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Assessing the respiratory system of a patient receiving mechanical ventilation is complex. We provide an overview of an approach at the bedside underpinned by physiology. We discuss the importance of distinguishing between extensive and intensive ventilatory variables. We outline methods to evaluate both passive patients and those making spontaneous respiratory efforts during assisted ventilation. We believe a comprehensive assessment can influence setting mechanical ventilatory support to achieve lung and diaphragm protective ventilation.

Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a supportive therapy for acute respiratory failure with increased risk of packed red blood cells (PRBC) transfusion. Blood cell salvage (BCS) aims to reduce blood transfusion, but its efficacy is unclear. This study aimed to estimate the effect of BCS at the time of removal of the ECMO circuit (ECMO decannulation) on PRBC transfused., Methods: To compare BCS to non-blood cell salvage (n-BCS), we conducted an emulated trial of patients at two ECMO centres in the United Kingdom. We used inverse propensity of treatment weighting to control for confounding and estimated the average treatment effect of BCS on PRBC transfused within two days of decannulation, and on changes in haemoglobin (Hb)., Results: We included 841 patients who underwent VV-ECMO decannulation. The estimated marginal mean number of PRBC transfused when using BCS was 0·2 (95%CI: 0·16, 0·25) units compared to 0·51 (95%CI: 0·44, 0·59) units with n-BCS; an average treatment effect of -0·31 (95%CI: -0·40, -0·22) units. BCS reduced the risk of receiving any PRBC transfusion by 17·1% (95%CI: 11·1%, 22·9%) equating to a number needed to treat for any PRBC transfusion of 6 (95%CI: 5, 9). The difference in expected Hb levels after decannulation between BCS and n-BCS was 5·0 (95%CI: 4·2, 5·8) g/L., Conclusions: The use of BCS during VV-ECMO decannulation may be an effective strategy to augment haemoglobin levels and reduce PRBC transfusions., Competing Interests: Declarations. Competing interests: RHK received funding from UK Research and Innovation through the Future Leaders Fellowship (MR/S017968/1, MR/X015017/1), with payments made to the London School of Hygiene & Tropical Medicine (LSHTM). BVP participated in the Data Safety Monitoring Board for Novartis and received speaker fees from Medtronic. LR received funding from NIHR and ICS, speaker fees from Dräger Medical, and participated in the Data Safety Monitoring Board for Hamilton Medical. AR is the Chief Medical Officer at Volition Diagnostics Limited, a diagnostic start-up. LG received consulting fees and speaker fees from General Electric, Kures, and Sidam, and participated in the Data Safety Monitoring Board for Grifols. DFM received grants from NIHR, Innovate UK, MRC, Novavax, Northern Ireland HSC R&D division, Randox, Wellcome Trust, and Queen’s University Belfast. He collaborates with Bayer, Aptarion, Direct Biologics, Aviceda, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, and SOBI. He also received speaker fees from GlaxoSmithKline and participated in the Data Safety Monitoring Board for Vir Biotechnology, Inc. and Faron Pharmaceuticals. DFM is the Co-director of Research for the Intensive Care Society, Director of the EME Programme for MRC and NIHR, and Scientific Director for NIHR Programmes. All other authors reported no conflicts of interest., (© 2024. The Author(s).)

During veno-venous extracorporeal membrane oxygenation (V-V ECMO), blood is drained from the central venous circulation to be oxygenated and decarbonated by an artificial lung. It is then reinfused into the right heart and pulmonary circulation where further gas-exchange occurs. Each of these steps is characterized by a peculiar physiology that this manuscript analyses, with the aim of providing bedside tools for clinical care: we begin by describing the factors that affect the efficiency of blood drainage, such as patient and cannulae position, fluid status, cardiac output and ventilatory strategies. We then dig into the complexity of extracorporeal gas-exchange, with particular reference to the effects of extracorporeal blood-flow (ECBF), fraction of delivered oxygen (FdO2) and sweep gas-flow (SGF) on oxygenation and decarbonation. Subsequently, we focus on the reinfusion of arterialized blood into the right heart, highlighting the effects on recirculation and, more importantly, on right ventricular function. The importance and challenges of haemodynamic monitoring during V-V ECMO are also analysed. Finally, we detail the interdependence between extracorporeal circulation, native lung function and mechanical ventilation in providing adequate arterial blood gases while allowing lung rest. In the absence of evidence-based strategies to care for this particular group of patients, clinical practice is underpinned by a sound knowledge of the intricate physiology of V-V ECMO., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the authorship, and/or publication of this article.

