Respiratory system compliance at the same PEEP level is similar in COVID and non-COVID ARDS

Background The comparison of respiratory system compliance (Crs) between COVID and non-COVID ARDS patients has been the object of debate, but few studies have evaluated it when considering applied positive end expiratory pressure (PEEP), which is one of the known determinants of Crs itself. The aim of this study was to compare Crs taking into account the applied PEEP. Methods Two cohorts of patients were created: those with COVID-ARDS and those with non-COVID ARDS. In the whole sample the association between Crs and type of ARDS at different PEEP levels was adjusted for anthropometric and clinical variables. As secondary analyses, patients were matched for predicted functional residual capacity and the same association was assessed. Moreover, the association between Crs and type of ARDS was reassessed at predefined PEEP level of 0, 5, 10, and 15 cmH2O with a propensity score-weighted linear model. Results 367 patients were included in the study, 276 patients with COVID-ARDS and 91 with non-COVID ARDS. The association between Crs and type of ARDS was not significant in both the complete cohorts (p = 0.17) and in the matched cohorts (p = 0.92). This was true also for the propensity score weighted association at PEEP 5, 10 and 15 cmH2O, while it was statistically significant at PEEP 0 (with a median difference of 3 ml/cmH2O, which in our opinion is not clinically significant). Conclusions The compliance of the respiratory system is similar between COVID ARDS and non-COVID ARDS when calculated at the same PEEP level and while taking into account patients’ anthropometric characteristics.

Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.

Positive end-expiratory pressure in COVID-19 acute respiratory distress syndrome: the heterogeneous effects

Background We hypothesized that as CARDS may present different pathophysiological features than classic ARDS, the application of high levels of end-expiratory pressure is questionable. Our first aim was to investigate the effects of 5–15 cmH2O of PEEP on partitioned respiratory mechanics, gas exchange and dead space; secondly, we investigated whether respiratory system compliance and severity of hypoxemia could affect the response to PEEP on partitioned respiratory mechanics, gas exchange and dead space, dividing the population according to the median value of respiratory system compliance and oxygenation. Thirdly, we explored the effects of an additional PEEP selected according to the Empirical PEEP-FiO2 table of the EPVent-2 study on partitioned respiratory mechanics and gas exchange in a subgroup of patients. Methods Sixty-one paralyzed mechanically ventilated patients with a confirmed diagnosis of SARS-CoV-2 were enrolled (age 60 [54–67] years, PaO2/FiO2 113 [79–158] mmHg and PEEP 10 [10–10] cmH2O). Keeping constant tidal volume, respiratory rate and oxygen fraction, two PEEP levels (5 and 15 cmH2O) were selected. In a subgroup of patients an additional PEEP level was applied according to an Empirical PEEP-FiO2 table (empirical PEEP). At each PEEP level gas exchange, partitioned lung mechanics and hemodynamic were collected. Results At 15 cmH2O of PEEP the lung elastance, lung stress and mechanical power were higher compared to 5 cmH2O. The PaO2/FiO2, arterial carbon dioxide and ventilatory ratio increased at 15 cmH2O of PEEP. The arterial–venous oxygen difference and central venous saturation were higher at 15 cmH2O of PEEP. Both the mechanics and gas exchange variables significantly increased although with high heterogeneity. By increasing the PEEP from 5 to 15 cmH2O, the changes in partitioned respiratory mechanics and mechanical power were not related to hypoxemia or respiratory compliance. The empirical PEEP was 18 ± 1 cmH2O. The empirical PEEP significantly increased the PaO2/FiO2 but also driving pressure, lung elastance, lung stress and mechanical power compared to 15 cmH2O of PEEP. Conclusions In COVID-19 ARDS during the early phase the effects of raising PEEP are highly variable and cannot easily be predicted by respiratory system characteristics, because of the heterogeneity of the disease.

