Relationship between D-dimers and dead-space on disease severity and mortality in COVID-19 acute respiratory distress syndrome: A retrospective observational cohort study

Background Despite its diagnostic and prognostic importance, physiologic dead space fraction is not included in the current ARDS definition or severity classification. ARDS caused by COVID-19 (C-ARDS) is characterized by increased physiologic dead space fraction and hypoxemia. Our aim was to investigate the relationship between dead space indices, markers of inflammation, immunothrombosis, severity and intensive care unit (ICU) mortality. Results Retrospective data including demographics, gas exchange, ventilatory parameters, and respiratory mechanics in the first 24 h of invasive ventilation. Plasma concentrations of D-dimers and ferritin were not significantly different across C-ARDS severity categories. Weak relationships were found between D-dimers and VR (r = 0.07, p = 0.13), PETCO2/PaCO2 (r = −0.1, p = 0.02), or estimated dead space fraction (r = 0.019, p = 0.68). Age, PaO2/FiO2, pH, PETCO2/PaCO2 and ferritin, were independently associated with ICU mortality. We found no association between D-dimers or ferritin and any dead-space indices adjusting for PaO2/FiO2, days of ventilation, tidal volume, and respiratory system compliance. Conclusions We report no association between dead space and inflammatory markers in mechanically ventilated patients with C-ARDS. Our results support theories suggesting that multiple mechanisms, in addition to immunothrombosis, play a role in the pathophysiology of respiratory failure and degree of dead space in C-ARDS.

Prone position: how understanding and clinical application of a technique progress with time

Historical background The prone position was first proposed on theoretical background in 1974 (more advantageous distribution of mechanical ventilation). The first clinical report on 5 ARDS patients in 1976 showed remarkable improvement of oxygenation after pronation. Pathophysiology The findings in CT scans enhanced the use of prone position in ARDS patients. The main mechanism of the improved gas exchange seen in the prone position is nowadays attributed to a dorsal ventilatory recruitment, with a substantially unchanged distribution of perfusion. Regardless of the gas exchange, the primary effect of the prone position is a more homogenous distribution of ventilation, stress and strain, with similar size of pulmonary units in dorsal and ventral regions. In contrast, in the supine position the ventral regions are more expanded compared with the dorsal regions, which leads to greater ventral stress and strain, induced by mechanical ventilation. Outcome in ARDS The number of clinical studies paralleled the evolution of the pathophysiological understanding. The first two clinical trials in 2001 and 2004 were based on the hypothesis that better oxygenation would lead to a better survival and the studies were more focused on gas exchange than on lung mechanics. The equations better oxygenation = better survival was disproved by these and other larger trials (ARMA trial). However, the first studies provided signals that some survival advantages were possible in a more severe ARDS, where both oxygenation and lung mechanics were impaired. The PROSEVA trial finally showed the benefits of prone position on mortality supporting the thesis that the clinical advantages of prone position, instead of improved gas exchange, were mainly due to a less harmful mechanical ventilation and better distribution of stress and strain. In less severe ARDS, in spite of a better gas exchange, reduced mechanical stress and strain, and improved oxygenation, prone position was ineffective on outcome. Prone position and COVID-19 The mechanisms of oxygenation impairment in early COVID-19 are different than in typical ARDS and relate more on perfusion alteration than on alveolar consolidation/collapse, which are minimal in the early phase. Bronchial shunt may also contribute to the early COVID-19 hypoxemia. Therefore, in this phase, the oxygenation improvement in prone position is due to a better matching of local ventilation and perfusion, primarily caused by the perfusion component. Unfortunately, the conditions for improved outcomes, i.e. a better distribution of stress and strain, are almost absent in this phase of COVID-19 disease, as the lung parenchyma is nearly fully inflated. Due to some contradictory results, further studies are needed to better investigate the effect of prone position on outcome in COVID-19 patients. Graphical

Pathophysiology of COVID-19 pneumonia and respiratory treatment.

COVID-19 pandemic has seen an unprecedented number of patients presenting with acute respiratory distress syndrome to the intensive care units all over the world. Between August and November 2022, we performed research on PubMed screening all publications on COVID-19 disease and respiratory failure and its treatment. In this review we focused on COVID-19 most common manifestations concerning lung function. The respiratory infection develops in three broad phases: early, intermediate, and late. The mainstay of the disease is the frequent presence of severe hypoxemia associated - at least at the beginning - to a near normal lung mechanics and PaCO2 tension. The management of symptomatic patients, progressing through these temporal phases, is not possible without understanding the pathophysiology underlying the respiratory manifestation.

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.

Biochemical shunt: where and how?

G. Harutyunyan and co-workers, in their reply to our correspondence, introduce the fascinating concept of "biochemical shunt” to help explain some of the gas exchange abnormalities reported in patients with early coronavirus disease 2019 (COVID-19). In brief, they assert the plausibility that the oxyhaemoglobin dissociation curve (ODC), which may be normal in the arterial and venous blood, could be altered (i.e. reduced oxygen affinity) in the pulmonary blood flowing through diseased alveolar capillaries. It is not easy for us to understand which COVID-19-related factors, or metabolites, might alter the ODC specifically in the pulmonary circulation, and to what extent they involve the lung parenchyma (partially or totally, where and why). Let us suppose, for example, that the biochemical shunt occurs in the whole parenchyma (nearly fully ventilated in early COVID-19). Response to Harutyunyan et al. "Hypoxaemia in the early stage of COVID-19: prevalence of physical or biochemical factors?”https://bit.ly/3K1NSKu

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.

