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There is a well-recognised importance for personalising mechanical ventilation settings to protect the lungs and the diaphragm for each individual patient. Measurement of oesophageal pressure (Poes) as an estimate of pleural pressure allows assessment of partitioned respiratory mechanics and quantification of lung stress, which helps our understanding of the patient's respiratory physiology and could guide individualisation of ventilator settings. Oesophageal manometry also allows breathing effort quantification, which could contribute to improving settings during assisted ventilation and mechanical ventilation weaning. In parallel with technological improvements,Poesmonitoring is now available for daily clinical practice. This review provides a fundamental understanding of the relevant physiological concepts that can be assessed usingPoesmeasurements, both during spontaneous breathing and mechanical ventilation. We also present a practical approach for implementing oesophageal manometry at the bedside. While more clinical data are awaited to confirm the benefits ofPoes-guided mechanical ventilation and to determine optimal targets under different conditions, we discuss potential practical approaches, including positive end-expiratory pressure setting in controlled ventilation and assessment of inspiratory effort during assisted modes.

Background Optimal noninvasive respiratory support for patients with hypoxemic respiratory failure should minimize work of breathing without increasing the transpulmonary pressure. Recently, an asymmetrical high flow nasal cannula (HFNC) interface (Duet, Fisher & Paykel Healthcare Ltd), in which the caliber of each nasal prong is different, was approved for clinical use. This system might reduce work of breathing by lowering minute ventilation and improving respiratory mechanics. Methods We enrolled 10 patients ≥ 18 years of age who were admitted to the Ospedale Maggiore Policlinico ICU in Milan, Italy, and had a PaO2/FiO2 Results Application of the asymmetrical interface resulted in a −13.5 [−19.4 to (−4.5)] % change in minute ventilation at a flow rate of 40 l/min, p = 0.006 and a −19.6 [−28.0 to (−7.5)] % change at 60 l/min, p = 0.002, that occurred despite no change in PaCO2 (35 [33–42] versus 35 [33–43] mmHg at 40 l/min and 35 [32–41] versus 36 [32–43] mmHg at 60 l/min). Correspondingly, the asymmetrical interface lowered the inspiratory esophageal pressure–time product from 163 [118–210] to 140 [84–159] (cmH2O*s)/min at a flow rate of 40 l/min, p = 0.02 and from 142 [123–178] to 117 [90–137] (cmH2O*s)/min at a flow rate of 60 l/min, p = 0.04. The asymmetrical cannula did not have any impact on oxygenation, the dorsal fraction of ventilation, dynamic lung compliance, or end-expiratory lung impedance, suggesting no major effect on PEEP, lung mechanics, or alveolar recruitment. Conclusions An asymmetrical HFNC interface reduces minute ventilation and work of breathing in patients with mild-to-moderate hypoxemic respiratory failure supported with a conventional interface. This appears to be primarily driven by increased ventilatory efficiency due to enhanced CO2 clearance from the upper airway.

PDF file - 54K, MFI values indicating basal and EPO and G-CSF induced activation of ERK1/2, STAT5, p38 MAPK, and caspase-3 in MDS subpopulations. Correlation between EPO response in vitro and in the clinic

PDF file - 55K, Dot plot indicating basal activation of P-ERK1/2, P-STAT5, P-p38 MAPK, and cleaved caspase-3 in CD45+ MDS and normal cells

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS.Experimental Design: Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and STAT5 specifically in defined CD34+, CD45+, or CD71+CD45− bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with granulocyte colony-stimulating factor (G-CSF) and erythropoietin.Results: In CD71+CD45− cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous erythropoietin levels, transfusion dependency, percentage of blasts in the BM), erythropoietin failed to activate ERK1/2 or STAT5 in 23 of 36 cases, but it was effective in 13 of 36 cases, although to a significantly lower degree than in CD71+CD45− cells from healthy donor BM. The erythropoietin response in vivo correlated with in vitro erythropoietin-dependent STAT5 activation in 20 of 22 cases. STAT5 was significantly activated at baseline in MDS cells compared with normal controls, whereas caspase-3 was activated in CD34+ and CD45+ MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34+ cells.Conclusions: Abnormalities in the response to growth factors are restricted to erythropoietin stimulation in CD71+CD45− cells and correlate with the clinical response to erythropoietin. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS but with different patterns among the various BM subpopulations. Clin Cancer Res; 18(11); 3079–89. ©2012 AACR.

