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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.

Acute respiratory distress syndrome (ARDS) is a clinical entity that acutely affects the lung parenchyma, and is characterized by diffuse alveolar damage and increased pulmonary vascular permeability. Currently, computed tomography (CT) is commonly used for classifying and prognosticating ARDS. However, performing this examination in critically ill patients is complex, due to the need to transfer these patients to the CT room. Fortunately, new technologies have been developed that allow the monitoring of patients at the bedside. Electrical impedance tomography (EIT) is a monitoring tool that allows one to evaluate at the bedside the distribution of pulmonary ventilation continuously, in real time, and which has proven to be useful in optimizing mechanical ventilation parameters in critically ill patients. Several clinical applications of EIT have been developed during the last years and the technique has been generating increasing interest among researchers. However, among clinicians, there is still a lack of knowledge regarding the technical principles of EIT and potential applications in ARDS patients. The aim of this review is to present the characteristics, technical concepts, and clinical applications of EIT, which may allow better monitoring of lung function during ARDS.

Hemodialysis, a cornerstone therapy for chronic kidney disease, represented a crucial advance in the evolution of artificial organs. While its success is largely due to its efficiency in removing uremic toxins, an equally important challenge is to uphold the primum non nocere principle by minimizing the harmful effects of membrane–blood interactions. This review examines the complex mechanisms and key interactions underlying membrane biocompatibility, including complement activation, inflammation, and coagulation disturbances, paving the way for their clinical implications. We also summarize recent innovations in membrane materials and surface engineering aimed at improving hemocompatibility and promoting safer hemodialysis treatments for improved clinical outcomes. Highlights Membrane biocompatibility is essential for safe and effective hemodialysis, while bioincompatibility can trigger complement activation, inflammation, and coagulation disorders. Synthetic membranes generally demonstrate superior hemocompatibility compared with cellulose-based membranes. Adverse immune and inflammatory responses to membrane–blood interactions may contribute to oxidative stress, endothelial dysfunction, and immune exhaustion, impacting patient prognosis. Advances in membrane design and surface engineering offer promising strategies to improve safety and clinical outcomes.

