Pulmonary Interstitial Matrix and Lung Fluid Balance From Normal to the Acutely Injured Lung

This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH2O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the “safety factor” opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both trans-endothelial and trans-epithelial gradients favor filtration leading to alveolar flooding. Neither CT scan nor ultrasound can identify this initial level of lung fluid balance perturbation. A suggestion is put forward to identify a non-invasive tool to detect the earliest stages of perturbation of lung fluid balance before the condition becomes life-threatening.

Prone Positioning May Increase Lung Overdistension in COVID-19-Induced ARDS

Background: Real-time effects of changing body position and positive end-expiratory pressure (PEEP) on regional lung overdistension and collapse in individual patients remain largely unknown and not timely monitored. The aim of this study was to individualize PEEP in supine and prone body positions seeking to reduce lung collapse and overdistension in mechanically ventilated patients with coronavirus disease (COVID-19)-induced acute respiratory distress syndrome (ARDS). We hypothesized that prone positioning with bedside titrated PEEP would provide attenuation of both overdistension and collapse.Methods: In this prospective observational study, patients with COVID-19-induced ARDS under mechanical ventilation were included. We used electrical impedance tomography (EIT) with decremental PEEP titration algorithm (PEEPEIT-titration), which provides information on regional lung overdistension and collapse, along with global respiratory system compliance, to individualize PEEP and body position. PEEPEIT-titration in supine position straightaway followed by PEEPEIT-titration in prone position were performed. Immediately before each PEEPEIT-titration, the same lung recruitment maneuver was performed: 2 min of PEEP 24 cmH2O and driving pressure of 15 cmH2O.Results: Forty-two PEEPEIT-titration were performed in ten patients (21 pairs supine and prone positions). We have found larger % of overdistension along the PEEP titration in prone than supine position (P = 0.042). A larger % of collapse along the PEEP titration was found in supine than prone position (P = 0.037). A smaller respiratory system compliance was found in prone than supine position (P < 0.0005).Conclusions: In patients with COVID-19-induced ARDS, prone body position, when compared with supine body position, decreased lung collapse at low PEEP levels, but increased lung overdistension at PEEP levels greater than 10 cm H2O.Trial registration number: NCT04460859

Potential for the Lung Recruitment and the Risk of Lung Overdistension During 21 Days of Mechanical Ventilation in Patients With COVID-19 After Noninvasive Ventilation Failure: the COVID-VENT Observational Trial

Background: Data on the lung respiratory mechanics and gas exchange in the time course of COVID-19-associated respiratory failure is limited. This study aimed to explore respiratory mechanics and gas exchange, the lung recruitability and risk of overdistension during the time course of mechanical ventilation. Methods: This was a prospective observational study in critically ill mechanically ventilated patients (n=116) with COVID-19 admitted into Intensive Care Units of Sechenov University. The primary endpoints were: «optimum» positive end-expiratory pressure (PEEP) level balanced between the lowest driving pressure and the highest SpO2 and number of patients with recruitable lung on Days 1 and 7 of mechanical ventilation. We measured driving pressure at different levels of PEEP (14, 12, 10 and 8 cmH2O) with preset tidal volume, and with the increase of tidal volume by 100 ml and 200 ml at preset PEEP level, and calculated static respiratory system compliance (CRS), PaO2/FiO2, alveolar dead space and ventilatory ratio on Days 1, 3, 5, 7, 10, 14 and 21.Results: The «optimum» PEEP levels on Day 1 were 11.0 (10.0-12.8) cmH2O and 10.0 (9.0-12.0) cmH2O on Day 7. Positive response to recruitment was observed on Day 1 in 27.6% and on Day 7 in 9.2% of patients. PEEP increase from 10 to 14 cmH2O and VT increase by 100 and 200 ml led to a significant decrease in CRS from Day 1 to Day 14 (p<0.05). Ventilatory ratio was 2.2 (1.7-2,7) in non-survivors and in 1.9 (1.6-2.6) survivors on Day 1 and decreased on Day 7 in survivors only (p<0.01). PaO2/FiO2 was 105.5 (76.2-141.7) mmHg in non-survivors on Day 1 and 136.6 (106.7-160.8) in survivors (p=0.002). In survivors, PaO2/FiO2 rose on Day 3 (p=0.008) and then between Days 7 and 10 (p=0.046). Conclusion: Lung recruitability was low in COVID-19 and decreased during the course of the disease, but lung overdistension occurred at «intermediate» PEEP and VT levels. In survivors gas exchange improvements after Day 7 mismatched CRS.Trial registration: ClinicalTrials.gov, NCT04445961. Registered 24 June 2020 - Retrospectively registered, http://https://clinicaltrials.gov/ct2/show/NCT04445961?cond=COVID-19&cntry=RU&city=Moscow&draw=3&rank=23