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PDF file - 58K, Basal activation of P-ERK1/2, P-STAT5, P-p38 MAPK, and cleaved caspase-3 in CD34+ MDS and normal cells

PDF file - 52K, Dot plot indicating basal activation of P-ERK1/2, P-STAT5, P-p38 and cleaved caspase-3 in CD71+CD45- MDS and normal cells

PDF file - 48K, Flow cytometric analysis of STAT5 activation after G-CSF and EPO stimulation

PDF file - 101K, Full-length immunoblots of ERK1/2 activation before and after TPA treatment in Kasumi-1 cells and ERK1/2 activation before and after TPA and EPO treatment in normal BMMC. Original graphic indicating a correlation between the EPO response in vitro and in vivo

Prone positioning allows to improve oxygenation and decrease mortality rate in COVID-19-associated acute respiratory distress syndrome (C-ARDS). However, the mechanisms leading to these effects are not fully understood. The aim of this study is to assess the physiologic effects of pronation by the means of CT scan and electrical impedance tomography (EIT).Experimental, physiologic study.Patients were enrolled from October 2020 to March 2021 in an Italian dedicated COVID-19 ICU.Twenty-one intubated patients with moderate or severe C-ARDS.First, patients were transported to the CT scan facility, and image acquisition was performed in prone, then supine position. Back to the ICU, gas exchange, respiratory mechanics, and ventilation and perfusion EIT-based analysis were provided toward the end of two 30 minutes steps (e.g., in supine, then prone position).Prone position induced recruitment in the dorsal part of the lungs (12.5% ± 8.0%; p0.001 from baseline) and derecruitment in the ventral regions (-6.9% ± 5.2%; p0.001). These changes led to a global increase in recruitment (6.0% ± 6.7%; p0.001). Respiratory system compliance did not change with prone position (45 ± 15 vs 45 ± 18 mL/cm H2O in supine and prone position, respectively; p = 0.957) suggesting a decrease in atelectrauma. This hypothesis was supported by the decrease of a time-impedance curve concavity index designed as a surrogate for atelectrauma (1.41 ± 0.16 vs 1.30 ± 0.16; p = 0.001). Dead space measured by EIT was reduced in the ventral regions of the lungs, and the dead-space/shunt ratio decreased significantly (5.1 [2.3-23.4] vs 4.3 [0.7-6.8]; p = 0.035), showing an improvement in ventilation-perfusion matching.Several changes are associated with prone position in C-ARDS: increased lung recruitment, decreased atelectrauma, and improved ventilation-perfusion matching. These physiologic effects may be associated with more protective ventilation.

COVID-19-related ARDS is characterized by severe hypoxemia with initially preserved lung compliance and impaired ventilation/perfusion (V̇/Q̇) matching. PEEP can increase end-expiratory lung volume, but its effect on V̇/Q̇ mismatch in COVID-19-related ARDS is not clear.We enrolled intubated and mechanically ventilated subjects with COVID-19 ARDS and used the automatic lung parameter estimator (ALPE) to measure V̇/Q̇. Respiratory mechanics measurements, shunt, and V̇/Q̇ mismatch (low V̇/Q̇ and high V̇/Q̇) were collected at 3 PEEP levels (clinical PEEP = intermediate PEEP, low PEEP [clinical - 50%], and high PEEP [clinical + 50%]). A mixed-effect model was used to evaluate the impact of PEEP on V̇/Q̇. We also investigated if PEEP might have a different effect on V̇/Q̇ mismatch in 2 different respiratory mechanics phenotypes, that is, high elastance/low compliance (phenotype H) and low elastance/high compliance (phenotype L).Seventeen subjects with COVID-related ARDS age 66 [60-71] y with a PIn subjects with COVID-related ARDS placed on invasive mechanical ventilation for48 h, PEEP had a heterogeneous effect on V̇/Q̇ mismatch and, on average, higher levels were not able to reduce shunt. The subject's compliance could influence the effect of PEEP on V̇/Q̇ mismatch since an increased shunt was observed in subjects with lower compliance, whereas the opposite occurred in those with higher compliance.

Monitoring with electrical impedance tomography (EIT) during a decremental PEEP trial has been used to identify the PEEP that yields the optimal balance of pulmonary overdistension and collapse. This method is based on pixel-level changes in respiratory system compliance and depends on fixed or measured airway driving pressure. We developed a novel approach to quantify overdistension and collapse during pressure support ventilation (PSV) by integrating transpulmonary pressure and EIT monitoring and performed pilot tests in three hypoxemic patients. We report that our experimental approach is feasible and capable of identifying a PEEP that balances overdistension and collapse in intubated hypoxemic patients undergoing PSV.