Electrical Impedance Tomography Analysis Between Two Similar Respiratory System Compliance During Decremetal PEEP Titration in ARDS Patients

Purpose The positive end-expiratory pressure (PEEP) level with best respiratory system compliance (Crs) is frequently used for PEEP selection in acute respiratory distress syndrome (ARDS) patients. On occasion, two similar best Crs (where the difference between the Crs of two PEEP levels is < 1 ml/cm H2O) may be identified during decremental PEEP titration. Selecting PEEP under such conditions is challenging. The aim of this study was to provide supplementary rationale for PEEP selection by assessing the global and regional ventilation distributions between two PEEP levels in this situation. Methods Eight ARDS cases with similar best Crs at two different PEEP levels were analyzed using examination-specific electrical impedance tomography (EIT) measures and airway stress index (SIaw). Five Crs were measured at PEEP values of 25 cm H2O (PEEP25), 20 cm H2O (PEEP20), 15 cm H2O (PEEPH), 11 cm H2O (PEEPI), and 7 cm H2O (PEEPL). The higher PEEP value of the two PEEPs with similar best Crs was designated as PEEPupper, while the lower designated as PEEPlower. Results PEEPH and PEEPI shared the best Crs in two cases, while similar Crs was found at PEEPI and PEEPL in the remaining six cases. SIaw was higher with PEEPupper as compared to PEEPlower (1.06 ± 0.10 versus 0.99 ± 0.09, p = 0.05). Proportion of lung hyperdistension was significantly higher with PEEPupper than PEEPlower (7.0 ± 5.1% versus 0.3 ± 0.5%, p = 0.0002). In contrast, proportion of recruitable lung collapse was higher with PEEPlower than PEEPupper (18.6 ± 4.4% versus 5.9 ± 3.7%, p < 0.0001). Cyclic alveolar collapse and reopening during tidal breathing was higher at PEEPlower than PEEPupper (34.4 ± 19.3% versus 16.0 ± 9.1%, p = 0.046). The intratidal gas distribution (ITV) index was also significantly higher at PEEPlower than PEEPupper (2.6 ± 1.3 versus 1.8 ± 0.7, p = 0.042). Conclusions PEEPupper is a rational selection in ARDS cases with two similar best Crs. EIT provides additional information for the selection of PEEP in such circumstances.

Using exhalation dynamics to evaluate PEEP levels in COVID-19 related ARDS

Background We hypothesized that measured expiratory time constant (TauE) could be a bedside parameter for evaluation of PEEP settings in mechanically ventilated COVID-19 patients during pressure-controlled ventilation (PCV) mode. TauE is an easily measured parameter to assess lung physiology, even in non-homogeneous lungs including COVID-19 ARDS. Methods A prospective study was conducted including consecutively admitted adults (n = 16) with COVID-19 related ARDS requiring mechanical ventilation. Ventilator settings for all patients included: PCV, RR 18/min, constant inspiratory pressure 14 cmH2O, I:E ratio 1:1.5 and FiO2 1.0. Escalating levels of PEEP (0 to 18 cmH2O) were applied and measured TauE and expiratory tidal volume (Vte) recorded. Next, a new parameter, TauE Index (TEI) was calculated (TEI = TauE * Vte) at each PEEP level in prone (n = 29) or supine (n = 24) positions. TEI maps were created to graphically show changes in individual physiology with PEEP. The PEEP setting with the highest TEI corresponded to the highest product of TauE and Vte and was considered the most suitable PEEP. Most suitable PEEP range was calculated as ± 10% from highest TEI. Results Two groups of patterns were observed in the TEI maps, recruitable (R) (75%) and non-recruitable (NR) (25%). In R group, the most suitable PEEP and PEEP range was 9±3 cmH2O and 6-12 cmH2O for prone position and 11±3 cmH2O and 7-13 cmH2O for supine position. In NR group, the most suitable PEEP and PEEP range was 7±3 cmH2O and 0-8 cmH2O for prone position and 4±2 cmH2O and 0-7 cmH2O for supine position, respectively. The R group showed significantly higher suitable PEEP (p<0.01) and PEEP ranges (p<0.01) than NR group. 45% of measurements resulted in most suitable PEEP being significantly different between the positions (p < 0.01). Conclusions Based on TEI mapping, responses to PEEP were easily measured. There was wide variation in patient responses to PEEP that indicate the need for personalized evaluation.