Individualization of PEEP and tidal volume in ARDS patients with electrical impedance tomography: a pilot feasibility study

Background In mechanically ventilated patients with acute respiratory distress syndrome (ARDS), electrical impedance tomography (EIT) provides information on alveolar cycling and overdistension as well as assessment of recruitability at the bedside. We developed a protocol for individualization of positive end-expiratory pressure (PEEP) and tidal volume (VT) utilizing EIT-derived information on recruitability, overdistension and alveolar cycling. The aim of this study was to assess whether the EIT-based protocol allows individualization of ventilator settings without causing lung overdistension, and to evaluate its effects on respiratory system compliance, oxygenation and alveolar cycling. Methods 20 patients with ARDS were included. Initially, patients were ventilated according to the recommendations of the ARDS Network with a VT of 6 ml per kg predicted body weight and PEEP adjusted according to the lower PEEP/FiO2 table. Subsequently, ventilator settings were adjusted according to the EIT-based protocol once every 30 min for a duration of 4 h. To assess global overdistension, we determined whether lung stress and strain remained below 27 mbar and 2.0, respectively. Results Prospective optimization of mechanical ventilation with EIT led to higher PEEP levels (16.5 [14–18] mbar vs. 10 [8–10] mbar before optimization; p = 0.0001) and similar VT (5.7 ± 0.92 ml/kg vs. 5.8 ± 0.47 ml/kg before optimization; p = 0.96). Global lung stress remained below 27 mbar in all patients and global strain below 2.0 in 19 out of 20 patients. Compliance remained similar, while oxygenation was significantly improved and alveolar cycling was reduced after EIT-based optimization. Conclusions Adjustment of PEEP and VT using the EIT-based protocol led to individualization of ventilator settings with improved oxygenation and reduced alveolar cycling without promoting global overdistension. Trial registrationThis study was registered at clinicaltrials.gov (NCT02703012) on March 9, 2016 before including the first patient.

Individualization of PEEP and Tidal Volume in ARDS Patients with Electrical Impedance Tomography

BackgroundIn mechanically ventilated patients with acute respiratory distress syndrome (ARDS), electrical impedance tomography (EIT) provides information on alveolar cycling and overdistension as well as assessment of recruitability at the bedside. We developed a protocol for individualization of positive end-expiratory pressure (PEEP) and tidal volume (VT) utilizing EIT-derived information on recruitability, overdistension and alveolar cycling. The aim of this study was to assess whether the EIT-based protocol allows individualization of ventilator settings without causing lung overdistension, and to evaluate its effects on respiratory system compliance, oxygenation and alveolar cycling. Methods20 patients with ARDS were included. Initially, patients were ventilated according to the recommendations of the ARDS-Network with a VT of 6 ml per kg predicted body weight and PEEP adjusted according to the fraction of inspired oxygen. Subsequently, ventilator settings were adjusted according to the EIT-based protocol once every 30 minutes for a duration of 4 hours. To assess global overdistension, we determined whether lung stress and strain remained below 27 and 2.0, respectively. ResultsWe found that prospective optimization of mechanical ventilation with EIT led to global lung stress below 27 mbar in all patients and global strain below 2.0 in 19 out of 20 patients. Compliance remained similar while oxygenation was significantly improved and alveolar cycling was reduced after EIT-based optimization.ConclusionsAdjustment of PEEP and VT using the EIT-based protocol led to individualization of ventilator settings with improved oxygenation and reduced alveolar cycling without promoting global overdistension. Trial registrationThis study was registered at clinicaltrials.gov (NCT02703012) on March 9, 2016 before including the first patient.