Veno-venous Extracorporeal Membrane Oxygenation (ECMO) is used in the most severe cases of respiratory failure and further exacerbates the patients’ inflammatory status. Antithrombin is supplemented during ECMO for its anticoagulant effects, but it also deploys anti-inflammatory properties. In this pre-specified ancillary study of the GATRA trial [NCT03208270] we aimed to evaluate the relationship between antithrombin and inflammation during ECMO. Forty-six patients were included in the study, 23 were randomized to receive antithrombin to maintain a level of 80–120% (study group) and 23 were randomized not to be supplemented (control group). Anticoagulation was provided in both groups with heparin infusion. Six cytokines were measured at 5 timepoints from prior to ECMO start to 7 days after ECMO removal. Cytokines decreased during the study but overall were not very different in the two groups. Testing the interaction between the study group and timepoints suggests that the administration of antithrombin led to a more rapid decrease over time of IL-6, IL-1β, TNF-⍺ and Pro-ADM. Plasma levels of antithrombin (either endogenous or exogenous) were negatively associated with all cytokines. Inflammation decreases during ECMO but a causal effect of antithrombin administration on the reduction of inflammation (and its clinical relevance) must be confirmed by appropriately powered studies.

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.

Purpose In the acute respiratory distress syndrome (ARDS), decreasing Ventilation-Perfusion $$\left( {{{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}} \right)$$ V ˙ / Q ˙ mismatch might enhance lung protection. We investigated the regional effects of higher Positive End Expiratory Pressure (PEEP) on $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch and their correlation with recruitability. We aimed to verify whether PEEP improves regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch, and to study the underlying mechanisms. Methods In fifteen patients with moderate and severe ARDS, two PEEP levels (5 and 15 cmH2O) were applied in random order. $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch was assessed by Electrical Impedance Tomography at each PEEP. Percentage of ventilation and perfusion reaching different ranges of $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ ratios were analyzed in 3 gravitational lung regions, leading to precise assessment of their distribution throughout different $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch compartments. Recruitability between the two PEEP levels was measured by the recruitment-to-inflation ratio method. Results In the non-dependent region, at higher PEEP, ventilation reaching the normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment (p = 0.018) increased, while it decreased in the high $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ one (p = 0.023). In the middle region, at PEEP 15 cmH2O, ventilation and perfusion to the low $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment decreased (p = 0.006 and p = 0.011) and perfusion to normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ increased (p = 0.003). In the dependent lung, the percentage of blood flowing through the non-ventilated compartment decreased (p = 0.041). Regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch improvement was correlated to lung recruitability and changes in regional tidal volume. Conclusions In patients with ARDS, higher PEEP optimizes the distribution of both ventilation (in the non-dependent areas) and perfusion (in the middle and dependent lung). Bedside measure of recruitability is associated with improved $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch.

BackgroundUnilateral ligation of the pulmonary artery (UPAL) induces bilateral lung injury in pigs undergoing controlled mechanical ventilation. Possible mechanisms include redistribution of ventilation toward the non-ligated lung and hypoperfusion of the ligated lung. The addition of 5% CO2 to the inspiratory gas (FiCO2) prevents the injury, but it is not clear whether lung protection is a direct effect of CO2 inhalation or it is mediated by plasmatic hypercapnia. This study aims to compare the effects and mechanisms of FiCO2vs. hypercapnia induced by low tidal volume ventilation or instrumental dead space.MethodsHealthy pigs underwent left UPAL and were allocated for 48 h to the following: Volume-controlled ventilation (VCV) with VT 10 ml/kg (injury, n = 6); VCV plus 5% FiCO2 (FiCO2, n = 7); VCV with VT 6 ml/kg (low VT, n = 6); VCV plus additional circuit dead space (instrumental VD, n = 6). Histological score, regional compliance, wet-to-dry ratio, and inflammatory infiltrate were assessed to evaluate lung injury at the end of the study. To investigate the mechanisms of protection, we quantified the redistribution of ventilation to the non-ligated lung, as the ratio between the percentage of tidal volume to the right and to the left lung (VTRIGHT/LEFT), and the hypoperfusion of the ligated lung as the percentage of blood flow reaching the left lung (PerfusionLEFT).ResultsIn the left ligated lung, injury was prevented only in the FiCO2 group, as indicated by lower histological score, higher regional compliance, lower wet-to-dry ratio and lower density of inflammatory cells compared to other groups. For the right lung, the histological score was lower both in the FiCO2 and in the low VT groups, but the other measures of injury showed lower intensity only in the FiCO2 group. VTRIGHT/LEFT was lower and PerfusionLEFT was higher in the FiCO2 group compared to other groups.ConclusionIn a model of UPAL, inhaled CO2 but not hypercapnia grants bilateral lung protection. Mechanisms of protection include reduced overdistension of the non-ligated and increased perfusion of the ligated lung.

