Resistive spontaneous breathing exacerbated lipopolysaccharide-induced lung injury in mice.

Background: Spontaneous respiratory mechanical force interacted with the primary lung injury and aggravated the progression of ARDS clinically. But the exact role and involved mechanism of it in the pathogenesis of ARDS animal model remained obscure. Aim: This study was to investigate the effect of spontaneous respiratory mechanical force on lung injury of ARDS in mice. Methods: Female C57BL/6 mice were subjected to resistive spontaneous breathing (RSB) by tracheal banding after 4-6 h of intranasal inhalation of LPS. Pulmonary function was examined by Buxco system, partial pressures of oxygen and carbon dioxide (PO2 and PCO2) were measured by a blood gas analyzer, and lung pathological changes were analyzed with hematoxylin and eosin staining. The levels of inflammatory markers were quantified by ELISA, total protein assay, and FACS analysis. The expression levels of mechanosensitive ion channels were detected by qRT-PCR and immunohistochemistry. Results: The airway resistance (Raw) was increased and the tidal volume (TV) was decreased remarkedly in RSB group. RSB treatment did not affect PO2, PCO2, pathology and inflammation levels of lung in mice. The Raw increased and ventilatory indicators decreased in RSB + ARDS compared to ARDS significantly. Besides, RSB treatment deteriorated the changes of PO2, PCO2 and level of lactic acid induced by LPS. Meanwhile, RSB significantly promoted LPS-induced pulmonary histopathological injury, and elevated the levels of IL-1ß, IL-6, TNF-α and total proteins, increased neutrophils infiltration. The expression level of Piezo1 in RSB + ARDS group was remarkably reduced compared to ARDS group and consistent with the severity of pulmonary damage. Conclusion: RSB exacerbated LPS-induced ARDS hypoxemia and hypercapnia, inflammation and damage. The mechanosensitive protein Piezo1 expression decreased and may play an important role in the process.

Diaphragm excursions as proxy for tidal volume during spontaneous breathing in invasively ventilated ICU patients.

There is a need to monitor tidal volume in critically ill patients with acute respiratory failure, given its relation with adverse clinical outcome. However, quantification of tidal volume in non-intubated patients is challenging. In this proof-of-concept study, we evaluated whether ultrasound measurements of diaphragm excursion could be a valid surrogate for tidal volume in patients with respiratory failure. Diaphragm excursions and tidal volumes were simultaneously measured in invasively ventilated patients (N = 21) and healthy volunteers (N = 20). Linear mixed models were used to estimate the ratio between tidal volume and diaphragm excursion. The tidal volume-diaphragm excursion ratio was 201 mL/cm in ICU patients [95% confidence interval (CI) 161-240 mL/cm], and 361 (294-428) mL/cm in healthy volunteers. An excellent association was shown within participants (R2 = 0.96 in ICU patients, R2 = 0.90 in healthy volunteers). However, the differences between observed tidal volume and tidal volume as predicted by the linear mixed models were considerable: the 95% limits of agreement in Bland-Altman plots were ± 91 mL in ICU patients and ± 396 mL in healthy volunteers. Likewise, the variability in tidal volume estimation between participants was large. This study shows that diaphragm excursions measured with ultrasound correlate with tidal volume, yet quantification of absolute tidal volume from diaphragm excursion is unreliable.

Effects of three spontaneous ventilation modes on respiratory drive and muscle effort in COVID-19 pneumonia patients.