It is commonly assumed that changes in plasma strong ion difference (SID) result in equal changes in whole blood base excess (BE). However, at varying pH, albumin ionic-binding and transerythrocyte shifts alter the SID of plasma without affecting that of whole blood (SID wb ), i.e., the BE. We hypothesize that, during acidosis, 1 ) an expected plasma SID (SID exp ) reflecting electrolytes redistribution can be predicted from albumin and hemoglobin's charges, and 2 ) only deviations in SID from SID exp reflect changes in SID wb , and therefore, BE. We equilibrated whole blood of 18 healthy subjects (albumin = 4.8 ± 0.2 g/dL, hemoglobin = 14.2 ± 0.9 g/dL), 18 septic patients with hypoalbuminemia and anemia (albumin = 3.1 ± 0.5 g/dL, hemoglobin = 10.4 ± 0.8 g/dL), and 10 healthy subjects after in vitro-induced isolated anemia (albumin = 5.0 ± 0.2 g/dL, hemoglobin = 7.0 ± 0.9 g/dL) with varying CO 2 concentrations (2-20%). Plasma SID increased by 12.7 ± 2.1, 9.3 ± 1.7, and 7.8 ± 1.6 mEq/L, respectively ( P < 0.01) and its agreement (bias[limits of agreement]) with SID exp was strong: 0.5[-1.9; 2.8], 0.9[-0.9; 2.6], and 0.3[-1.4; 2.1] mEq/L, respectively. Separately, we added 7.5 or 15 mEq/L of lactic or hydrochloric acid to whole blood of 10 healthy subjects obtaining BE of -6.6 ± 1.7, -13.4 ± 2.2, -6.8 ± 1.8, and -13.6 ± 2.1 mEq/L, respectively. The agreement between ΔBE and ΔSID was weak (2.6[-1.1; 6.3] mEq/L), worsening with varying CO 2 (2-20%): 6.3[-2.7; 15.2] mEq/L. Conversely, ΔSID wb (the deviation of SID from SID exp ) agreed strongly with ΔBE at both constant and varying CO 2 : -0.1[-2.0; 1.7], and -0.5[-2.4; 1.5] mEq/L, respectively. We conclude that BE reflects only changes in plasma SID that are not expected from electrolytes redistribution, the latter being predictable from albumin and hemoglobin's charges. NEW & NOTEWORTHY This paper challenges the assumed equivalence between changes in plasma strong ion difference (SID) and whole blood base excess (BE) during in vitro acidosis. We highlight that redistribution of strong ions, in the form of albumin ionic-binding and transerythrocyte shifts, alters SID without affecting BE. We demonstrate that these expected SID alterations are predictable from albumin and hemoglobin's charges, or from the noncarbonic whole blood buffer value, allowing a better interpretation of SID and BE during in vitro acidosis.

