Impact of Positive End-Expiratory Pressure and FiO2 on Lung Mechanics and Intrapulmonary Shunt in Mechanically Ventilated Patients with ARDS Due to COVID-19 Pneumonia.

Purpose: This study aimed to investigate the effects of inspired oxygen fraction (FiO2) and positive end-expiratory pressure (PEEP) on gas exchange in mechanically ventilated patients with COVID-19. Methods: Two FiO2 (100%, 40%) were tested at 3 decreasing levels of PEEP (15, 10, and 5 cmH2O). At each FiO2 and PEEP, gas exchange, respiratory mechanics, hemodynamics, and the distribution of ventilation and perfusion were assessed with electrical impedance tomography. The impact of FiO2 on the intrapulmonary shunt (delta shunt) was analyzed as the difference between the calculated shunt at FiO2 100% (shunt) and venous admixture at FiO2 40% (venous admixture). Results: Fourteen patients were studied. Decreasing PEEP from 15 to 10 cmH2O did not change shunt (24 [21-28] vs 27 [24-29]%) or venous admixture (18 [15-26] vs 23 [18-34]%) while partial pressure of arterial oxygen (FiO2 100%) was higher at PEEP 15 (262 [198-338] vs 256 [147-315] mmHg; P < .05). Instead when PEEP was decreased from 10 to 5 cmH2O, shunt increased to 36 [30-39]% (P < .05) and venous admixture increased to 33 [30-43]% (P < .05) and partial pressure of arterial oxygen (100%) decreased to 109 [76-177] mmHg (P < .05). At PEEP 15, administration of 100% FiO2 resulted in a shunt greater than venous admixture at 40% FiO2, ((24 [21-28] vs 18 [15-26]%, P = .005), delta shunt 5.5% (2.3-8.8)). Compared to PEEP 10, PEEP of 5 and 15 cmH2O resulted in decreased global and pixel-level compliance. Cardiac output at FiO2 100% resulted higher at PEEP 5 (5.4 [4.4-6.5]) compared to PEEP 10 (4.8 [4.1-5.5], P < .05) and PEEP 15 cmH2O (4.7 [4.5-5.4], P < .05). Conclusion: In this study, PEEP of 15 cmH2O, despite resulting in the highest oxygenation, was associated with overdistension. PEEP of 5 cmH2O was associated with increased shunt and alveolar collapse. Administration of 100% FiO2 was associated with an increase in intrapulmonary shunt in the setting of high PEEP. Trial registration: NCT05132933.

Extracorporeal Chloride Removal by Electrodialysis. A Novel Approach to Correct Acidemia.

Rationale: Acidemia is a severe condition among critically ill patients. Despite lack of evidence, sodium bicarbonate is frequently used to correct pH; however, its administration is burdened by several side effects. We hypothesized that the reduction of plasma chloride concentration could be an alternative strategy to correct acidemia.Objectives: To evaluate feasibility, safety, and effectiveness of a novel strategy to correct acidemia through extracorporeal chloride removal by electrodialysis.Methods: Ten swine (six treated and four control animals) were sedated, mechanically ventilated and connected to an extracorporeal electrodialysis device capable of selectively removing chloride. In random order, an arterial pH of 7.15 was induced either through reduction of ventilation (respiratory acidosis) or through lactic acid infusion (metabolic acidosis). Acidosis was subsequently sustained for 12-14 hours. In treatment pigs, soon after reaching target acidemia, electrodialysis was started to restore pH.Measurements and Main Results: During respiratory acidosis, electrodialysis reduced plasma chloride concentration by 26 ± 5 mEq/L within 6 hours (final pH = 7.36 ± 0.04). Control animals exhibited incomplete and slower compensatory response to respiratory acidosis (final pH = 7.29 ± 0.03; P < 0.001). During metabolic acidosis, electrodialysis reduced plasma chloride concentration by 15 ± 3 mEq/L within 4 hours (final pH = 7.34 ± 0.07). No effective compensatory response occurred in control animals (final pH = 7.11 ± 0.08; P < 0.001). No complications occurred.Conclusions: We described the first in vivo application of an extracorporeal system targeted to correct severe acidemia by lowering plasma chloride concentration. Extracorporeal chloride removal by electrodialysis proved to be feasible, safe, and effective. Further studies are warranted to assess its performance in the presence of impaired respiratory and renal functions.

