Causes of Hypoxemia in COVID-19 Acute Respiratory Distress Syndrome: A Combined Multiple Inert Gas Elimination Technique and Dual-energy Computed Tomography Study.

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.

The ventilator of the future: key principles and unmet needs.

Persistent shortcomings of invasive positive pressure ventilation make it less than an ideal intervention. Over the course of more than seven decades, clinical experience and scientific investigation have helped define its range of hazards and limitations. Apart from compromised airway clearance and lower airway contamination imposed by endotracheal intubation, the primary hazards inherent to positive pressure ventilation may be considered in three broad categories: hemodynamic impairment, potential for ventilation-induced lung injury, and impairment of the respiratory muscle pump. To optimize care delivery, it is crucial for monitoring and machine outputs to integrate information with the potential to impact the underlying requirements of the patient and/or responses of the cardiopulmonary system to ventilatory interventions. Trending analysis, timely interventions, and closer communication with the caregiver would limit adverse clinical trajectories. Judging from the rapid progress of recent years, we are encouraged to think that insights from physiologic research and emerging technological capability may eventually address important aspects of current deficiencies.

High- versus Low-Flow Extracorporeal Respiratory Support in Experimental Hypoxemic Acute Lung Injury.

Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO2 removal (ECCO2R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO2R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (PaO2:FiO2 ⩽ 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO2R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o2, [Formula: see text]co2, gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P < 0.001), worse oxygenation (PaO2:FiO2 = 125 ± 14 vs. 151 ± 11 mm Hg; P < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H2O; P = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO2R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P = 0.003). [Formula: see text]o2 and [Formula: see text]co2, irrespective of lung injury model, were lower during ECMO, resulting in lower PaCO2 and [Formula: see text]e but worse respiratory elastance compared with ECCO2R (64 ± 27 vs. 40 ± 8 cm H2O/L; P < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o2, and better hemodynamics. ECCO2R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.

Integral assessment of gas exchange during veno-arterial ECMO: accuracy and precision of a modified Fick principle in a porcine model.

Assessment of native cardiac output during extracorporeal circulation is challenging. We assessed a modified Fick principle under conditions such as dead space and shunt in 13 anesthetized swine undergoing centrally cannulated veno-arterial extracorporeal membrane oxygenation (V-A ECMO, 308 measurement periods) therapy. We assumed that the ratio of carbon dioxide elimination (V̇co2) or oxygen uptake (V̇o2) between the membrane and native lung corresponds to the ratio of respective blood flows. Unequal ventilation/perfusion (V̇/Q̇) ratios were corrected towards unity. Pulmonary blood flow was calculated and compared to an ultrasonic flow probe on the pulmonary artery with a bias of 99 mL/min (limits of agreement -542 to 741 mL/min) with blood content V̇o2 and no-shunt, no-dead space conditions, which showed good trending ability (least significant change from 82 to 129 mL). Shunt conditions led to underestimation of native pulmonary blood flow (bias -395, limits of agreement -1,290 to 500 mL/min). Bias and trending further depended on the gas (O2, CO2) and measurement approach (blood content vs. gas phase). Measurements in the gas phase increased the bias (253 [LoA -1,357 to 1,863 mL/min] for expired V̇o2 bias 482 [LoA -760 to 1,724 mL/min] for expired V̇co2) and could be improved by correction of V̇/Q̇ inequalities. Our results show that common assumptions of the Fick principle in two competing circulations give results with adequate accuracy and may offer a clinically applicable tool. Precision depends on specific conditions. This highlights the complexity of gas exchange in membrane lungs and may further deepen the understanding of V-A ECMO.

The Impact of the Society of Critical Care Medicine's Flagship Journal: Critical Care Medicine: Reflections of Critical Care Pioneers.

On the 50th anniversary of the Society of Critical Care Medicine's journal Critical Care Medicine, critical care pioneers reflect on the importance of the journal to their careers and to the development of the field of adult and pediatric critical care.

Curiosity, Opportunity, and Luck: Were the 1970s Different?