Background: Despite the fervent scientific effort, a state-of-the art assessment of the different causes of hypoxemia (shunt, ventilation-perfusion mismatch, and diffusion limitation) in COVID-19 acute respiratory distress syndrome (ARDS) is currently lacking. In this study, the authors hypothesized a multifactorial genesis of hypoxemia and aimed to measure the relative contribution of each of the different mechanism and their relationship with the distribution of tissue and blood within the lung., Methods: In this cross-sectional study, the authors prospectively enrolled 10 patients with COVID-19 ARDS who had been intubated for less than 7 days. The multiple inert gas elimination technique (MIGET) and a dual-energy computed tomography (DECT) were performed and quantitatively analyzed for both tissue and blood volume. Variables related to the respiratory mechanics and invasive hemodynamics (PiCCO [Getinge, Sweden]) were also recorded., Results: The sample (51 ± 15 yr; Pao2/Fio2, 172 ± 86 mmHg) had a mortality of 50%. The MIGET showed a shunt of 25 ± 16% and a dead space of 53 ± 11%. Ventilation and perfusion were mismatched (LogSD, Q, 0.86 ± 0.33). Unexpectedly, evidence of diffusion limitation or postpulmonary shunting was also found. In the well aerated regions, the blood volume was in excess compared to the tissue, while the opposite happened in the atelectasis. Shunt was proportional to the blood volume of the atelectasis (R2 = 0.70, P = 0.003). V˙A/Q˙T mismatch was correlated with the blood volume of the poorly aerated tissue (R2 = 0.54, P = 0.016). The overperfusion coefficient was related to Pao2/Fio2 (R2 = 0.66, P = 0.002), excess tissue mass (R2 = 0.84, P < 0.001), and Etco2/Paco2 (R2 = 0.63, P = 0.004)., Conclusions: These data support the hypothesis of a highly multifactorial genesis of hypoxemia. Moreover, recent evidence from post-mortem studies (i.e., opening of intrapulmonary bronchopulmonary anastomosis) may explain the findings regarding the postpulmonary shunting. The hyperperfusion might be related to the disease severity., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Monitoring the patient receiving veno-venous extracorporeal membrane oxygenation (VV ECMO) is challenging due to the complex physiological interplay between native and membrane lung. Understanding these interactions is essential to understand the utility and limitations of different approaches to respiratory monitoring during ECMO. We present a summary of the underlying physiology of native and membrane lung gas exchange and describe different tools for titrating and monitoring gas exchange during ECMO. However, the most important role of VV ECMO in severe respiratory failure is as a means of avoiding further ergotrauma. Although optimal respiratory management during ECMO has not been defined, over the last decade there have been advances in multimodal respiratory assessment which have the potential to guide care. We describe a combination of imaging, ventilator-derived or invasive lung mechanic assessments as a means to individualise management during ECMO., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Several studies explored the interdependence between Paco2 and bicarbonate during respiratory acid-base derangements. The authors aimed to reframe the bicarbonate adaptation to respiratory disorders according to the physical-chemical approach, hypothesizing that (1) bicarbonate concentration during respiratory derangements is associated with strong ion difference; and (2) during acute respiratory disorders, strong ion difference changes are not associated with standard base excess., Methods: This is an individual participant data meta-analysis from multiple canine and human experiments published up to April 29, 2021. Studies testing the effect of acute or chronic respiratory derangements and reporting the variations of Paco2, bicarbonate, and electrolytes were analyzed. Strong ion difference and standard base excess were calculated., Results: Eleven studies were included. Paco2 ranged between 21 and 142 mmHg, while bicarbonate and strong ion difference ranged between 12.3 and 43.8 mM, and 32.6 and 60.0 mEq/l, respectively. Bicarbonate changes were linearly associated with the strong ion difference variation in acute and chronic respiratory derangement (β-coefficient, 1.2; 95% CI, 1.2 to 1.3; P < 0.001). In the acute setting, sodium variations justified approximately 80% of strong ion difference change, while a similar percentage of chloride variation was responsible for chronic adaptations. In the acute setting, strong ion difference variation was not associated with standard base excess changes (β-coefficient, -0.02; 95% CI, -0.11 to 0.07; P = 0.719), while a positive linear association was present in chronic studies (β-coefficient, 1.04; 95% CI, 0.84 to 1.24; P < 0.001)., Conclusions: The bicarbonate adaptation that follows primary respiratory alterations is associated with variations of strong ion difference. In the acute phase, the variation in strong ion difference is mainly due to sodium variations and is not paralleled by modifications of standard base excess. In the chronic setting, strong ion difference changes are due to chloride variations and are mirrored by standard base excess., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: in COVID-19 acute respiratory failure, the effects of CPAP and FiO 2 on respiratory effort and lung stress are unclear. We hypothesize that, in the compliant lungs of early Sars-CoV-2 pneumonia, the application of positive pressure through Helmet-CPAP may not decrease respiratory effort, and rather worsen lung stress and oxygenation when compared to higher FiO 2 delivered via oxygen masks., Methods: In this single-center (S.Luigi Gonzaga University-Hospital, Turin, Italy), randomized, crossover study, we included patients receiving Helmet-CPAP for early (< 48 h) COVID-19 pneumonia without additional cardiac or respiratory disease. Healthy subjects were included as controls. Participants were equipped with an esophageal catheter, a non-invasive cardiac output monitor, and an arterial catheter. The protocol consisted of a random sequence of non-rebreather mask (NRB), Helmet-CPAP (with variable positive pressure and FiO 2 ) and Venturi mask (FiO 2 0.5), each delivered for 20 min. Study outcomes were changes in respiratory effort (esophageal swing), total lung stress (dynamic + static transpulmonary pressure), gas-exchange and hemodynamics., Results: We enrolled 28 COVID-19 patients and 7 healthy controls. In all patients, respiratory effort increased from NRB to Helmet-CPAP (5.0 ± 3.7 vs 8.3 ± 3.9 cmH 2 O, p < 0.01). However, Helmet's pressure decreased by a comparable amount during inspiration (- 3.1 ± 1.0 cmH 2 O, p = 0.16), therefore dynamic stress remained stable (p = 0.97). Changes in static and total lung stress from NRB to Helmet-CPAP were overall not significant (p = 0.07 and p = 0.09, respectively), but showed high interpatient variability, ranging from - 4.5 to + 6.1 cmH 2 O, and from - 5.8 to + 5.7 cmH 2 O, respectively. All findings were confirmed in healthy subjects, except for an increase in dynamic stress (p < 0.01). PaO 2 decreased from NRB to Helmet-CPAP with FiO 2 0.5 (107 ± 55 vs 86 ± 30 mmHg, p < 0.01), irrespective of positive pressure levels (p = 0.64). Conversely, with Helmet's FiO 2 0.9, PaO 2 increased (p < 0.01), but oxygen delivery remained stable (p = 0.48) as cardiac output decreased (p = 0.02). When PaO 2 fell below 60 mmHg with VM, respiratory effort increased proportionally (p < 0.01, r = 0.81)., Conclusions: In early COVID-19 pneumonia, Helmet-CPAP increases respiratory effort without altering dynamic stress, while the effects upon static and total stress are variable, requiring individual assessment. Oxygen masks with higher FiO 2 provide better oxygenation with lower respiratory effort. Trial registration Retrospectively registered (13-May-2021): clinicaltrials.gov (NCT04885517), https://clinicaltrials.gov/ct2/show/NCT04885517 ., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