BACKGROUND: High drive and high effort during spontaneous breathing can generate patient self-inflicted lung injury (P-SILI) due to uncontrolled high transpulmonary and transvascular pressures, with deterioration of respiratory failure. P-SILI has been demonstrated in experimental studies and supported in recent computational models. Different treatment strategies have been proposed according to the phenotype of elastance of the respiratory system (Ers) for patients with COVID-19. This study aimed to investigate the effect of three spontaneous ventilation modes on respiratory drive and muscle effort in clinical practice and their relationship with different phenotypes. This was achieved by obtaining the following respiratory signals: airway pressure (Paw), flow (V´) and volume (V) and calculating muscle pressure (Pmus). METHODS: A physiologic observational study of a series of cases in a university medical-surgical ICU involving 11 mechanically ventilated patients with COVID-19 pneumonia at the initiation of spontaneous breathing was conducted. Three spontaneous ventilation modes were evaluated in each of the patients: pressure support ventilation (PSV), airway pressure release ventilation (APRV), and BiLevel positive airway pressure ventilation (BIPAP). Pmus was calculated through the equation of motion. For this purpose, we acquired the signals of Paw, V´ and V directly from the data transmission protocol of the ventilator (Dräger). The main physiological measurements were calculation of the respiratory drive (P0.1), muscle effort through the ΔPmus, pressure‒time product (PTP/min) and work of breathing of the patient in joules multiplied by respiratory frequency (WOBp, J/min). RESULTS: Ten mechanically ventilated patients with COVID-19 pneumonia at the initiation of spontaneous breathing were evaluated. Our results showed similar high drive and muscle effort in each of the spontaneous ventilatory modes tested, without significant differences between them: median (IQR): P0.1 6.28 (4.92-7.44) cm H2O, ∆Pmus 13.48 (11.09-17.81) cm H2O, PTP 166.29 (124.02-253.33) cm H2O*sec/min, and WOBp 12.76 (7.46-18.04) J/min. High drive and effort were found in patients even with low Ers. There was a significant relationship between respiratory drive and WOBp and Ers, though the coefficient of variation widely varied. CONCLUSIONS: In our study, none of the spontaneous ventilatory methods tested succeeded in reducing high respiratory drive or muscle effort, regardless of the Ers, with subsequent risk of P-SILI.

Long-term outcome of COVID-19 patients treated with helmet noninvasive ventilation vs. high-flow nasal oxygen: a randomized trial.

BACKGROUND: Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. METHODS: In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. RESULTS: Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47-77] of predicted vs. 80% [71-88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53-70] vs. 80 [70-83], p = 0.01). CONCLUSIONS: In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients. Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 2020.

Physiological adaptations during weaning from veno-venous extracorporeal membrane oxygenation.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) has an established evidence base in acute respiratory distress syndrome (ARDS) and has seen exponential growth in its use over the past decades. However, there is a paucity of evidence regarding the approach to weaning, with variation of practice and outcomes between centres. Preconditions for weaning, management of patients' sedation and mechanical ventilation during this phase, criteria defining success or failure, and the optimal duration of a trial prior to decannulation are all debated subjects. Moreover, there is no prospective evidence demonstrating the superiority of weaning the sweep gas flow (SGF), the extracorporeal blood flow (ECBF) or the fraction of oxygen of the SGF (FdO2), thereby a broad inter-centre variability exists in this regard. Accordingly, the aim of this review is to discuss the required physiological basis to interpret different weaning approaches: first, we will outline the physiological changes in blood gases which should be expected from manipulations of ECBF, SGF and FdO2. Subsequently, we will describe the resulting adaptation of patients' control of breathing, with special reference to the effects of weaning on respiratory effort. Finally, we will discuss pertinent elements of the monitoring and mechanical ventilation of passive and spontaneously breathing patients during a weaning trial. Indeed, to avoid lung injury, invasive monitoring is often required in patients making spontaneous effort, as pressures measured at the airway may not reflect the degree of lung strain. In the absence of evidence, our approach to weaning is driven largely by an understanding of physiology.

Lesión pulmonar autoinflingida por el paciente en la Unidad de Cuidados Intensivos / Patient Self-Inflicted Lung Injury (P-SILI) in the Intensive Care Unit / Lesão pulmonar auto-infligida pelo paciente na Unidade de Cuidados Intensivos

Resumen: Hasta la fecha, no se ha demostrado superioridad de algún modo de ventilación mecánica invasiva en particular, la mayoría de los autores destacan la individualización de la programación y modalidad de la ventilación mecánica, teniendo en cuenta la presencia de asincronías y buscando el mejor confort del paciente, incluso la ventilación espontánea, aunque al parecer se asemeja a la manera fisiológica de la mecánica respiratoria, no está exenta de complicaciones. Tres mecanismos potenciales se proponen para el desarrollo de lesión pulmonar por esfuerzo respiratorio espontáneo: sobredistensión global y local, aumento de la perfusión pulmonar y la presencia de asincronías paciente-ventilador, derivadas en una lesión autoinfligida por el paciente o «P-SILI¼, por sus siglas en inglés Patient Self Inflicted Lung Injury. En los últimos 20 años se han desarrollado estrategias que permiten minimizar los riesgos asociados a la ventilación mecánica, la más importante de todas es mantener soporte ventilatorio guiado por metas, identificación del posible desarrollo del paciente y extubar al paciente lo más rápido posible, siempre y cuando sus condiciones lo permitan.