Control of Breathing Using an Extracorporeal Membrane Lung. By T Kolobow, L Gattinoni, TA Tomlinson, JE Pierce. Anesthesiology 1977; 46:138-41. Reprinted with permission. Body Position Changes Redistribute Lung Computed-Tomographic Density in Patients with Acute Respiratory Failure. By L Gattinoni, P Pelosi, G Vitale, A Pesenti, L D'Andrea, D Mascheroni. Anesthesiology 1991; 74:15-23. Reprinted with permission. Dr. Gattinoni's scientific career was primarily driven by curiosity. His generation was not formally trained, but he was part of a community of young and enthusiastic colleagues who were forging a new discipline: intensive care medicine. The most significant opportunity of Dr. Gattinoni's career was becoming the research fellow of a visionary genius, Dr. Theodor Kolobow, who focused on extracorporeal carbon dioxide removal after the failure of the first trial on extracorporeal membrane oxygenation. CO2 removal, by allowing control over the intensity of mechanical ventilation, opened the path to "lung rest" to prevent ventilator-induced lung injury. A unique opportunity for research was the spontaneous birth of a network of scientists who became friends in the European Group of Research in Intensive Care Medicine. In this environment, it was possible to develop core concepts such as the "baby lung" and to understand the mechanisms underlying computed tomography-density redistribution in the prone position. Physiology guided us in the 1970s, and understanding mechanisms remains of paramount importance today.

Mechanical Power Ratio and Respiratory Treatment Escalation in COVID-19 Pneumonia: A Secondary Analysis of a Prospectively Enrolled Cohort.

BACKGROUND: Under the hypothesis that mechanical power ratio could identify the spontaneously breathing patients with a higher risk of respiratory failure, this study assessed lung mechanics in nonintubated patients with COVID-19 pneumonia, aiming to (1) describe their characteristics; (2) compare lung mechanics between patients who received respiratory treatment escalation and those who did not; and (3) identify variables associated with the need for respiratory treatment escalation. METHODS: Secondary analysis of prospectively enrolled cohort involving 111 consecutive spontaneously breathing adults receiving continuous positive airway pressure, enrolled from September 2020 to December 2021. Lung mechanics and other previously reported predictive indices were calculated, as well as a novel variable: the mechanical power ratio (the ratio between the actual and the expected baseline mechanical power). Patients were grouped according to the outcome: (1) no-treatment escalation (patient supported in continuous positive airway pressure until improvement) and (2) treatment escalation (escalation of the respiratory support to noninvasive or invasive mechanical ventilation), and the association between lung mechanics/predictive scores and outcome was assessed. RESULTS: At day 1, patients undergoing treatment escalation had spontaneous tidal volume similar to those of patients who did not (7.1 ± 1.9 vs. 7.1 ± 1.4 ml/kgIBW; P = 0.990). In contrast, they showed higher respiratory rate (20 ± 5 vs. 18 ± 5 breaths/min; P = 0.028), minute ventilation (9.2 ± 3.0 vs. 7.9 ± 2.4 l/min; P = 0.011), tidal pleural pressure (8.1 ± 3.7 vs. 6.0 ± 3.1 cm H2O; P = 0.003), mechanical power ratio (2.4 ± 1.4 vs. 1.7 ± 1.5; P = 0.042), and lower partial pressure of alveolar oxygen/fractional inspired oxygen tension (174 ± 64 vs. 220 ± 95; P = 0.007). The mechanical power (area under the curve, 0.738; 95% CI, 0.636 to 0.839] P < 0.001), the mechanical power ratio (area under the curve, 0.734; 95% CI, 0.625 to 0.844; P < 0.001), and the pressure-rate index (area under the curve, 0.733; 95% CI, 0.631 to 0.835; P < 0.001) showed the highest areas under the curve. CONCLUSIONS: In this COVID-19 cohort, tidal volume was similar in patients undergoing treatment escalation and in patients who did not; mechanical power, its ratio, and pressure-rate index were the variables presenting the highest association with the clinical outcome.

Practical assessment of risk of VILI from ventilating power: a conceptual model.

