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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 (VentriQlar), based on the same conceptual grounds described by J.B. West in 1969. We set 498 ventilation–perfusion (VA/Q) compartments and, after calculating their blood composition (PO2, PCO2, and pH), we randomly chose 106 combinations of five parameters controlling a bimodal distribution of blood flow. The solutions were accepted if the predicted PaO2 and PaCO2 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 PaO2/FiO2 was 91.1 ± 18.6 mmHg and PaCO2 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 VA/Q (Qmean = 0.06 ± 0.02) and a smaller fraction in regions with moderately high VA/Q. Overall LogSD, Q was 1.66 ± 0.14, suggestive of high VA/Q inequality. Our data suggest that shunt alone cannot completely account for the observed hypoxemia and a significant VA/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 (VA/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 VA/Q distribution.

BackgroundExcessive 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.MethodsThree 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).ResultsAt 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.ConclusionsDifferent 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.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

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 CO2 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.

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.In this retrospective observational cohort study we enrolled a study population consisting of 213 COVID-19 patients with PaOinf2/inf/FiOinf2/infratio300 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.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. PaOinf2/inf/FiOinf2/infratio was 225±68 mmHg and 192±78 mmHg in silent and dyspneic hypoxemia respectively (P=0.002). Eighteen percent of the patients with PaOinf2/inf/FiOinf2/inffrom 50 to 150 mmHg presented silent hypoxemia. Silent and dyspneic hypoxemic patients had similar PaCOinf2/inf(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.Silent hypoxemia is remarkably present in COVID-19. The presence of dyspnea is associated with a more severe clinical condition.

Critically ill COVID-19 patients have pathophysiological lung features characterized by perfusion abnormalities. However, to date no study has evaluated whether the changes in the distribution of pulmonary gas and blood volume are associated with the severity of gas-exchange impairment and the type of respiratory support (non-invasive versus invasive) in patients with severe COVID-19 pneumonia.This was a single-center, retrospective cohort study conducted in a tertiary care hospital in Northern Italy during the first pandemic wave. Pulmonary gas and blood distribution was assessed using a technique for quantitative analysis of dual-energy computed tomography. Lung aeration loss (reflected by percentage of normally aerated lung tissue) and the extent of gas:blood volume mismatch (percentage of non-aerated, perfused lung tissue-shunt; aerated, non-perfused dead space; and non-aerated/non-perfused regions) were evaluated in critically ill COVID-19 patients with different clinical severity as reflected by the need for non-invasive or invasive respiratory support.Thirty-five patients admitted to the intensive care unit between February 29th and May 30th, 2020 were included. Patients requiring invasive versus non-invasive mechanical ventilation had both a lower percentage of normally aerated lung tissue (median [interquartile range] 33% [24-49%] vs. 63% [44-68%], p 0.001); and a larger extent of gas:blood volume mismatch (43% [30-49%] vs. 25% [14-28%], p = 0.001), due to higher shunt (23% [15-32%] vs. 5% [2-16%], p = 0.001) and non-aerated/non perfused regions (5% [3-10%] vs. 1% [0-2%], p = 0.001). The PaOIn critically ill patients with severe COVID-19 pneumonia, the need for invasive mechanical ventilation and oxygenation impairment were associated with loss of aeration and the extent of gas:blood volume mismatch.

Rationale: Understanding the physiology of CO2 stores mobilization is a prerequisite for intermittent extracorporeal CO2 removal (ECCO2R) in patients with chronic hypercapnia.Objectives: To describ...

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.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).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.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.

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.

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 cmH2O. In the supine position, the difference amounted to 7.3 ± 2.8 cmH2O. In the supine position, the estimated compressive forces on the mediastinum were 10.5 ± 3.1 cmH2O and on the iso-gravitational pleural plane 3.2 ± 1.8 cmH2O. 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 ( r2 = 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 (Ecw) measured by intrathoracic (Ecw = ΔPpl/tidal volume) or esophageal pressure (Ecw = 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.

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.