Background: Data on the prevalence and clinical impact of extrapulmonary findings at screening computed tomography (CT) on initiation of veno-venous extracorporeal membrane oxygenation (V-V ECMO) are limited. We aimed to identify the prevalence of extrapulmonary findings on screening CT following V-V ECMO initiation. We hypothesized that extrapulmonary findings would influence clinical management and outcome., Methods: Retrospective analysis (2011-2021) of admission screening CT including head, abdomen and pelvis with contrast of consecutive patients on initiation of V-V ECMO. CT findings identified by the attending consultant radiologist were extracted. Demographics, admission physiological and laboratory data, clinical decision-making following CT and ECMO ICU mortality were recorded from the electronic medical record. We used multivariable logistic regression and Kaplan-Meier curves to evaluate associations between extrapulmonary findings and ECMO ICU mortality., Results: Of the 833 patients receiving V-V ECMO, 761 underwent routine admission CT (91.4%). ECMO ICU length of stay was 19 days (IQR 12-23); ICU mortality at the ECMO centre was 18.9%. An incidental extrapulmonary finding was reported in 227 patients (29.8%), leading to an invasive procedure in 12/227 cases (5.3%) and a change in medical management (mainly in anticoagulation strategy) in 119/227 (52.4%). Extrapulmonary findings associated with mortality were intracranial haemorrhage (OR 2.34 (95% CI 1.31-4.12), cerebral infarction (OR 3.59 (95% CI 1.26-9.86) and colitis (OR 2.80 (95% CI 1.35-5.67)., Conclusions: Screening CT frequently identifies extrapulmonary findings of clinical significance. Newly detected intracranial haemorrhage, cerebral infarction and colitis were associated with increased ICU mortality., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

In this retrospective observational cohort study, we aimed to describe the rate of extracorporeal membrane oxygenation (ECMO) circuit change, the associated risk factors and its relationship with patient characteristics and outcome in patients receiving venovenous (VV) ECMO at our center between January 2015 and November 2017. Twenty-seven percent of the patients receiving VV ECMO (n = 224) had at least one circuit change, which was associated with lower ICU survival (68% vs 82% p=0.032) and longer ICU stay (30 vs . 17 days p < 0.001). Circuit duration was similar when stratified by gender, clinical severity, or prior circuit change. Hematological abnormalities and increased transmembrane lung pressure (TMLP) were the most frequent indication for circuit change. The change in transmembrane lung resistance (Δ TMLR) gave better prediction of circuit change than TMLP, TMLR, or ΔTMLP. Low postoxygenator PO 2 was indicated as a reason for one-third of the circuit changes. However, the ECMO oxygen transfer was significantly higher in cases of circuit change with documented "low postoxygenator PO 2 " than those without (244 ± 62 vs. 200 ± 57 ml/min; p = 0.009). The results suggest that circuit change in VV ECMO is associated with worse outcomes, that the Δ TMLR is a better predictor of circuit change than TMLP, and that the postoxygenator PO 2 is an unreliable proxy for the oxygenator function., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

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., (© 2023. The Author(s).)

Rationale: Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) is based on oxygenation and not on carbon dioxide elimination. Objectives: To predict readiness to wean from VV-ECMO. Methods: In this multicenter study of mechanically ventilated adults with severe acute respiratory distress syndrome receiving VV-ECMO, we investigated a variable based on CO 2 elimination. The study included a prospective interventional study of a physiological cohort ( n  = 26) and a retrospective clinical cohort ( n  = 638). Measurements and Main Results: Weaning failure in the clinical and physiological cohorts were 37% and 42%, respectively. The main cause of failure in the physiological cohort was high inspiratory effort or respiratory rate. All patients exhaled similar amounts of CO 2 , but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the Pa CO 2 unchanged. The effort to eliminate one unit-volume of CO 2 , was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H 2 O/[L/min]; P  = 0.007), owing to the higher physiological Vd (68 [58.73] % vs. 54 [41.64] %; P  = 0.012). End-tidal partial carbon dioxide pressure (Pet CO 2 )/Pa CO 2 ratio was a clinical variable strongly associated with weaning outcome at baseline, with area under the receiver operating characteristic curve of 0.87 (95% confidence interval [CI], 0.71-1). Similarly, the Pet CO 2 /Pa CO 2 ratio was associated with weaning outcome in the clinical cohort both before the weaning trial (odds ratio, 4.14; 95% CI, 1.32-12.2; P  = 0.015) and at a sweep gas flow of zero (odds ratio, 13.1; 95% CI, 4-44.4; P  < 0.001). Conclusions: The primary reason for weaning failure from VV-ECMO is high effort to eliminate CO 2 . A higher Pet CO 2 /Pa CO 2 ratio was associated with greater likelihood of weaning from VV-ECMO.