Background Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant. Research Question Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study Design and Methods We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm H2O for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days. Results Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, –7%; 95% CI, –18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group. Interpretation Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk. Trial Registry ClinicalTrials.gov ; No.: NCT03201263 ; URL: www.clinicaltrials.gov

Rationale: Unilateral ligation of the pulmonary artery may induce lung injury through multiple mechanisms, which might be dampened by inhaled CO2. Objectives: This study aims to characterize bilateral lung injury owing to unilateral ligation of the pulmonary artery in healthy swine undergoing controlled mechanical ventilation and its prevention by 5% CO2 inhalation and to investigate relevant pathophysiological mechanisms. Methods: Sixteen healthy pigs were allocated to surgical ligation of the left pulmonary artery (ligation group), seven to surgical ligation of the left pulmonary artery and inhalation of 5% CO2 (ligation + FiCO2 5%), and six to no intervention (no ligation). Then, all animals received mechanical ventilation with Vt 10 ml/kg, positive end-expiratory pressure 5 cm H2O, respiratory rate 25 breaths/min, and FiO2 50% (±FiCO2 5%) for 48 hours or until development of severe lung injury. Measurements and Main Results: Histological, physiological, and quantitative computed tomography scan data were compared between groups to characterize lung injury. Electrical impedance tomography and immunohistochemistry analysis were performed in a subset of animals to explore mechanisms of injury. Animals from the ligation group developed bilateral lung injury as assessed by significantly higher histological score, larger increase in lung weight, poorer oxygenation, and worse respiratory mechanics compared with the ligation + FiCO2 5% group. In the ligation group, the right lung received a larger fraction of Vt and inflammation was more represented, whereas CO2 dampened both processes. Conclusions: Mechanical ventilation induces bilateral lung injury within 48 hours in healthy pigs undergoing left pulmonary artery ligation. Inhalation of 5% CO2 prevents injury, likely through decreased stress to the right lung and antiinflammatory effects.

Unilateral ligation of the pulmonary artery (UPAL) induces bilateral lung injury in pigs undergoing controlled mechanical ventilation. Possible mechanisms include redistribution of ventilation toward the non-ligated lung and hypoperfusion of the ligated lung. The addition of 5% COHealthy pigs underwent left UPAL and were allocated for 48 h to the following: Volume-controlled ventilation (VCV) with VIn the left ligated lung, injury was prevented only in the FiCOIn a model of UPAL, inhaled CO

Objectives Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. Design Prospective randomized controlled trial. Setting ICUs of two Italian referral extracorporeal membrane oxygenation centers. Patients Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. Interventions Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. Measurements and main results The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. Conclusions Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

Neural respiratory drive, i.e., the activity of respiratory centres controlling breathing, is an overlooked physiologic variable which affects the pathophysiology and the clinical outcome of acute respiratory distress syndrome (ARDS). Spontaneous breathing may offer multiple physiologic benefits in these patients, including decreased need for sedation, preserved diaphragm activity and improved cardiovascular function. However, excessive effort to breathe due to high respiratory drive may lead to patient self-inflicted lung injury (P-SILI), even in the absence of mechanical ventilation. In the present review, we focus on the physiological and clinical implications of control of respiratory drive in ARDS patients. We summarize the main determinants of neural respiratory drive and the mechanisms involved in its potentiation, in health and ARDS. We also describe potential and pitfalls of the available bedside methods for drive assessment and explore classical and more “futuristic” interventions to control drive in ARDS patients.

Background In acute respiratory distress syndrome (ARDS), response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP based on patients’ individual response is warranted. End-expiratory lung volume (EELV) assessment by nitrogen washin-washout aids bedside estimation of PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient’s individual recruitability. We designed a randomized trial to test whether an individualized PEEP setting protocol driven by EELV measurement may improve a composite clinical outcome in patients with moderate-to-severe ARDS (IPERPEEP trial). Methods IPERPEEP is an open-label, multicenter, randomized trial that will be conducted in 10 intensive care units in Italy and will enroll 132 ARDS patients showing PaO2/FiO2 ratio ≤ 150 mmHg within 24 h from endotracheal intubation while on mechanical ventilation with PEEP 5 cmH2O. To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume of 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O for 30 min (EXPRESS PEEP). Afterwards, a 5-step decremental PEEP trial will be conducted (EXPRESS PEEP to PEEP 5 cmH2O), and EELV will be measured at each step. Recruitment-to-inflation ratio will be calculated for each PEEP range from EELV difference. Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or to achieve a plateau pressure of 28–30 cmH2O (control arm, EXPRESS strategy). In both groups, tidal volume size, use of prone positioning and neuromuscular blocking agents, and weaning from PEEP and from mechanical ventilation will be standardized. The primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator-free days, and serum interleukin-6 concentration over the course of the initial 72 h of treatment. Discussion The IPERPEEP study is a randomized trial powered to elucidate whether an individualized PEEP setting protocol based on bedside assessment of lung recruitability can improve a composite clinical outcome during moderate-to-severe ARDS. Trial registration ClinicalTrials.govNCT04012073. Registered 9 July 2019.