Abstract: To date, the superiority of any particular mode of invasive mechanical ventilation has not been demonstrated; most authors emphasize the individualization of the programming and modality of mechanical ventilation, taking into account the presence of asynchronies and seeking the best patient comfort; even spontaneous ventilation, although it seems to resemble the physiological manner of respiratory mechanics, is not free of complications. Three potential mechanisms are proposed for the development of lung injury by spontaneous respiratory effort: global and local overdistension, increased pulmonary perfusion and the presence of patient-ventilator asynchronies, resulting in a Patient Self-Inflicted Injury or «P-SILI¼. In the last twenty years, strategies have been developed to minimize the risks associated with mechanical ventilation, the most important of which is to maintain goal-directed ventilatory support, identify the possible development of the patient and extubate the patient as quickly as possible, as long as the patient's conditions allow it.

Resumo: Até o momento, nenhum modo específico de ventilação mecânica invasiva se mostrou superior, a maioria dos autores enfatiza a individualização da programação e modalidade de ventilação mecânica, levando em consideração a presença de assincronia e buscando o melhor conforto do paciente. Mesmo a ventilação espontânea, embora pareça assemelhar-se à maneira fisiológica da mecânica respiratória, não é isenta de complicações. Três mecanismos potenciais são propostos para o desenvolvimento de lesão pulmonar por esforço respiratório espontâneo: hiperdistensão global e local, aumento da perfusão pulmonar e presença de assincronia paciente-ventilador, derivada de uma lesão autoinfligida pelo paciente ou «P-SILI¼ por suas siglas em inglês patient self inflicted lung injury. Nos últimos vinte anos, foram desenvolvidas estratégias para minimizar os riscos associados à ventilação mecânica. O mais importante de tudo é manter o suporte ventilatório guiado por metas, identificar o possível desenvolvimento do paciente e extubar o paciente o mais rápido possível, enquanto suas condições permitirem.

Clinical Outcomes of COVID-19-Induced Acute Respiratory Distress Syndrome in Patients With Three Different Respiratory Support Modalities: A Retrospective Cohort Study.

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute respiratory failure and acute respiratory distress syndrome (ARDS) had a considerable impact on intensive care utilization and resource optimization. Multiple modalities for respiratory support were implemented during the COVID-19 pandemic with the main concern of being able to identify those patients at high risk of rapidly progressive respiratory failure, whom the early initiation of invasive respiratory support would, in particular, affect the outcome in comparison to the noninvasive management strategy. Objectives In our cohort study, we describe demographic characteristics, respiratory support modalities, and their relation to patient outcomes. Method Patients 18 years of age and older who were admitted to a tertiary center COVID-19-dedicated medical intensive care unit (MICU) in Qatar between March 2020 and May 2020 with a confirmed diagnosis of COVID-19 pneumonia were included in this study. Patients were divided into invasive or noninvasive, and those who required invasive strategy were subdivided into the early intubation group (patients who were intubated within 72 hours of intensive care unit (ICU) admission) and the late intubation group (patients who were intubated after 72 hours from ICU admission). The primary outcome was ICU and hospital mortality, and the secondary effects were the length of stay and mortality determinants. Results A total of 686 patients were admitted to the medical intensive care unit (MICU) during the study period. There were 222 (32.4%), 131 (19.1%), and 333 (48.5%) patients in the early, late, and not intubated groups, respectively. Compared to the late intubated group, the early intubated group had a higher proportion of males. Diabetes (39.8%) was the most common comorbidity, followed by hypertension (HTN) (36%) and heart disease (9.8%). The 30-day ICU and hospital mortality were significantly higher in the late intubated group compared to the early intubated group (30.5% versus 15.8%, and 30% versus 16.2%). The median ICU and hospital stay days in the total sample were 8 (interquartile range (IQR): 5-14) and 19 (IQR: 14-25), respectively. The mean estimates of 30-day ICU survival times for early intubated, late intubated, and not intubated groups were 25.14 (95% confidence interval (CI): 23.71, 26.57), 23.35 (95% CI: 21.63, 25.07), and 29.91 (95% CI: 29.74, 30.09) respectively. Conclusions In our study, the COVID-19 ARDS patients who required early invasive ventilatory support and in whom the physiological parameter was more severe (Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores) had a better outcome than the late intubation group. Age more than 60 years old, diabetes, hypertension, chronic kidney disease (CKD), and chronic liver disease (CLD) were the main predictor of mortality in total.

Accuracy of noncontact surface imaging for tidal volume and respiratory rate measurements in the ICU.