The extent of ventilator-induced lung injury may be related to the intensity of mechanical ventilation--expressed as mechanical power. In the present study, we investigated whether there is a safe threshold, below which lung damage is absent. Three groups of six healthy pigs (29.5 ± 2.5 kg) were ventilated prone for 48 h at mechanical power of 3, 7, or 12 J/min. Strain never exceeded 1.0. PEEP was set at 4 cmH 2 O. Lung volumes were measured every 12 h; respiratory, hemodynamics, and gas exchange variables every 6. End-experiment histological findings were compared with a control group of eight pigs which did not undergo mechanical ventilation. Functional residual capacity decreased by 10.4% ± 10.6% and 8.1% ± 12.1% in the 7 J and 12 J groups (p = 0.017, p < 0.001) but not in the 3 J group (+1.7% ± 17.7%, p = 0.941). In 3 J group, lung elastance, PaO 2 and PaCO 2 were worse compared to 7 J and 12 J groups (all p < 0.001), due to lower ventilation-perfusion ratio (0.54 ± 0.13, 1.00 ± 0.25, 1.78 ± 0.36 respectively, p < 0.001). The lung weight was lower (p < 0.001) in the controls (6.56 ± 0.90 g/kg) compared to 3, 7, and 12 J groups (12.9 ± 3.0, 16.5 ± 2.9, and 15.0 ± 4.1 g/kg, respectively). The wet-to-dry ratio was 5.38 ± 0.26 in controls, 5.73 ± 0.52 in 3 J, 5.99 ± 0.38 in 7 J, and 6.13 ± 0.59 in 12 J group (p = 0.03). Vascular congestion was more extensive in the 7 J and 12 J compared to 3 J and control groups. Mechanical ventilation (with anesthesia/paralysis) increase lung weight, and worsen lung histology, regardless of the mechanical power. Ventilating at 3 J/min led to better anatomical variables than at 7 and 12 J/min but worsened the physiological values., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Inflammation and oxidative stress characterize sepsis and determine its severity. In this study, we investigated the relationship between albumin oxidation and sepsis severity in a selected cohort of patients from the Albumin Italian Outcome Study (ALBIOS). A retrospective analysis was conducted on the oxidation forms of human albumin [human mercapto-albumin (HMA), human non-mercapto-albumin form 1 (HNA1) and human non-mercapto-albumin form 2 (HNA2)] in 60 patients with severe sepsis or septic shock and 21 healthy controls. The sepsis patients were randomized (1:1) to treatment with 20% albumin and crystalloid solution or crystalloid solution alone. The albumin oxidation forms were measured at day 1 and day 7. To assess the albumin oxidation forms as a function of oxidative stress, the 60 sepsis patients, regardless of the treatment, were grouped based on baseline sequential organ failure assessment (SOFA) score as surrogate marker of oxidative stress. At day 1, septic patients had significantly lower levels of HMA and higher levels of HNA1 and HNA2 than healthy controls. HMA and HNA1 concentrations were similar in patients treated with albumin or crystalloids at day 1, while HNA2 concentration was significantly greater in albumin-treated patients ( p < 0.001). On day 7, HMA was significantly higher in albumin-treated patients, while HNA2 significantly increased only in the crystalloids-treated group, reaching values comparable with the albumin group. When pooling the septic patients regardless of treatment, albumin oxidation was similar across all SOFA groups at day 1, but at day 7 HMA was lower at higher SOFA scores. Mortality rate was independently associated with albumin oxidation levels measured at day 7 (HMA log-rank = 0.027 and HNA2 log-rank = 0.002), irrespective of treatment group. In adjusted regression analyses for 90-day mortality, this effect remained significant for HMA and HNA2. Our data suggest that the oxidation status of albumin is modified according to the time of exposure to oxidative stress (differences between day 1 and day 7). After 7 days of treatment, lower SOFA scores correlate with higher albumin antioxidant capacity. The trend toward a positive effect of albumin treatment, while not statistically significant, warrants further investigation., Competing Interests: MC, FM, and AP are full-time employees of Grifols, a manufacturer of plasma derivatives. Grifols had no access to clinical data from ALBIOS and did not perform statistical analyses of data, but only provided editorial support. Publication costs of this manuscript were sustained by Grifols. LG and PC received honoraria from Grifols., (Copyright © 2021 Bonifazi, Meessen, Pérez, Vasques, Busana, Vassalli, Novelli, Bernasconi, Signori, Masson, Romitti, Giosa, Macrì, Pasticci, Palumbo, Mota, Costa, Caironi, Latini, Quintel and Gattinoni.)