Since its very first description, understanding the acute respiratory distress syndrome (ARDS) has been a major research and clinical challenge due to heterogeneity in causes, manifestations, physiologic derangements and response to treatment. Recently, growing evidences on the mechanisms underlying ARDS pathophysiology and randomized trials yielding negative results generated a worldwide collaborative effort to define more homogenous subgroups of ARDS subjects and titrate personalized interventions. A recently published trial (the LIVE study) tried to maximize this effort and compared for the first time personalized vs. conventional protective ventilation strategies (1). In the present article, we describe how ventilation in ARDS could be personalized based on sound pathophysiological subgroups and comment the results from the LIVE study.

BackgroundHigh inspiratory flow might damage the lungs by mechanisms not fully understood yet. We hypothesized that increasing inspiratory flow would increase lung stress, ventilation heterogeneity, and pendelluft in ARDS patients undergoing volume-controlled ventilation with constant tidal volume and that higher PEEP levels would reduce this phenomenon.MethodsTen ARDS patients were studied during protective volume-controlled ventilation. Three inspiratory flows (400, 800, and 1200 ml/s) and two PEEP levels (5 and 15 cmH2O) were applied in random order to each patient. Airway and esophageal pressures were recorded, end-inspiratory and end-expiratory holds were performed, and ventilation distribution was measured with electrical impedance tomography. Peak and plateau airway and transpulmonary pressures were recorded, together with the airway and transpulmonary pressure corresponding to the first point of zero end-inspiratory flow (P1). Ventilation heterogeneity was measured by the EIT-based global inhomogeneity (GI) index. Pendelluft was measured as the absolute difference between pixel-level inflation measured at plateau pressure minus P1.ResultsPlateau airway and transpulmonary pressure was not affected by inspiratory flow, while P1 increased at increasing inspiratory flow. The difference between P1 and plateau pressure was higher at higher flows at both PEEP levels (p p = 0.05), irrespective of the PEEP level. Finally, gas volume undergoing pendelluft was larger at higher inspiratory flow (p ConclusionsThe present exploratory analysis suggests that higher inspiratory flow increases additional inspiratory pressure, heterogeneity of ventilation, and pendelluft while PEEP has negligible effects on these flow-dependent phenomena. The clinical significance of these findings needs to be further clarified.

Acute respiratory distress syndrome (ARDS) remains an important clinical challenge with a mortality rate of 35–45%. It is being increasingly demonstrated that the improvement of outcomes requires a tailored, individualized approach to therapy, guided by a detailed understanding of each patient’s pathophysiology. In patients with ARDS, disturbances in the physiological matching of alveolar ventilation (V) and pulmonary perfusion (Q) (V/Q mismatch) are a hallmark derangement. The perfusion of collapsed or consolidated lung units gives rise to intrapulmonary shunting and arterial hypoxemia, whereas the ventilation of non-perfused lung zones increases physiological dead-space, which potentially necessitates increased ventilation to avoid hypercapnia. Beyond its impact on gas exchange, V/Q mismatch is a predictor of adverse outcomes in patients with ARDS; more recently, its role in ventilation-induced lung injury and worsening lung edema has been described. Innovations in bedside imaging technologies such as electrical impedance tomography readily allow clinicians to determine the regional distributions of V and Q, as well as the adequacy of their matching, providing new insights into the phenotyping, prognostication, and clinical management of patients with ARDS. The purpose of this review is to discuss the pathophysiology, identification, consequences, and treatment of V/Q mismatch in the setting of ARDS, employing experimental data from clinical and preclinical studies as support.