Tidal volume monitoring may help minimize lung injury during respiratory assistance. Surface imaging using time-of-flight camera is a new, non-invasive, non-contact, radiation-free, and easy-to-use technique that enables tidal volume and respiratory rate measurements. The objectives of the study were to determine the accuracy of Time-of-Flight volume (VTTOF) and respiratory rate (RRTOF) measurements at the bedside, and to validate its application for spontaneously breathing patients under high flow nasal canula. Data analysis was performed within the ReaSTOC data-warehousing project (ClinicalTrials.gov identifier NCT02893462). All data were recorded using standard monitoring devices, and the computerized medical file. Time-of-flight technique used a Kinect V2 (Microsoft, Redmond, WA, USA) to acquire the distance information, based on measuring the phase delay between the emitted light-wave and received backscattered signals. 44 patients (32 under mechanical ventilation; 12 under high-flow nasal canula) were recorded. High correlation (r = 0.84; p < 0.001), with low bias (-1.7 mL) and acceptable deviation (75 mL) was observed between VTTOF and VTREF under ventilation. Similar performance was observed for respiratory rate (r = 0.91; p < 0.001; bias < 1b/min; deviation ≤ 5b/min). Measurements were possible for all patients under high-flow nasal canula, detecting overdistension in 4 patients (tidal volume > 8 mL/kg) and low ventilation in 6 patients (tidal volume < 6 mL/kg). Tidal volume monitoring using time-of-flight camera (VTTOF) is correlated to reference values. Time-of-flight camera enables continuous and non-contact respiratory monitoring under high-flow nasal canula, and enables to detect tidal volume and respiratory rate changes, while modifying flow. It enables respiratory monitoring for spontaneously patients, especially while using high-flow nasal oxygenation.

Expert opinion document: "Electrical impedance tomography: applications from the intensive care unit and beyond".

Mechanical ventilation is a life-saving technology, but it can also inadvertently induce lung injury and increase morbidity and mortality. Currently, there is no easy method of assessing the impact that ventilator settings have on the degree of lung inssflation. Computed tomography (CT), the gold standard for visually monitoring lung function, can provide detailed regional information of the lung. Unfortunately, it necessitates moving critically ill patients to a special diagnostic room and involves exposure to radiation. A technique introduced in the 1980s, electrical impedance tomography (EIT) can non-invasively provide similar monitoring of lung function. However, while CT provides information on the air content, EIT monitors ventilation-related changes of lung volume and changes of end expiratory lung volume (EELV). Over the past several decades, EIT has moved from the research lab to commercially available devices that are used at the bedside. Being complementary to well-established radiological techniques and conventional pulmonary monitoring, EIT can be used to continuously visualize the lung function at the bedside and to instantly assess the effects of therapeutic maneuvers on regional ventilation distribution. EIT provides a means of visualizing the regional distribution of ventilation and changes of lung volume. This ability is particularly useful when therapy changes are intended to achieve a more homogenous gas distribution in mechanically ventilated patients. Besides the unique information provided by EIT, its convenience and safety contribute to the increasing perception expressed by various authors that EIT has the potential to be used as a valuable tool for optimizing PEEP and other ventilator settings, either in the operative room and in the intensive care unit. The effects of various therapeutic interventions and applications on ventilation distribution have already been assessed with the help of EIT, and this document gives an overview of the literature that has been published in this context.

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.

Non-invasive ventilatory support and high-flow nasal oxygen as first-line treatment of acute hypoxemic respiratory failure and ARDS.

The role of non-invasive respiratory support (high-flow nasal oxygen and noninvasive ventilation) in the management of acute hypoxemic respiratory failure and acute respiratory distress syndrome is debated. The oxygenation improvement coupled with lung and diaphragm protection produced by non-invasive support may help to avoid endotracheal intubation, which prevents the complications of sedation and invasive mechanical ventilation. However, spontaneous breathing in patients with lung injury carries the risk that vigorous inspiratory effort, combined or not with mechanical increases in inspiratory airway pressure, produces high transpulmonary pressure swings and local lung overstretch. This ultimately results in additional lung damage (patient self-inflicted lung injury), so that patients intubated after a trial of noninvasive support are burdened by increased mortality. Reducing inspiratory effort by high-flow nasal oxygen or delivery of sustained positive end-expiratory pressure through the helmet interface may reduce these risks. In this physiology-to-bedside review, we provide an updated overview about the role of noninvasive respiratory support strategies as early treatment of hypoxemic respiratory failure in the intensive care unit. Noninvasive strategies appear safe and effective in mild-to-moderate hypoxemia (PaO2/FiO2 > 150 mmHg), while they can yield delayed intubation with increased mortality in a significant proportion of moderate-to-severe (PaO2/FiO2 ≤ 150 mmHg) cases. High-flow nasal oxygen and helmet noninvasive ventilation represent the most promising techniques for first-line treatment of severe patients. However, no conclusive evidence allows to recommend a single approach over the others in case of moderate-to-severe hypoxemia. During any treatment, strict physiological monitoring remains of paramount importance to promptly detect the need for endotracheal intubation and not delay protective ventilation.

