stands at approximately 50%. Here, we report three patients that successfully recovered from COVID-19-induced ARDS after VV-ECMO and implementation of an ultra-protective ventilation. This ventilation strategy involved maintaining a peak inspiratory pressure of ≤20 cmH2O and a positive end-expiratory pressure (PEEP) of ≤ 10 cmH2O, which are lower values than have been previously reported. Thus, we suggest that this ultra-protective ventilation be considered during VV-ECMO as it minimizes the ventilator-induced lung injury.