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.

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.

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.

Mechanisms of oxygenation responses to proning and recruitment in COVID-19 pneumonia.

PURPOSE: This study aimed at investigating the mechanisms underlying the oxygenation response to proning and recruitment maneuvers in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Twenty-five patients with COVID-19 pneumonia, at variable times since admission (from 1 to 3 weeks), underwent computed tomography (CT) lung scans, gas-exchange and lung-mechanics measurement in supine and prone positions at 5 cmH2O and during recruiting maneuver (supine, 35 cmH2O). Within the non-aerated tissue, we differentiated the atelectatic and consolidated tissue (recruitable and non-recruitable at 35 cmH2O of airway pressure). Positive/negative response to proning/recruitment was defined as increase/decrease of PaO2/FiO2. Apparent perfusion ratio was computed as venous admixture/non aerated tissue fraction. RESULTS: The average values of venous admixture and PaO2/FiO2 ratio were similar in supine-5 and prone-5. However, the PaO2/FiO2 changes (increasing in 65% of the patients and decreasing in 35%, from supine to prone) correlated with the balance between resolution of dorsal atelectasis and formation of ventral atelectasis (p = 0.002). Dorsal consolidated tissue determined this balance, being inversely related with dorsal recruitment (p = 0.012). From supine-5 to supine-35, the apparent perfusion ratio increased from 1.38 ± 0.71 to 2.15 ± 1.15 (p = 0.004) while PaO2/FiO2 ratio increased in 52% and decreased in 48% of patients. Non-responders had consolidated tissue fraction of 0.27 ± 0.1 vs. 0.18 ± 0.1 in the responding cohort (p = 0.04). Consolidated tissue, PaCO2 and respiratory system elastance were higher in patients assessed late (all p < 0.05), suggesting, all together, "fibrotic-like" changes of the lung over time. CONCLUSION: The amount of consolidated tissue was higher in patients assessed during the third week and determined the oxygenation responses following pronation and recruitment maneuvers.

COVID-19 pneumonia: pathophysiology and management.

Coronavirus disease 2019 (COVID-19) pneumonia is an evolving disease. We will focus on the development of its pathophysiologic characteristics over time, and how these time-related changes determine modifications in treatment. In the emergency department: the peculiar characteristic is the coexistence, in a significant fraction of patients, of severe hypoxaemia, near-normal lung computed tomography imaging, lung gas volume and respiratory mechanics. Despite high respiratory drive, dyspnoea and respiratory rate are often normal. The underlying mechanism is primarily altered lung perfusion. The anatomical prerequisites for PEEP (positive end-expiratory pressure) to work (lung oedema, atelectasis, and therefore recruitability) are lacking. In the high-dependency unit: the disease starts to worsen either because of its natural evolution or additional patient self-inflicted lung injury (P-SILI). Oedema and atelectasis may develop, increasing recruitability. Noninvasive supports are indicated if they result in a reversal of hypoxaemia and a decreased inspiratory effort. Otherwise, mechanical ventilation should be considered to avert P-SILI. In the intensive care unit: the primary characteristic of the advance of unresolved COVID-19 disease is a progressive shift from oedema or atelectasis to less reversible structural lung alterations to lung fibrosis. These later characteristics are associated with notable impairment of respiratory mechanics, increased arterial carbon dioxide tension (P aCO2 ), decreased recruitability and lack of response to PEEP and prone positioning.

Using Artificial Intelligence for Automatic Segmentation of CT Lung Images in Acute Respiratory Distress Syndrome.

Knowledge of gas volume, tissue mass and recruitability measured by the quantitative CT scan analysis (CT-qa) is important when setting the mechanical ventilation in acute respiratory distress syndrome (ARDS). Yet, the manual segmentation of the lung requires a considerable workload. Our goal was to provide an automatic, clinically applicable and reliable lung segmentation procedure. Therefore, a convolutional neural network (CNN) was used to train an artificial intelligence (AI) algorithm on 15 healthy subjects (1,302 slices), 100 ARDS patients (12,279 slices), and 20 COVID-19 (1,817 slices). Eighty percent of this populations was used for training, 20% for testing. The AI and manual segmentation at slice level were compared by intersection over union (IoU). The CT-qa variables were compared by regression and Bland Altman analysis. The AI-segmentation of a single patient required 5-10 s vs. 1-2 h of the manual. At slice level, the algorithm showed on the test set an IOU across all CT slices of 91.3 ± 10.0, 85.2 ± 13.9, and 84.7 ± 14.0%, and across all lung volumes of 96.3 ± 0.6, 88.9 ± 3.1, and 86.3 ± 6.5% for normal lungs, ARDS and COVID-19, respectively, with a U-shape in the performance: better in the lung middle region, worse at the apex and base. At patient level, on the test set, the total lung volume measured by AI and manual segmentation had a R 2 of 0.99 and a bias -9.8 ml [CI: +56.0/-75.7 ml]. The recruitability measured with manual and AI-segmentation, as change in non-aerated tissue fraction had a bias of +0.3% [CI: +6.2/-5.5%] and -0.5% [CI: +2.3/-3.3%] expressed as change in well-aerated tissue fraction. The AI-powered lung segmentation provided fast and clinically reliable results. It is able to segment the lungs of seriously ill ARDS patients fully automatically.