The Role of High Flow Nasal Cannula in COVID-19 Associated Pneumomediastinum and Pneumothorax.

BACKGROUND: Pneumomediastinum, subcutaneous emphysema and pneumothorax are not rarely observed during the COVID-19 pandemic. Such complications can worsen gas exchange and the overall prognosis in critical patients. The aim of this study is to investigate what predisposing factors are related to pneumomediastinum and pneumothorax in SARS-CoV2-Acute Respiratory Distress Syndrome (ARDS), what symptoms may predict a severe and potentially fatal complication and what therapeutical approach may provide a better outcome. METHODS: In this single center cohort study, we recorded data from 45 critically ill COVID-19 patients who developed one or more complicating events among pneumomediastinum, subcutaneous emphysema and pneumothorax. All patients showed ARDS and underwent non-invasive ventilation (NIV) at baseline. Patients with mild to moderate ARDS and pneumomediastinum/pneumothorax (n = 25) received High Flow Nasal Cannula (HFNC), while patients with severe ARDS and pneumomediastinum/pneumothorax underwent HFNC (n = 10) or invasive mechanical ventilation (IMV) (n = 10). RESULTS: Pneumomediastinum/pneumothorax developed in 10.5% of subjects affected by SARS-coV2-ARDS. Dyspnea affected 40% and cough affected 37% of subjects. High resolution computed tomography of the chest showed bilateral diffuse ground glass opacities (GGO) in 100% of subjects. Traction bronchiolectasis, reticulation, crazy paving and distortion were observed in 64%. Furthermore, 36% showed subcutaneous emphysema. Non-severe ARDS cases received HFNC, and 76% patients recovered from pneumomediastinum/pneumothorax over a median follow up of 5 days. Among severe ARDS cases the recovery rate of pneumomediastinum/pneumothorax was 70% with the HFNC approach, and 10% with IMV. CONCLUSION: HFNC is a safe and effective ventilatory approach for critical COVID-19 and has a positive role in associated complications such as pneumomediastinum and pneumothorax.

Bilateral phrenic nerve block as an effective means of controlling inspiratory efforts in a COVID-19 patient.

Bilateral continuous phrenic nerve block effectively regulates refractory persistent, strong inspiratory effort in a patient with coronavirus disease (COVID-19). A 73-year-old man with acute respiratory distress syndrome (ARDS) due to COVID-19 was admitted to the intensive care unit (ICU). Use of neuromuscular blocking agents (NMBAs) was stopped due to uncontrollable strong inspiratory efforts and worsened lung injury. We performed bilateral continuous phrenic nerve block, which suppressed inspiratory efforts, resulting in lung injury improvement. A bilateral continuous phrenic nerve block is a viable alternative to control refractory strong inspiratory effort leading to lung injury in cases with prolonged NMBA use.

Pulmonary Interstitial Matrix and Lung Fluid Balance From Normal to the Acutely Injured Lung.

This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH2O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the "safety factor" opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both trans-endothelial and trans-epithelial gradients favor filtration leading to alveolar flooding. Neither CT scan nor ultrasound can identify this initial level of lung fluid balance perturbation. A suggestion is put forward to identify a non-invasive tool to detect the earliest stages of perturbation of lung fluid balance before the condition becomes life-threatening.

A physiological approach to understand the role of respiratory effort in the progression of lung injury in SARS-CoV-2 infection.

Deterioration of lung function during the first week of COVID-19 has been observed when patients remain with insufficient respiratory support. Patient self-inflicted lung injury (P-SILI) is theorized as the responsible, but there is not robust experimental and clinical data to support it. Given the limited understanding of P-SILI, we describe the physiological basis of P-SILI and we show experimental data to comprehend the role of regional strain and heterogeneity in lung injury due to increased work of breathing.In addition, we discuss the current approach to respiratory support for COVID-19 under this point of view.