After the description of the baby lung concept [10], which revealed a physiologically small lungs in patients with ARDS, several studies in the 1990s tested the hypothesis that limiting Vt or airway pressures during mechanical ventilation might improve the outcome of these patients. In a pioneering single center study, Amato et al. were the first to show a reduction in mortality in this setting using a strategy based on maintaining low inspiratory driving pressures (lower than 20 cmH2O) along low Vt and high PEEP levels [11]. Shortly after, the large multicenter ARDSnet trial showed a decrease in mortality by nearly 25% in more than 800 patients with ARDS when using 6, instead of 12 mL/kg, IBW, confirming that Vt limitation is a fundamental strategy to improve survival of patients with ARDS [1]. However, some controversy was generated about the best way to titrate Vt: IBW, body surface area, lung size, airway pressures, etc. Going further back, the rationale of limiting Vt emerged from the description of the concept of baby lung, which tells us that in ARDS we are facing physiologically small lungs, and not rigid lungs as previously thought [10]. In Gattinoni et al.’s original study, while oxygenation and shunt were correlated with non-aerated tissue, static lung compliance was strongly correlated with the residual aerated lung volume [12], the volume of the baby lung. With that being said, driving pressure (DP) is the difference between the airway pressure at the end of inspiration (plateau pressure, Ppl) and PEEP [7, 13]. In turn, static compliance of the respiratory system (CRS) is the quotient between Vt and driving pressure. Ergo, by simple arithmetic, driving pressure is the quotient between the Vt and CRS of the patient: $$ \\begin{array}{l}\\mathrm{DP}={\\mathrm{P}}_{\\mathrm{pl}}-\\mathrm{PEEP}\\\ {}{\\mathrm{C}}_{\\mathrm{RS}}=\\frac{\\mathrm{Vt}}{{\\mathrm{P}}_{\\mathrm{pl}}-\\mathrm{PEEP}}=\\frac{\\mathrm{Vt}}{\\mathrm{DP}}\\\ {}\\mathrm{DP}=\\frac{\\mathrm{Vt}}{{\\mathrm{C}}_{\\mathrm{RS}}}\\end{array} $$ Thus, driving pressure represents the Vt corrected for the patient’s CRS, and using driving pressure as a safety limit may be a better way to adjust Vt in order to decrease cyclic or dynamic strain during mechanical ventilation. Despite the fact that no study has prospectively tested the relationship between driving pressure and Vt, some scattered physiological data indicate it exists. In nine patients with ARDS, we applied both ventilatory strategies from the original ARDSnet study, 6 and 12 mL/kg IBW, at a constant PEEP (9 cm H2O), and minute ventilation. The use of lower Vt decreased airway driving pressure (11.6 ± 2.2 versus 22.7 ± 5.4, p < 0.01) and driving transpulmonary pressure (8.1 ± 2.2 versus 16.8 ± 6.0, p < 0.01) (Fig. 1), as well as cyclic recruitment-derecruitment and tidal hyperinflation [14]. Needless to say, Vt limitation decreased all the physical mechanisms involved in the genesis of VILI. Fig. 1 Airway (P ao ) and esophageal (P eso ) pressures in a patient with pneumonia and ARDS under volume-controlled ventilation with Vt 6 (left) and Vt 12 (right) mL/kg IBW and similar PEEP. Transpulmonary driving pressure (shown as gray bars) is the difference between airway driving pressure (DP, solid arrows) and esophageal driving pressure (DP eso , dotted arrows). Both airway DP and transpulmonary DP increased when using a higher Vt. Modified from [11] Transpulmonary driving pressure (the difference between airway plateau minus PEEP pressure and esophageal plateau minus end-expiratory esophageal pressure), when taking into account the chest wall elastance, could better reflect lung stress and be the safest way to titrate mechanical ventilation (Fig. 2) [13, 15, 16]. In this context, Chiumello et al. [13] conducted a retrospective analysis of 150 deeply sedated, paralyzed patients with ARDS enrolled in previous studies, in which a PEEP trial of 5 and 15 cm H2O was performed at constant Vt and respiratory rate. At both PEEP levels, the higher airway driving pressure group had a significantly higher lung stress, respiratory system, and lung elastance compared to the lower airway driving pressure group. More importantly, airway driving pressure was significantly related to lung stress (transpulmonary pressure), and driving pressure higher than 15 cm H2O and transpulmonary driving pressure higher than 11.7 cm H2O, both measured at PEEP 15 cm H2O, were associated with dangerous levels of stress. Fig. 2 Airway (black line) and esophageal (gray line) pressure in an experimental model of abdominal hypertension secondary to pneumoperitoneum in pigs (data not published). During volume-controlled ventilation (Vt 10 mL/kg and PEEP 5 cm H2O), increases in intra abdominal pressure (IAP) from 5 (left) to 15 (middle) and 25 cm H2O (right) induced an increase in plateau pressure and driving pressure. However, driving transpulmonary pressure (arrows) remained constant Differences between transpulmonary driving pressure and airway driving pressure are mainly due to increases in chest wall elastance [15, 17]. Airway driving pressure may vary from minimal differences (skinny patient, pneumonia) to a large overestimation (morbid obesity, abdominal hypertension) of transpulmonary driving pressure. However, in the patient without spontaneous ventilatory activity, transpulmonary driving pressure will always be lower than airway driving pressure [13]. In summary, driving pressure during mechanical ventilation is directly related to stress forces in the lung. Sizing Vt in proportion to the size of the baby lung by targeting driving pressure, rather than to IBW, might better protect the lungs in patients with more severe lung injury and low end-expiratory lung volumes [8, 13].

Vigorous spontaneous breathing has emerged as a promotor of lung damage in acute lung injury, an entity known as “patient self-inflicted lung injury”. Mechanical ventilation may prevent this second injury by decreasing intrathoracic pressure swings and improving regional air distribution. Therefore, we aimed to determine the effects of spontaneous breathing during the early stage of acute respiratory failure on lung injury and determine whether early and late controlled mechanical ventilation may avoid or revert these harmful effects. A model of partial surfactant depletion and lung collapse was induced in eighteen intubated pigs of 32 ±4 kg. Then, animals were randomized to (1) SB‐group: spontaneous breathing with very low levels of pressure support for the whole experiment (eight hours), (2) Early MV-group: controlled mechanical ventilation for eight hours, or (3) Late MV-group: first half of the experiment on spontaneous breathing (four hours) and the second half on controlled mechanical ventilation (four hours). Respiratory, hemodynamic, and electric impedance tomography data were collected. After the protocol, animals were euthanized, and lungs were extracted for histologic tissue analysis and cytokines quantification. SB-group presented larger esophageal pressure swings, progressive hypoxemia, lung injury, and more dorsal and inhomogeneous ventilation compared to the early MV-group. In the late MV-group switch to controlled mechanical ventilation improved the lung inhomogeneity and esophageal pressure swings but failed to prevent hypoxemia and lung injury. In a lung collapse model, spontaneous breathing is associated to large esophageal pressure swings and lung inhomogeneity, resulting in progressive hypoxemia and lung injury. Mechanical ventilation prevents these mechanisms of patient self-inflicted lung injury if applied early, before spontaneous breathing occurs, but not when applied late.