At the bedside, assessing the risk of ventilator-induced lung injury (VILI) requires parameters readily measured by the clinician. For this purpose, driving pressure (DP) and end-inspiratory static 'plateau' pressure ([Formula: see text]) of the tidal cycle are unquestionably useful but lack key information relating to associated volume changes and cumulative strain. 'Mechanical power', a clinical term which incorporates all dissipated ('non-elastic') and conserved ('elastic') energy components of inflation, has drawn considerable interest as a comprehensive 'umbrella' variable that accounts for the influence of ventilating frequency per minute as well as the energy cost per tidal cycle. Yet, like the raw values of DP and [Formula: see text], the absolute levels of energy and power by themselves may not carry sufficiently precise information to guide safe ventilatory practice. In previous work we introduced the concept of 'damaging energy per cycle'. Here we describe how-if only in concept-the bedside clinician might gauge the theoretical hazard of delivered energy using easily observed static circuit pressures ([Formula: see text] and positive end expiratory pressure) and an estimate of the maximally tolerated (threshold) non-dissipated ('elastic') airway pressure that reflects the pressure component applied to the alveolar tissues. Because its core inputs are already in use and familiar in daily practice, the simplified mathematical model we propose here for damaging energy and power may promote deeper comprehension of the key factors in play to improve lung protective ventilation.

Ventilatory ratio, dead space, and venous admixture in patients with acute respiratory distress syndrome.

BACKGROUND: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO2 volume expired per minute (VCO2). METHODS: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure PaO2/FiO2 ratio. VCO2 was estimated through the resting energy expenditure derived from the Harris-Benedict formula. RESULTS: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the PaO2/FiO2 ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO2. At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO2 equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for VD/VTphys, VCO2, PaO2/FiO2 (ORadj=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (VD/VTphys [ORadj=17.9; 95% CI, 1.8-185; P<0.05]; VCO2 [ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]; and PaO2/FiO2 (ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]). CONCLUSIONS: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO2 and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness.

End-Tidal to Arterial Pco2 Ratio as Guide to Weaning from Venovenous Extracorporeal Membrane Oxygenation.

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 CO2 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 CO2, but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the PaCO2 unchanged. The effort to eliminate one unit-volume of CO2, was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H2O/[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 (PetCO2)/PaCO2 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 PetCO2/PaCO2 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 CO2. A higher PetCO2/PaCO2 ratio was associated with greater likelihood of weaning from VV-ECMO.

Acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is an acute respiratory illness characterised by bilateral chest radiographical opacities with severe hypoxaemia due to non-cardiogenic pulmonary oedema. The COVID-19 pandemic has caused an increase in ARDS and highlighted challenges associated with this syndrome, including its unacceptably high mortality and the lack of effective pharmacotherapy. In this Seminar, we summarise current knowledge regarding ARDS epidemiology and risk factors, differential diagnosis, and evidence-based clinical management of both mechanical ventilation and supportive care, and discuss areas of controversy and ongoing research. Although the Seminar focuses on ARDS due to any cause, we also consider commonalities and distinctions of COVID-19-associated ARDS compared with ARDS from other causes.

Paradoxical Positioning: Does "Head Up" Always Improve Mechanics and Lung Protection?

OBJECTIVES: Head-elevated body positioning, a default clinical practice, predictably increases end-expiratory transpulmonary pressure and aerated lung volume. In acute respiratory distress syndrome (ARDS), however, the net effect of such vertical inclination on tidal mechanics depends upon whether lung recruitment or overdistension predominates. We hypothesized that in moderate to severe ARDS, bed inclination toward vertical unloads the chest wall but adversely affects overall respiratory system compliance (C rs ). DESIGN: Prospective physiologic study. SETTING: Two medical ICUs in the United States. PATIENTS: Seventeen patients with ARDS, predominantly moderate to severe. INTERVENTION: Patients were ventilated passively by volume control. We measured airway pressures at baseline (noninclined) and following bed inclination toward vertical by an additional 15°. At baseline and following inclination, we manually loaded the chest wall to determine if C rs increased or paradoxically declined, suggestive of end-tidal overdistension. MEASUREMENTS AND MAIN RESULTS: Inclination resulted in a higher plateau pressure (supineΔ: 2.8 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.5 cm H 2 O [ p = 0.004]), higher driving pressure (supineΔ: 2.9 ± 3.3 cm H 2 O [ p = 0.01]; proneΔ: 3.3 ± 2.8 cm H 2 O [ p = 0.007]), and lower C rs (supine Δ: 3.4 ± 3.7 mL/cm H 2 O [ p = 0.01]; proneΔ: 3.1 ± 3.2 mL/cm H 2 O [ p = 0.02]). Following inclination, manual loading of the chest wall restored C rs and driving pressure to baseline (preinclination) values. CONCLUSIONS: In advanced ARDS, bed inclination toward vertical adversely affects C rs and therefore affects the numerical values for plateau and driving tidal pressures commonly targeted in lung protective strategies. These changes are fully reversed with manual loading of the chest wall, suggestive of end-tidal overdistension in the upright position. Body inclination should be considered a modifiable determinant of transpulmonary pressure and lung protection, directionally similar to tidal volume and positive end-expiratory pressure.