Computed tomographic assessment of lung aeration at different positive end-expiratory pressures in a porcine model of intra-abdominal hypertension and lung injury

Background Intra-abdominal hypertension (IAH) is common in critically ill patients and is associated with increased morbidity and mortality. High positive end-expiratory pressures (PEEP) can reverse lung volume and oxygenation decline caused by IAH, but its impact on alveolar overdistension is less clear. We aimed to find a PEEP range that would be high enough to reduce atelectasis, while low enough to minimize alveolar overdistention in the presence of IAH and lung injury. Methods Five anesthetized pigs received standardized anesthesia and mechanical ventilation. Peritoneal insufflation of air was used to generate intra-abdominal pressure of 27 cmH2O. Lung injury was created by intravenous oleic acid. PEEP levels of 5, 12, 17, 22, and 27 cmH2O were applied. We performed computed tomography and measured arterial oxygen levels, respiratory mechanics, and cardiac output 5 min after each new PEEP level. The proportion of overdistended, normally aerated, poorly aerated, and non-aerated atelectatic lung tissue was calculated based on Hounsfield units. Results PEEP decreased the proportion of poorly aerated and atelectatic lung, while increasing normally aerated lung. Overdistension increased with each incremental increase in applied PEEP. “Best PEEP” (respiratory mechanics or oxygenation) was higher than the “optimal CT inflation PEEP range” (difference between lower inflection points of atelectatic and overdistended lung) in healthy and injured lungs. Conclusions Our findings in a large animal model suggest that titrating a PEEP to respiratory mechanics or oxygenation in the presence of IAH is associated with increased alveolar overdistension.

A Protective Tidal Volume Adapted To Lung Compliance and The PEEP Level With Lowest Transpulmonary Driving Pressure May Be Determined By a Rapid PEEP-Step Procedure

Background: A protective ventilation strategy should be based on lung mechanics and transpulmonary pressure, as this is the pressure that directly “hits” the lung. Esophageal pressure has been used for this purpose but has not gained widespread clinical acceptance. Instead, respiratory system mechanics and airway driving pressure have been used as surrogate measures. We have shown that the lung pressure/volume (P/V) curve coincides with the line connecting the end-expiratory airway P/V points of a PEEP trial. Consequently, transpulmonary pressure increases as much as PEEP and lung compliance (CL) can be determined as ΔEELV/ΔPEEP and transpulmonary driving pressure (ΔPTP) as tidal volume divided by ΔEELV/ΔPEEP.Methods: In ten patients with acute respiratory failure, ΔEELV was measured during each 4 cmH2O PEEP-step from 0 to 16 cmH2O and CL for each PEEP interval calculated as ΔEELV/ΔPEEP giving a lung P/V curve for the whole PEEP trial. Similarily, a lung P/V curve was obtained also for the PEEP levels 8, 12, and 16 cmH2O only.Results: A two-step PEEP procedure starting from a clinical PEEP level of 8 cmH2O gave almost identical lung P/V curves as the four PEEP-step procedure. The lung P/V curves showed a marked individual variation with an over-all CL (CLoa ) 50-137 ml/cmH2O. ΔPTP of a tidal volume of 6-7 ml/kg ideal body weight divided by CLoa ranged from 8.6-2.8 cmH2O, while ΔPTP of tidal volume adapted to CLoa ranged from 3.3 in the patient with lowest to 4.3 cmH 2 O in the patient with highest CLoa . The ratio of airway driving pressure to transpulmonary driving pressure (ΔPTP/ΔPAW) varied between patients and changed with PEEP, reducing the value of ΔPAW as surrogate for ΔPTP in individual patients.Conclusion: Only a two PEEP-step procedure is required for obtaining a lung P/V curve from baseline clinical PEEP to end-inspiration at the highest PEEP level, i.e. without esophageal pressure measurements. The best-fit equation for the curve can be used to determine a tidal volume related to lung compliance instead of ideal body weight and the PEEP level where transpulmonary driving pressure is lowest and possibly least injurious for any given tidal volume.