COVID-19 infection may lead to acute respiratory distress syndrome (CARDS) where severe gas exchange derangements may be associated, at least in the early stages, only with minor pulmonary infiltrates. This may suggest that the shunt associated to the gasless lung parenchyma is not sufficient to explain CARDS hypoxemia. We designed an algorithm (Vent ri Q lar ), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation-perfusion (V A /Q) compartments and, after calculating their blood composition (PO 2 , PCO 2 , and pH), we randomly chose 10 6 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO 2 and PaCO 2 were within 10% of the patient's values. We assumed that the shunt fraction equaled the fraction of non-aerated lung tissue at the CT quantitative analysis. Five critically-ill patients later deceased were studied. The PaO 2 /FiO 2 was 91.1 ± 18.6 mmHg and PaCO 2 69.0 ± 16.1 mmHg. Cardiac output was 9.58 ± 0.99 L/min. The fraction of non-aerated tissue was 0.33 ± 0.06. The model showed that a large fraction of the blood flow was likely distributed in regions with very low V A /Q (Q mean  = 0.06 ± 0.02) and a smaller fraction in regions with moderately high V A /Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high V A /Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant V A /Q inequality must be present in COVID-19. The high cardiac output and the extensive microthrombosis later found in the autopsy further support the hypothesis of a pathological perfusion of non/poorly ventilated lung tissue. NEW & NOTEWORTHY Hypothesizing that the non-aerated lung fraction as evaluated by the quantitative analysis of the lung computed tomography (CT) equals shunt (V A /Q = 0), we used a computational approach to estimate the magnitude of the ventilation-perfusion inequality in severe COVID-19. The results show that a severe hyperperfusion of poorly ventilated lung region is likely the cause of the observed hypoxemia. The extensive microthrombosis or abnormal vasodilation of the pulmonary circulation may represent the pathophysiological mechanism of such V A /Q distribution.

Background: In the early stages of COVID-19 pneumonia, hypoxemia has been described in absence of dyspnea ("silent" or "happy" hypoxemia). Our aim was to report its prevalence and outcome in a series of hypoxemic patients upon Emergency Department admission., Methods: In this retrospective observational cohort study we enrolled a study population consisting of 213 COVID-19 patients with PaO2/FiO2 ratio <300 mmHg at hospital admission. Two groups (silent and dyspneic hypoxemia) were defined. Symptoms, blood gas analysis, chest X-ray (CXR) severity, need for intensive care and outcome were recorded., Results: Silent hypoxemic patients (68-31.9%) compared to the dyspneic hypoxemic patients (145-68.1%) showed greater frequency of extra respiratory symptoms (myalgia, diarrhea and nausea) and lower plasmatic LDH. PaO2/FiO2 ratio was 225±68 mmHg and 192±78 mmHg in silent and dyspneic hypoxemia respectively (P=0.002). Eighteen percent of the patients with PaO2/FiO2 from 50 to 150 mmHg presented silent hypoxemia. Silent and dyspneic hypoxemic patients had similar PaCO2 (34.2±6.8 mmHg vs. 33.5±5.7 mmHg, P=0.47) but different respiratory rates (24.6±5.9 bpm vs. 28.6±11.3 bpm respectively, P=0.002). Even when CXR was severely abnormal, 25% of the population was silent hypoxemic. Twenty-six point five percent and 38.6% of silent and dyspneic patients were admitted to the ICU respectively (P=0.082). Mortality rate was 17.6% and 29.7% (log-rank P=0.083) in silent and dyspneic patients., Conclusions: Silent hypoxemia is remarkably present in COVID-19. The presence of dyspnea is associated with a more severe clinical condition.

Rationale: Understanding the physiology of CO 2 stores mobilization is a prerequisite for intermittent extracorporeal CO 2 removal (ECCO 2 R) in patients with chronic hypercapnia. Objectives: To describe the dynamics of CO 2 stores. Methods: Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper," n  = 4); 48 hours of hypoventilation (group "Hypo," n  = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline," n  = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCO 2 R (group "Hypo-ECCO 2 R," n  = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig. Measurements and Main Results: We evaluated [Formula: see text]co 2 , [Formula: see text]o 2 , and metabolic [Formula: see text]co 2 ([Formula: see text]o 2 times the metabolic respiratory quotient). Changes in the CO 2 stores were calculated as [Formula: see text]co 2  - metabolic V̇co 2 . After 48 hours, the CO 2 stores decreased by 0.77 ± 0.17 l kg -1 in group Hyper and increased by 0.32 ± 0.27 l kg -1 in group Hypo ( P  = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg -1 , whereas in group Hypo-ECCO 2 R, they decreased by 0.32 ± 0.24 l kg -1 ( P  = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCO 2 R, the CO2 stores decreased by 0.15 ± 0.09 l kg -1 and 0.51 ± 0.06 l kg -1 , respectively ( P  = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a Pa CO 2 rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h -1 in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCO 2 R, respectively ( P  < 0.001). The Pa CO 2 rise was inversely related to the previous CO 2 stores mobilization ( P  < 0.001). Conclusions: CO 2 from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCO 2 R in patients with chronic hypercapnia.