Background Experimental and pilot clinical data suggest that spontaneously breathing patients with sepsis and septic shock may present increased respiratory drive and effort, even in the absence of pulmonary infection. The study hypothesis was that respiratory drive and effort may be increased in septic patients and correlated with extrapulmonary determinant and that high-flow nasal cannula may modulate drive and effort. Methods Twenty-five nonintubated patients with extrapulmonary sepsis or septic shock were enrolled. Each patient underwent three consecutive steps: low-flow oxygen at baseline, high-flow nasal cannula, and then low-flow oxygen again. Arterial blood gases, esophageal pressure, and electrical impedance tomography data were recorded toward the end of each step. Respiratory effort was measured as the negative swing of esophageal pressure (ΔPes); drive was quantified as the change in esophageal pressure during the first 500 ms from start of inspiration (P0.5). Dynamic lung compliance was calculated as the tidal volume measured by electrical impedance tomography, divided by ΔPes. The results are presented as medians [25th to 75th percentile]. Results Thirteen patients (52%) were in septic shock. The Sequential Organ Failure Assessment score was 5 [4 to 9]. During low-flow oxygen at baseline, respiratory drive and effort were elevated and significantly correlated with arterial lactate (r = 0.46, P = 0.034) and inversely with dynamic lung compliance (r = –0.735, P < 0.001). Noninvasive support by high-flow nasal cannula induced a significant decrease of respiratory drive (P0.5: 6.0 [4.4 to 9.0] vs. 4.3 [3.5 to 6.6] vs. 6.6 [4.9 to 10.7] cm H2O, P < 0.001) and effort (ΔPes: 8.0 [6.0 to 11.5] vs. 5.5 [4.5 to 8.0] vs. 7.5 [6.0 to 12.6] cm H2O, P < 0.001). Oxygenation and arterial carbon dioxide levels remained stable during all study phases. Conclusions Patients with sepsis and septic shock of extrapulmonary origin present elevated respiratory drive and effort, which can be effectively reduced by high-flow nasal cannula. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Transpulmonary driving pressure (DPL) corresponds to the cyclical stress imposed on the lung parenchyma during tidal breathing and, therefore, can be used to assess the risk of ventilator-induced lung injury (VILI). Its measurement at the bedside requires the use of esophageal pressure (Peso), which is sometimes technically challenging. Recently, it has been demonstrated how in an animal model of ARDS, the transpulmonary pressure (PL) measured with Peso calculated with the absolute values method (PL = Paw—Peso) is equivalent to the transpulmonary pressure directly measured using pleural sensors in the central-dependent part of the lung. We hypothesized that, since the PL derived from Peso reflects the regional behavior of the lung, it could exist a relationship between regional parameters measured by electrical impedance tomography (EIT) and driving PL (DPL). Moreover, we explored if, by integrating airways pressure data and EIT data, it could be possible to estimate non-invasively DPL and consequently lung elastance (EL) and elastance-derived inspiratory PL (PI). We analyzed 59 measurements from 20 patients with ARDS. There was a significant intra-patient correlation between EIT derived regional compliance in regions of interest (ROI1) (r = 0.5, p = 0.001), ROI2 (r = −0.68, p < 0.001), and ROI3 (r = −0.4, p = 0.002), and DPL. A multiple linear regression successfully predicted DPL based on respiratory system elastance (Ers), ideal body weight (IBW), roi1%, roi2%, and roi3% (R2 = 0.84, p < 0.001). The corresponding Bland-Altmann analysis showed a bias of −1.4e-007 cmH2O and limits of agreement (LoA) of −2.4–2.4 cmH2O. EL and PI calculated using EIT showed good agreement (R2 = 0.89, p < 0.001 and R2 = 0.75, p < 0.001) with the esophageal derived correspondent variables. In conclusion, DPL has a good correlation with EIT-derived parameters in the central lung. DPL, PI, and EL can be estimated with good accuracy non-invasively combining information coming from EIT and airway pressure.

Nasal high flow (NHF) is a promising novel oxygen delivery device, whose mechanisms of action offer some beneficial effects over conventional oxygen systems. It is considered to have a number of physiological effects: it improves oxygenation, dynamic lung compliance, homogeneity and end expiratory lung volume; it decreases anatomical dead space and generates a positive airway pressure that can reduce respiratory rate, the work of breathing, and enhance patient comfort. NHF has been used as a prophylactic tool or as a treatment device mostly in patients with acute hypoxemic respiratory failure such as pre-oxygenation before intubation, immunocompromised patients and acute heart failure. Moreover, there is some evidence that NHF could be used during procedural sedation. Finally, NHF was deemed to be effective in chronic obstructive pulmonary disease patients with its positive end expiratory pressure effects and dead-space washout. However, careful monitoring is crucial to maximize NHF settings aimed at maximizing patient comfort while limiting the risk of delayed intubation. The present review presents the most updated evidence for NHF use in the adult acute care setting with the goal of providing clinicians with useful insights on the physiologic effects, main clinical indications, and safety issues of NHF treatment.