The vascular waterfall phenomenon, rooted in Starling resistor principles, describes how blood flow becomes independent of downstream pressure when intraluminal pressure falls below a critical closing pressure (Pcrit). This review first introduces the classic arterial vascular waterfall, where local Pcrit enables organ-specific autoregulation of blood flow despite varying metabolic demands. Building on this framework, we extend the concept to the venous side, where similar mechanisms govern venous return and protect against congestion. The pulmonary vascular waterfall serves as a prototype, illustrating how alveolar pressures redefine downstream limits, shaping the effects of mechanical ventilation and positive end-expiratory pressure (PEEP). In valveless venous beds such as the hepatic veins, a reverse vascular waterfall may occur when elevated downstream pressure, typically right atrial pressure, causes brief, localized backflow buffered by vessel collapse and the emergence of a new Pcrit. These mechanisms explain organ-specific vulnerabilities to venous congestion: organs with effective venous waterfalls, such as the liver and intestine, can partially buffer overload, whereas the kidney, lacking such protection, is highly susceptible to venous pressure-dependent injury. Clinical implications include refined approaches to PEEP titration, fluid management balancing responsiveness with tolerance, and congestion assessment through Doppler ultrasound. Reframing congestion as a dynamic Starling resistor process explains why similar CVP elevations produce heterogeneous organ effects and provides a mechanistic basis for individualized, physiology-guided critical care.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a prevalent respiratory disease that presents a high rate of underdiagnosis during onset and early stages. Studies have shown that in mild COPD patients, remodeling of the small airways occurs concurrently with morphological changes in the proximal airways. Despite this evidence, the geometrical study of the airway tree from computed tomography (CT) lung images remains underexplored due to poor representations and limited tools to characterize the airway structure. Methods: We perform a comprehensive morphometric study of the proximal airways based on geometrical measures associated with the different airway generations. To this end, we leverage the geometric flexibility of the Snakes IsoGeometric Analysis method to accurately represent and characterize the airway luminal surface and volume informed by CT images of the respiratory tree. Based on this framework, we study the airway geometry of smoking pre-COPD and mild COPD individuals. Results: Our results show a significant difference between groups in airway volume, length, luminal eccentricity, minimum radius, and surface-area-to-volume ratio in the most distal airways. Discussion: Our findings suggest a higher degree of airway narrowing and collapse in COPD patients when compared to pre-COPD patients. We envision that our work has the potential to deliver a comprehensive tool for assessing morphological changes in airway geometry that take place in the early stages of COPD.

BackgroundProphylactic high-flow nasal cannula (HFNC) oxygen therapy can decrease the risk of extubation failure. It is frequently used in the postextubation phase alone or in combination with noninvasive ventilation. However, its physiological effects in this setting have not been thoroughly investigated. The aim of this study was to determine comprehensively the effects of HFNC applied after extubation on respiratory effort, diaphragm activity, gas exchange, ventilation distribution, and cardiovascular biomarkers.MethodsThis was a prospective randomized crossover physiological study in critically ill patients comparing 1 h of HFNC versus 1 h of standard oxygen after extubation. The main inclusion criteria were mechanical ventilation for at least 48 h due to acute respiratory failure, and extubation after a successful spontaneous breathing trial (SBT). We measured respiratory effort through esophageal/transdiaphragmatic pressures, and diaphragm electrical activity (ΔEAdi). Lung volumes and ventilation distribution were estimated by electrical impedance tomography. Arterial and central venous blood gases were analyzed, as well as cardiac stress biomarkers.ResultsWe enrolled 22 patients (age 59 ± 17 years; 9 women) who had been intubated for 8 ± 6 days before extubation. Respiratory effort was significantly lower with HFNC than with standard oxygen therapy, as evidenced by esophageal pressure swings (5.3 [4.2–7.1] vs. 7.2 [5.6–10.3] cmH2O; p < 0.001), pressure–time product (85 [67–140] vs. 156 [114–238] cmH2O*s/min; p < 0.001) and ΔEAdi (10 [7–13] vs. 14 [9–16] µV; p = 0.022). In addition, HFNC induced increases in end-expiratory lung volume and PaO2/FiO2 ratio, decreases in respiratory rate and ventilatory ratio, while no changes were observed in systemic hemodynamics, Troponin T, or in amino-terminal pro-B-type natriuretic peptide.ConclusionsProphylactic application of HFNC after extubation provides substantial respiratory support and unloads respiratory muscles.Trial registration January 15, 2021. NCT04711759.