Lung Ultrasound and Electrical Impedance Tomography During Ventilator-Induced Lung Injury.

OBJECTIVES: Lung damage during mechanical ventilation involves lung volume and alveolar water content, and lung ultrasound (LUS) and electrical impedance tomography changes are related to these variables. We investigated whether these techniques may detect any signal modification during the development of ventilator-induced lung injury (VILI). DESIGN: Experimental animal study. SETTING: Experimental Department of a University Hospital. SUBJECTS: Forty-two female pigs (24.2 ± 2.0 kg). INTERVENTIONS: The animals were randomized into three groups (n = 14): high tidal volume (TV) (mean TV, 803.0 ± 121.7 mL), high respiratory rate (RR) (mean RR, 40.3 ± 1.1 beats/min), and high positive-end-expiratory pressure (PEEP) (mean PEEP, 24.0 ± 1.1 cm H2O). The study lasted 48 hours. At baseline and at 30 minutes, and subsequently every 6 hours, we recorded extravascular lung water, end-expiratory lung volume, lung strain, respiratory mechanics, hemodynamics, and gas exchange. At the same time-point, end-expiratory impedance was recorded relatively to the baseline. LUS was assessed every 12 hours in 12 fields, each scoring from 0 (presence of A-lines) to 3 (consolidation). MEASUREMENTS AND MAIN RESULTS: In a multiple regression model, the ratio between extravascular lung water and end-expiratory lung volume was significantly associated with the LUS total score (p < 0.002; adjusted R2, 0.21). The variables independently associated with the end-expiratory difference in lung impedance were lung strain (p < 0.001; adjusted R2, 0.18) and extravascular lung water (p < 0.001; adjusted R2, 0.11). CONCLUSIONS: Data suggest as follows. First, what determines the LUS score is the ratio between water and gas and not water alone. Therefore, caution is needed when an improvement of LUS score follows a variation of the lung gas content, as after a PEEP increase. Second, what determines the end-expiratory difference in lung impedance is the strain level that may disrupt the intercellular junction, therefore altering lung impedance. In addition, the increase in extravascular lung water during VILI development contributed to the observed decrease in impedance.

Pathophysiology of coronavirus-19 disease acute lung injury.

PURPOSE OF REVIEW: More than 230 million people have tested positive for severe acute respiratory syndrome-coronavirus-2 infection globally by September 2021. The infection affects primarily the function of the respiratory system, where ∼20% of infected individuals develop coronavirus-19 disease (COVID-19) pneumonia. This review provides an update on the pathophysiology of the COVID-19 acute lung injury. RECENT FINDINGS: In patients with COVID-19 pneumonia admitted to the intensive care unit, the PaO2/FiO2 ratio is typically <26.7 kPa (200 mmHg), whereas lung volume appears relatively unchanged. This hypoxaemia is likely determined by a heterogeneous mismatch of pulmonary ventilation and perfusion, mainly associated with immunothrombosis, endothelialitis and neovascularisation. During the disease, lung weight, elastance and dead space can increase, affecting respiratory drive, effort and dyspnoea. In some severe cases, COVID-19 pneumonia may lead to irreversible pulmonary fibrosis. SUMMARY: This review summarises the fundamental pathophysiological features of COVID-19 in the context of the respiratory system. It provides an overview of the key clinical manifestations of COVID-19 pneumonia, including gas exchange impairment, altered pulmonary mechanics and implications of abnormal chemical and mechanical stimuli. It also critically discusses the clinical implications for mechanical ventilation therapy.

Paradoxical response to chest wall loading predicts a favorable mechanical response to reduction in tidal volume or PEEP.