Measurement of Electrical Impedance Tomography-Based Regional Ventilation Delay for Individualized Titration of End-Expiratory Pressure

Rationale: Individualized positive end-expiratory pressure (PEEP) titration might be beneficial in preventing tidal recruitment. To detect tidal recruitment by electrical impedance tomography (EIT), the time disparity between the regional ventilation curves (regional ventilation delay inhomogeneity [RVDI]) can be measured during controlled mechanical ventilation when applying a slow inflation of 12 mL/kg of body weight (BW). However, repeated large slow inflations may result in high end-inspiratory pressure (PEI), which might limit the clinical applicability of this method. We hypothesized that PEEP levels that minimize tidal recruitment can also be derived from EIT-based RVDI through the use of reduced slow inflation volumes. Methods: Decremental PEEP trials were performed in 15 lung-injured pigs. The PEEP level that minimized tidal recruitment was estimated from EIT-based RVDI measurement during slow inflations of 12, 9, 7.5, or 6 mL/kg BW. We compared RVDI and PEI values resulting from different slow inflation volumes and estimated individualized PEEP levels. Results: RVDI values from slow inflations of 12 and 9 mL/kg BW showed excellent linear correlation (R2 = 0.87, p < 0.001). Correlations decreased for RVDI values from inflations of 7.5 (R2 = 0.68, p < 0.001) and 6 (R2 = 0.42, p < 0.001) mL/kg BW. Individualized PEEP levels estimated from 12 and 9 mL/kg BW were comparable (bias −0.3 cm H2O ± 1.2 cm H2O). Bias and scatter increased with further reduction in slow inflation volumes (for 7.5 mL/kg BW, bias 0 ± 3.2 cm H2O; for 6 mL/kg BW, bias 1.2 ± 4.0 cm H2O). PEI resulting from 9 mL/kg BW inflations were comparable with PEI during regular tidal volumes. Conclusions: PEEP titration to minimize tidal recruitment can be individualized according to EIT-based measurement of the time disparity of regional ventilation courses during slow inflations with low inflation volumes. This sufficiently decreases PEI and may reduce potential clinical risks.

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

The eSpiro Ventilator: An Open-Source Response to a Worldwide Pandemic

Objective: To address the issue of ventilator shortages, our group (eSpiro Network) developed a freely replicable, open-source hardware ventilator. Design: We performed a bench study. Setting: Dedicated research room as part of an ICU affiliated to a university hospital. Subjects: We set the lung model with three conditions of resistance and linear compliance for mimicking different respiratory mechanics of representative intensive care unit (ICU) patients. Interventions: The performance of the device was tested using the ASL5000 lung model. Measurements and Main Results: Twenty-seven conditions were tested. All the measurements fell within the ±10% limits for the tidal volume (VT). The volume error was influenced by the mechanical condition (p = 5.9 × 10−15) and the PEEP level (P = 1.1 × 10−12) but the clinical significance of this finding is likely meaningless (maximum −34 mL in the error). The PEEP error was not influenced by the mechanical condition (p = 0.25). Our experimental results demonstrate that the eSpiro ventilator is reliable to deliver VT and PEEP accurately in various respiratory mechanics conditions. Conclusions: We report a low-cost, easy-to-build ventilator, which is reliable to deliver VT and PEEP in passive invasive mechanical ventilation.