BackgroundTrunk inclination from semirecumbent head-upright to supine-flat positioning reduces driving pressure and increases respiratory system compliance in patients with acute respiratory distress syndrome (ARDS). These effects are associated with an improved ventilatory ratio and reduction in the partial pressure of carbon dioxide (PaCO2). However, these physiological effects have not been completely studied, and their mechanisms have not yet been elucidated. Therefore, this study aimed to evaluate the effects of a change in trunk inclination from semirecumbent (45°) to supine-flat (10°) on physiological dead space and ventilation distribution in different lung regions.ResultsTwenty-two ARDS patients on pressure-controlled ventilation underwent three 60-min steps in which trunk inclination was changed from 45° (baseline) to 10° (intervention) and back to 45° (control) in the last step. Tunk inclination from a semirecumbent (45°) to a supine-flat (10°) position resulted in a higher tidal volume [371 (± 76) vs. 433 (± 84) mL (P < 0.001)] and respiratory system compliance [34 (± 10) to 41 (± 12) mL/cmH2O (P < 0.001)]. The CO2 exhaled per minute improved from 191 mL/min (± 34) to 227 mL/min (± 38) (P < 0.001). Accordingly, Bohr’s dead space ratio decreased from 0.49 (± 0.07) to 0.41 (± 0.06) (p < 0.001), and PaCO2 decreased from 43 (± 5) to 36 (± 4) mmHg (p < 0.001). In addition, the impedance ratio, which divides the ventilation activity of the ventral region by the dorsal region ventilation activity in tidal images, dropped from 1.27 (0.83–1.78) to 0.86 (0.51–1.33) (p < 0.001). These results, calculated from functional EIT images, indicated further ventilation activity in the dorsal lung regions. These effects rapidly reversed once the patient was repositioned at 45°.ConclusionsA change in trunk inclination from a semirecumbent (45 degrees) to a supine-flat position (10 degrees) improved Bohr’s dead space ratio and reduced PaCO2 in patients with ARDS. This effect is associated with an increase in tidal volume and respiratory system compliance, along with further favourable impedance ventilation distribution toward the dorsal lung regions. This study highlights the importance of considering trunk inclination as a modifiable determinant of physiological parameters. The angle of trunk inclination is essential information that must be reported in ARDS patients.

Background The respiratory rate (RR) is a key determinant of the mechanical power of ventilation (MP). The effect of reducing the RR on MP and its potential to mitigate ventilator-induced lung injury remains unclear. Objectives To compare invasive ventilation using a lower versus a higher RR with respect to MP and plasma biomarkers of lung injury in COVID-19 ARDS patients. Methods In a randomized cross-over clinical study in COVID-19 ARDS patients, we compared ventilation using a lower versus a higher RR in time blocks of 12 h. Patients were ventilated with tidal volumes of 6 ml/kg predicted body weight, and positive-end-expiratory pressure and fraction of inspired oxygen according to an ARDS network table. Respiratory mechanics and hemodynamics were assessed at the end of each period, and blood samples were drawn for measurements of inflammatory cytokines, epithelial and endothelial lung injury markers. In a subgroup of patients, we performed echocardiography and esophageal pressure measurements. Results We enrolled a total of 32 patients (26 males [81%], aged 52 [44–64] years). The median respiratory rate during ventilation with a lower and a higher RR was 20 [16–22] vs. 30 [26–32] breaths/min ( p  < 0.001), associated with a lower median minute ventilation (7.3 [6.5–8.5] vs. 11.6 [10–13] L/min [ p  < 0.001]) and a lower median MP (15 [11–18] vs. 25 [21–32] J/min [ p  < 0.001]). No differences were observed in any inflammatory (IL-6, IL-8, and TNF-R1), epithelial (s-RAGE and SP-D), endothelial (Angiopoietin-2), or pro-fibrotic activity (TGF-ß) marker between high or low RR. Cardiac function by echocardiography, and respiratory mechanics using esophageal pressure measurements were also not different. Conclusions Reducing the respiratory rate decreases mechanical power in COVID-19 ARDS patients but does not reduce plasma lung injury biomarkers levels in this cross-over study. Study registration This study is registered at clinicaltrials.gov (study identifier NCT04641897)