Objective: To investigate the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their relationships with sepsis severity and oxygen transport/utilization impairment., Design: Retrospective analysis of PTX3, hsTnT, NT-proBNP levels at day 1, 2, and 7 after admission in the intensive care unit in a subset of the Albumin Italian Outcome Sepsis database., Setting: Forty Italian intensive care units., Patients: Nine hundred fifty-eight septic patients enrolled in the randomized clinical trial comparing albumin replacement plus crystalloids and crystalloids alone., Interventions: The patients were divided into sextiles of lactate (marker of severity), ScvO2 (marker of oxygen transport), and fluid balance (marker of therapeutic strategy)., Measurements and Main Results: PTX3 and hsTnT were remarkably similar in the two treatment arms, while NT-proBNP was almost double in the albumin treatment group. However, as the distribution of all these biomarkers was similar between control and treatment arms, for the sake of clarity, we analyzed the patients as a single cohort. PTX3 (71.8 [32.9-186.3] ng/mL), hsTnT (50.4 [21.6-133.6] ng/L), and NT-proBNP (4,393 [1,313-13,837] ng/L) were abnormally elevated in 100%, 84.5%, 93.4% of the 953 patients and all decreased from day 1 to day 7. PTX3 monotonically increased with increasing lactate levels. The hsTnT levels were significantly higher when ScvO2 levels were abnormally low (< 70%), suggesting impaired oxygen transport compared with higher ScvO2 levels, suggesting impaired oxygen utilization. NT-proBNP was higher with higher lactate and fluid balance. At ScvO2 levels < 70%, the NT-proBNP was higher than at higher ScvO2 levels. However, even with higher ScvO2, the NT-proBNP was remarkably elevated, suggesting volume expansion. Increased level of NT-proBNP showed the strongest association with 90-day mortality., Conclusions: The selected biomarkers seem related to different mechanisms during sepsis: PTX3 to sepsis severity, hsTnT to impaired oxygen transport, NT-proBNP to sepsis severity, oxygen transport, and aggressive fluid strategy.

Background: Excessive tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP) are all potential causes of ventilator-induced lung injury, and all contribute to a single variable: the mechanical power. The authors aimed to determine whether high tidal volume or high respiratory rate or high PEEP at iso-mechanical power produce similar or different ventilator-induced lung injury., Methods: Three ventilatory strategies-high tidal volume (twice baseline functional residual capacity), high respiratory rate (40 bpm), and high PEEP (25 cm H2O)-were each applied at two levels of mechanical power (15 and 30 J/min) for 48 h in six groups of seven healthy female piglets (weight: 24.2 ± 2.0 kg, mean ± SD)., Results: At iso-mechanical power, the high tidal volume groups immediately and sharply increased plateau, driving pressure, stress, and strain, which all further deteriorated with time. In high respiratory rate groups, they changed minimally at the beginning, but steadily increased during the 48 h. In contrast, after a sudden huge increase, they decreased with time in the high PEEP groups. End-experiment specific lung elastance was 6.5 ± 1.7 cm H2O in high tidal volume groups, 10.1 ± 3.9 cm H2O in high respiratory rate groups, and 4.5 ± 0.9 cm H2O in high PEEP groups. Functional residual capacity decreased and extravascular lung water increased similarly in these three categories. Lung weight, wet-to-dry ratio, and histologic scores were similar, regardless of ventilatory strategies and power levels. However, the alveolar edema score was higher in the low power groups. High PEEP had the greatest impact on hemodynamics, leading to increased need for fluids. Adverse events (early mortality and pneumothorax) also occurred more frequently in the high PEEP groups., Conclusions: Different ventilatory strategies, delivered at iso-power, led to similar anatomical lung injury. The different systemic consequences of high PEEP underline that ventilator-induced lung injury must be evaluated in the context of the whole body.