BACKGROUND: Chest wall loading has been shown to paradoxically improve respiratory system compliance (CRS) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The most likely, albeit unconfirmed, mechanism is relief of end-tidal overdistension in 'baby lungs' of low-capacity. The purpose of this study was to define how small changes of tidal volume (VT) and positive end-expiratory pressure (PEEP) affect CRS (and its associated airway pressures) in patients with ARDS who demonstrate a paradoxical response to chest wall loading. We hypothesized that small reductions of VT or PEEP would alleviate overdistension and favorably affect CRS and conversely, that small increases of VT or PEEP would worsen CRS. METHODS: Prospective, multi-center physiologic study of seventeen patients with moderate to severe ARDS who demonstrated paradoxical responses to chest wall loading. All patients received mechanical ventilation in volume control mode and were passively ventilated. Airway pressures were measured before and after decreasing/increasing VT by 1 ml/kg predicted body weight and decreasing/increasing PEEP by 2.5 cmH2O. RESULTS: Decreasing either VT or PEEP improved CRS in all patients. Driving pressure (DP) decreased by a mean of 4.9 cmH2O (supine) and by 4.3 cmH2O (prone) after decreasing VT, and by a mean of 2.9 cmH2O (supine) and 2.2 cmH2O (prone) after decreasing PEEP. CRS increased by a mean of 3.1 ml/cmH2O (supine) and by 2.5 ml/cmH2O (prone) after decreasing VT. CRS increased by a mean of 5.2 ml/cmH2O (supine) and 3.6 ml/cmH2O (prone) after decreasing PEEP (P < 0.01 for all). Small increments of either VT or PEEP worsened CRS in the majority of patients. CONCLUSION: Patients with a paradoxical response to chest wall loading demonstrate uniform improvement in both DP and CRS following a reduction in either VT or PEEP, findings in keeping with prior evidence suggesting its presence is a sign of end-tidal overdistension. The presence of 'paradox' should prompt re-evaluation of modifiable determinants of end-tidal overdistension, including VT, PEEP, and body position.

Breathing face down.

The prone position has been used to improve oxygenation in patients affected by acute respiratory distress syndrome, but its role in patients with COVID-19 is still unclear when these patients are breathing spontaneously. Mechanisms of ventilation and perfusion in the prone position are discussed, with new insights on how these changes relate to patients with COVID-19.

Mobilizing Carbon Dioxide Stores. An Experimental Study.

Rationale: Understanding the physiology of CO2 stores mobilization is a prerequisite for intermittent extracorporeal CO2 removal (ECCO2R) in patients with chronic hypercapnia.Objectives: To describe the dynamics of CO2 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 ECCO2R (group "Hypo-ECCO2R," 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]co2, [Formula: see text]o2, and metabolic [Formula: see text]co2 ([Formula: see text]o2 times the metabolic respiratory quotient). Changes in the CO2 stores were calculated as [Formula: see text]co2 - metabolic V̇co2. After 48 hours, the CO2 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-ECCO2R, 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-ECCO2R, 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 PaCO2 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-ECCO2R, respectively (P < 0.001). The PaCO2 rise was inversely related to the previous CO2 stores mobilization (P < 0.001).Conclusions: CO2 from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCO2R in patients with chronic hypercapnia.

Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study.

BACKGROUND: Current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS). METHODS: An international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared. FINDINGS: 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved. INTERPRETATION: More than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.

Improving lung compliance by external compression of the chest wall.

As exemplified by prone positioning, regional variations of lung and chest wall properties provide possibilities for modifying transpulmonary pressures and suggest that clinical interventions related to the judicious application of external pressure may yield benefit. Recent observations made in late-phase patients with severe ARDS caused by COVID-19 (C-ARDS) have revealed unexpected mechanical responses to local chest wall compressions over the sternum and abdomen in the supine position that challenge the clinician's assumptions and conventional bedside approaches to lung protection. These findings appear to open avenues for mechanism-defining research investigation with possible therapeutic implications for all forms and stages of ARDS.

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

BACKGROUND: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock. METHODS: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization. RESULTS: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points. CONCLUSION: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time. CLINICAL TRIAL REGISTRATION: ALBIOS ClinicalTrials.gov number NCT00707122.