Rationale: Reducing the respiratory rate during extracorporeal membrane oxygenation (ECMO) decreases the mechanical power, but it might induce alveolar de-recruitment. Dissecting de-recruitment due to lung edema vs. the fraction due to hypoventilation may be challenging in injured lungs.Objectives: We characterized changes in lung physiology (primary endpoint: development of atelectasis) associated with progressive reduction of the respiratory rate in healthy animals on ECMO.Methods: Six female pigs underwent general anesthesia and volume control ventilation (Baseline: PEEP 5 cmH2O, Vt 10 ml/kg, I:E = 1:2, FiO2 0.5, rate 24 bpm). Veno-venous ECMO was started and respiratory rate was progressively reduced to 18, 12, and 6 breaths per minute (6-h steps), while all other settings remained unchanged. ECMO blood flow was kept constant while gas flow was increased to maintain stable PaCO2.Measurements and Main Results: At Baseline (without ECMO) and toward the end of each step, data from quantitative CT scan, electrical impedance tomography, and gas exchange were collected. Increasing ECMO gas flow while lowering the respiratory rate was associated with an increase in the fraction of non-aerated tissue (i.e., atelectasis) and with a decrease of tidal ventilation reaching the gravitationally dependent lung regions (p = 0.009 and p = 0.018). Intrapulmonary shunt increased (p < 0.001) and arterial PaO2 decreased (p < 0.001) at lower rates. The fraction of non-aerated lung was correlated with longer expiratory time spent at zero flow (r = 0.555, p = 0.011).Conclusions: Progressive decrease of respiratory rate coupled with increasing CO2 removal in mechanically ventilated healthy pigs is associated with development of lung atelectasis, higher shunt, and poorer oxygenation.

Background In acute respiratory distress syndrome (ARDS), non-ventilated perfused regions coexist with non-perfused ventilated regions within lungs. The number of unmatched regions might reflect ARDS severity and affect the risk of ventilation-induced lung injury. Despite pathophysiological relevance, unmatched ventilation and perfusion are not routinely assessed at the bedside. The aims of this study were to quantify unmatched ventilation and perfusion at the bedside by electrical impedance tomography (EIT) investigating their association with mortality in patients with ARDS and to explore the effects of positive end-expiratory pressure (PEEP) on unmatched ventilation and perfusion in subgroups of patients with different ARDS severity based on PaO2/FiO2 and compliance. Methods Prospective observational study in 50 patients with mild (36%), moderate (46%), and severe (18%) ARDS under clinical ventilation settings. EIT was applied to measure the regional distribution of ventilation and perfusion using central venous bolus of saline 5% during end-inspiratory pause. We defined unmatched units as the percentage of only ventilated units plus the percentage of only perfused units. Results Percentage of unmatched units was significantly higher in non-survivors compared to survivors (32[27–47]% vs. 21[17–27]%, p p = 0.004) with an area under the ROC curve of 0.88 (95% CI 0.79–0.97, p p p Higher percentage of only perfused units was correlated with lower dorsal ventilation (r = − 0.486, p 2/FiO2 ratio (r = − 0.293, p = 0.039). Conclusions EIT allows bedside assessment of unmatched ventilation and perfusion in mechanically ventilated patients with ARDS. Measurement of unmatched units could identify patients at higher risk of death and could guide personalized treatment.

Purpose Optimal esophageal balloon filling volume (Vbest) depends on the intrathoracic pressure. During Sigh breath delivered by the ventilator machine, esophageal balloon is surrounded by elevated intrathoracic pressure that might require higher filling volume for accurate measure of tidal changes in esophageal pressure (Pes). The primary aim of our investigation was to evaluate and compare Vbest during volume controlled and pressure support breaths vs. Sigh breath. Materials and methods Twenty adult patients requiring invasive volume-controlled ventilation (VCV) for hypoxemic acute respiratory failure were enrolled. After the insertion of a naso-gastric catheter equipped with 10 ml esophageal balloon, each patient underwent three 30-min trials as follows: VCV, pressure support ventilation (PSV), and PSV + Sigh. Sigh was added to PSV as 35 cmH2O pressure-controlled breath over 4 s, once per minute. PSV and PSV + Sigh were randomly applied and, at the end of each step, esophageal balloon calibration was performed. Results Vbest was higher for Sigh breath (4.5 [3.0–6.8] ml) compared to VCV (1.5 [1.0–2.9] ml, P = 0.0004) and PSV tidal breath (1.0 [0.5–2.4] ml, P Conclusions During Sigh breath, applying a calibrated approach for Pes assessment, a higher Vbest was required compared to VCV and PSV tidal breath.