Influence of overdistension/recruitment induced by high positive end-expiratory pressure on ventilation–perfusion matching assessed by electrical impedance tomography with saline bolus

Background High positive end-expiratory pressures (PEEP) may induce overdistension/recruitment and affect ventilation–perfusion matching (VQMatch) in mechanically ventilated patients. This study aimed to investigate the association between PEEP-induced lung overdistension/recruitment and VQMatch by electrical impedance tomography (EIT). Methods The study was conducted prospectively on 30 adult mechanically ventilated patients: 18/30 with ARDS and 12/30 with high risk for ARDS. EIT measurements were performed at zero end-expiratory pressures (ZEEP) and subsequently at high (12–15 cmH2O) PEEP. The number of overdistended pixels over the number of recruited pixels (O/R ratio) was calculated, and the patients were divided into low O/R (O/R ratio < 15%) and high O/R groups (O/R ratio ≥ 15%). The global inhomogeneity (GI) index was calculated to evaluate the ventilation distribution. Lung perfusion image was calculated from the EIT impedance–time curves caused by 10 ml 10% NaCl injection during a respiratory pause (> 8 s). DeadSpace%, Shunt%, and VQMatch% were calculated based on lung EIT perfusion and ventilation images. Results Increasing PEEP resulted in recruitment mainly in dorsal regions and overdistension mainly in ventral regions. ΔVQMatch% (VQMatch% at high PEEP minus that at ZEEP) was significantly correlated with recruited pixels (r = 0.468, P = 0.009), overdistended pixels (r = − 0.666, P < 0.001), O/R ratio (r = − 0.686, P < 0.001), and ΔSpO2 (r = 0.440, P = 0.015). Patients in the low O/R ratio group (14/30) had significantly higher Shunt% and lower VQMatch% than those in the high O/R ratio group (16/30) at ZEEP but not at high PEEP. Comparable DeadSpace% was found in both groups. A high PEEP caused a significant improvement of VQMatch%, DeadSpace%, Shunt%, and GI in the low O/R ratio group, but not in the high O/R ratio group. Using O/R ratio of 15% resulted in a sensitivity of 81% and a specificity of 100% for an increase of VQMatch% > 20% in response to high PEEP. Conclusions Change of ventilation–perfusion matching was associated with regional overdistention and recruitment induced by PEEP. A low O/R ratio induced by high PEEP might indicate a more homogeneous ventilation and improvement of VQMatch. Trial registration ClinicalTrials.gov, NCT04081155. Registered on 9 September 2019—retrospectively registered.

Electrical Impedance Tomography for Cardio-Pulmonary Monitoring

Electrical impedance tomography (EIT) is a bedside monitoring tool that noninvasively visualizes local ventilation and arguably lung perfusion distribution. This article reviews and discusses both methodological and clinical aspects of thoracic EIT. Initially, investigators addressed the validation of EIT to measure regional ventilation. Current studies focus mainly on its clinical applications to quantify lung collapse, tidal recruitment, and lung overdistension to titrate positive end-expiratory pressure (PEEP) and tidal volume. In addition, EIT may help to detect pneumothorax. Recent studies evaluated EIT as a tool to measure regional lung perfusion. Indicator-free EIT measurements might be sufficient to continuously measure cardiac stroke volume. The use of a contrast agent such as saline might be required to assess regional lung perfusion. As a result, EIT-based monitoring of regional ventilation and lung perfusion may visualize local ventilation and perfusion matching, which can be helpful in the treatment of patients with acute respiratory distress syndrome (ARDS).