Esophageal pressure has been suggested as adequate surrogate of the pleural pressure. We investigate after lung surgery the determinants of the esophageal and intrathoracic pressures and their differences. The esophageal pressure (through esophageal balloon) and the intrathoracic/pleural pressure (through the chest tube on the surgery side) were measured after surgery in 28 patients immediately after lobectomy or wedge resection. Measurements were made in the nondependent lateral position (without or with ventilation of the operated lung) and in the supine position. In the lateral position with the nondependent lung, collapsed or ventilated, the differences between esophageal and pleural pressure amounted to 4.4 ± 1.6 and 5.1 ± 1.7 cmH 2 O. In the supine position, the difference amounted to 7.3 ± 2.8 cmH 2 O. In the supine position, the estimated compressive forces on the mediastinum were 10.5 ± 3.1 cmH 2 O and on the iso-gravitational pleural plane 3.2 ± 1.8 cmH 2 O. A simple model describing the roles of chest, lung, and pneumothorax volume matching on the pleural pressure genesis was developed; modeled pleural pressure = 1.0057 × measured pleural pressure + 0.6592 ( r 2 = 0.8). Whatever the position and the ventilator settings, the esophageal pressure changed in a 1:1 ratio with the changes in pleural pressure. Consequently, chest wall elastance (E cw ) measured by intrathoracic (E cw  = ΔPpl/tidal volume) or esophageal pressure (E cw  = ΔPes/tidal volume) was identical in all the positions we tested. We conclude that esophageal and pleural pressures may be largely different depending on body position (gravitational forces) and lung-chest wall volume matching. Their changes, however, are identical. NEW & NOTEWORTHY Esophageal and pleural pressure changes occur at a 1:1 ratio, fully justifying the use of esophageal pressure to compute the chest wall elastance and the changes in pleural pressure and in lung stress. The absolute value of esophageal and pleural pressures may be largely different, depending on the body position (gravitational forces) and the lung-chest wall volume matching. Therefore, the absolute value of esophageal pressure should not be used as a surrogate of pleural pressure.

Background: Mechanical power is a summary variable including all the components which can possibly cause VILI (pressures, volume, flow, respiratory rate). Since the complexity of its mathematical computation is one of the major factors that delay its clinical use, we propose here a simple and easy to remember equation to estimate mechanical power under volume-controlled ventilation: [Formula: see text] where the mechanical power is expressed in Joules/minute, the minute ventilation (VE) in liters/minute, the inspiratory flow (F) in liters/minute, and peak pressure and positive end-expiratory pressure (PEEP) in centimeter of water. All the components of this equation are continuously displayed by any ventilator under volume-controlled ventilation without the need for clinician intervention. To test the accuracy of this new equation, we compared it with the reference formula of mechanical power that we proposed for volume-controlled ventilation in the past. The comparisons were made in a cohort of mechanically ventilated pigs (485 observations) and in a cohort of ICU patients (265 observations)., Results: Both in pigs and in ICU patients, the correlation between our equation and the reference one was close to the identity. Indeed, the R 2 ranged from 0.97 to 0.99 and the Bland-Altman showed small biases (ranging from + 0.35 to - 0.53 J/min) and proportional errors (ranging from + 0.02 to - 0.05)., Conclusions: Our new equation of mechanical power for volume-controlled ventilation represents a simple and accurate alternative to the more complex ones available to date. This equation does not need any clinical intervention on the ventilator (such as an inspiratory hold) and could be easily implemented in the software of any ventilator in volume-controlled mode. This would allow the clinician to have an estimation of mechanical power at a simple glance and thus increase the clinical consciousness of this variable which is still far from being used at the bedside. Our equation carries the same limitations of all other formulas of mechanical power, the most important of which, as far as it concerns VILI prevention, are the lack of normalization and its application to the whole respiratory system (including the chest wall) and not only to the lung parenchyma.

Introduction : Transpulmonary pressure (PL) is the pressure distending the lung. This pressure equals the stress which develops into the parenchyma at each insufflation and it depends, for a given airway pressure, on the relationship between the lung and the chest wall elastance: a given stress is associated to a given strain, therefor PL is strictly related to ventilator-induced lung injury (VILI). Insufficient knowledge and increased workload account for its limited use in the clinical setting: indeed, the current recommendations for protective ventilation still rely only on the pressures applied to the respiratory system in total (Plateau pressure), without a direct measurement of the real lung stress. Areas covered : We reviewed the significance, the assessment, the application and the limits of transpulmonary pressure in the clinical setting. Expert opinion : Transpulmonary pressure represents a physiologically sound safety limit for mechanical ventilation that should be measured and targeted at least in the most severe ARDS patients. Targeting transpulmonary pressure means 'personalizing' the ventilatory settings.

Prone positioning is nowadays considered as one of the most effective strategies for patients with severe acute respiratory distress syndrome (ARDS). The evolution of the pathophysiological understanding surrounding the prone position closely follows the history of ARDS. At the beginning, the focus of the prone position was the improvement in oxygenation attributed to a perfusion redistribution. However, the mechanisms behind the prone position are more complex. Indeed, the positive effects on oxygenation and CO 2 clearance of the prone position are to be ascribed to a more homogeneous inflation-ventilation, to the lung/thoracic shape mismatch, and to the change of chest wall elastance. In the past 20 years, five major trials have tried, starting from different theories, hypotheses, and designs, to demonstrate the effectiveness of the prone position, which finally found its definitive place among the different ARDS supportive therapies., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)