Swings of central venous pressure (ΔCVP) may reflect those of pleural and esophageal (ΔPES) pressure and, therefore, the strength of inspiration. Strong inspiratory efforts can produce some harm. Herein we preliminarily assessed the diagnostic accuracy of ΔCVP for strong inspiratory efforts in critically-ill subjects breathing spontaneously.We measured ΔCVP and ΔPES in 48 critically-ill subjects breathing spontaneously with zero end-expiratory pressure (ZEEP) or 10 cmHinf2/infO of continuous positive airway pressure (CPAP). The overall diagnostic accuracy of ΔCVP for strong inspiratory efforts (arbitrarily defined as ΔPES8 mmHg) was described as the area under the receiver operating characteristic (ROC) curve, with 0.50 indicating random guess. The agreement between ΔCVP and ΔPES was assessed with the Bland-Altman analysis.ΔCVP recognized strong inspiratory efforts with an area under the ROC curve of 0.95 (95% confidence intervals, 0.85-0.99) with ZEEP and 0.89 (0.76-0.96) with CPAP, both significantly larger than 0.50 (P0.001). With the best cut-off value around 8 mmHg, the diagnostic accuracy of ΔCVP was 0.92 (0.80-0.98) with ZEEP and 0.94 (0.83-0.99) with CPAP. With ZEEP, the median difference between ΔCVP and ΔPES (bias) was -0.2 mmHg, and the 95% limits of agreement (LoA) were -3.9 and +5.5 mmHg. With CPAP, bias was -0.1 mmHg, and 95%-LoA were -5.8 and +4.5 mmHg. In both cases, ΔCVP correlated with ΔPES (rinfs/inf0.81 and 0.67; P0.001 for both).In critically-ill subjects breathing spontaneously, ΔCVP recognized strong inspiratory efforts with acceptable accuracy. Even so, it sometimes largely differed from ∆PES.

Background Nasal high flow delivered at flow rates higher than 60 L/min in patients with acute hypoxemic respiratory failure might be associated with improved physiological effects. However, poor comfort might limit feasibility of its clinical use. Methods We performed a prospective randomized cross-over physiological study on 12 ICU patients with acute hypoxemic respiratory failure. Patients underwent three steps at the following gas flow: 0.5 L/kg PBW/min, 1 L/kg PBW/min, and 1.5 L/kg PBW/min in random order for 20 min. Temperature and FiO2 remained unchanged. Toward the end of each phase, we collected arterial blood gases, lung volumes, and regional distribution of ventilation assessed by electrical impedance tomography (EIT), and comfort. Results In five patients, the etiology was pulmonary; infective disease characterized seven patients; median PaO2/FiO2 at enrollment was 213 [IQR 136–232]. The range of flow rate during NHF 1.5 was 75–120 L/min. PaO2/FiO2 increased with flow, albeit non significantly (p = 0.064), PaCO2 and arterial pH remained stable (p = 0.108 and p = 0.105). Respiratory rate decreased at higher flow rates (p = 0.014). Inhomogeneity of ventilation decreased significantly at higher flows (p = 0.004) and lung volume at end-expiration significantly increased (p = 0.007), but mostly in the non-dependent regions. Comfort was significantly poorer during the step performed at the highest flow (p Conclusions NHF delivered at rates higher than 60 L/min in critically ill patients with acute hypoxemic respiratory failure is associated with reduced respiratory rate, increased lung homogeneity, and additional positive pressure effect, but also with worse comfort.

Background The physiological behavior of lungs affected by the acute respiratory distress syndrome (ARDS) differs between inspiration and expiration and presents heterogeneous gravity-dependent distribution. This phenomenon, highlighted by the different distribution of opening/closing pressure and by the hysteresis of the pressure–volume curve, can be studied by CT scan, but the technique expose the patient to radiations, cannot track changes during time and is not feasible at the bedside. Electrical impedance tomography (EIT) could help in assessing at the bedside regional inspiratory and expiratory mechanical properties. We evaluated regional opening/closing pressures, hysteresis and atelectrauma during inspiratory and expiratory low-flow pressure–volume curves in ARDS using electrical impedance tomography. Methods Pixel-level inspiratory and expiratory PV curves (PVpixel) between 5 and 40 cmH2O were constructed integrating EIT images and airway opening pressure signal from 8 ARDS patients. The lower inflection point in the inspiratory and expiratory PVpixel were used to find opening (OPpixel) and closing (CPpixel) pressures. A novel atelectrauma index (AtI) was calculated as the percentage of pixels opening during the inspiratory and closing during the expiratory PV curves. The maximal hysteresis (HysMax) was calculated as the maximal difference between normalized expiratory and inspiratory PV curves. Analyses were conducted in the global, dependent and non-dependent lung regions. Results Gaussian distribution was confirmed for both global OPpixel (r2 = 0.90) and global CPpixel (r2 = 0.94). The two distributions were significantly different with higher values for OPpixel (p pixel and CPpixel distributions were Gaussian, and in the dependent lung regions, both were significantly higher than in the non-dependent ones (p Conclusions Gravity impacts the regional distribution of opening and closing pressure, hysteresis and atelectrauma, with higher values in the dorsal lung. Regional differences between inspiratory and expiratory lung physiology are detectable at the bedside using EIT and could allow in-depth characterization of ARDS phenotypes and guide personalized ventilation settings. Graphic abstract