Enhanced extracorporeal carbon dioxide removal by acidification and metabolic control.

BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) promotes protective ventilation in patients with acute respiratory failure, but devices with high CO2 extraction capacity are required for clinically relevant impact. This study evaluates three novel low-flow techniques based on dialysate acidification, also combined with renal replacement therapy, and metabolic control. METHODS: Eight swine were connected to a low-flow (350 mL/min) extracorporeal circuit including a dialyzer with a closed-loop dialysate circuit, and two membrane lungs on blood (MLb) and dialysate (MLd), respectively. The following 2-hour steps were performed: 1) MLb-start (MLb ventilated); 2) MLbd-start (MLb and MLd ventilated); 3) HLac (lactic acid infusion before MLd); 4) HCl-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate); 5) HCl-ßHB-NaLac (hydrochloric acid infusion before MLd combined with renal replacement therapy and reinfusion of sodium lactate and sodium 3-hydroxybutyrate). Caloric and fluid inputs, temperature, blood glucose and arterial carbon dioxide pressure were kept constant. RESULTS: The total MLs CO2 removal in HLac (130±25 mL/min), HCl-NaLac (130±21 mL/min) and HCl-ßHB-NaLac (124±18 mL/min) were higher compared with MLbd-start (81±15 mL/min, P<0.05) and MLb-start (55±7 mL/min, P<0.05). Minute ventilation in HLac (4.3±0.9 L/min), HCl-NaLac (3.6±0.8 L/min) and HCl-ßHB-NaLac (3.6±0.8 L/min) were lower compared to MLb-start (6.2±1.1 L/min, P<0.05) and MLbd-start (5.8±2.1 L/min, P<0.05). Arterial pH was 7.40±0.03 at MLb-start and decreased only during HCl-ßHB-NaLac (7.35±0.03, P<0.05). No relevant changes in electrolyte concentrations, hemodynamics and significant adverse events were detected. CONCLUSIONS: The three techniques achieved a significant extracorporeal CO2 removal allowing a relevant reduction in minute ventilation with a sufficient safety profile.

Detection of strong inspiratory efforts from the analysis of central venous pressure swings: a preliminary clinical study.

BACKGROUND: Swings of central venous pressure (ΔCVP) may reflect those of pleural and esophageal (ΔPES) pressure and, therefore, the strength of inspiration. Strong inspiratory efforts can produce some harm. Herein we preliminarily assessed the diagnostic accuracy of ΔCVP for strong inspiratory efforts in critically-ill subjects breathing spontaneously. METHODS: We measured ΔCVP and ΔPES in 48 critically-ill subjects breathing spontaneously with zero end-expiratory pressure (ZEEP) or 10 cmH2O of continuous positive airway pressure (CPAP). The overall diagnostic accuracy of ΔCVP for strong inspiratory efforts (arbitrarily defined as ΔPES >8 mmHg) was described as the area under the receiver operating characteristic (ROC) curve, with 0.50 indicating random guess. The agreement between ΔCVP and ΔPES was assessed with the Bland-Altman analysis. RESULTS: ΔCVP recognized strong inspiratory efforts with an area under the ROC curve of 0.95 (95% confidence intervals, 0.85-0.99) with ZEEP and 0.89 (0.76-0.96) with CPAP, both significantly larger than 0.50 (P<0.001). With the best cut-off value around 8 mmHg, the diagnostic accuracy of ΔCVP was 0.92 (0.80-0.98) with ZEEP and 0.94 (0.83-0.99) with CPAP. With ZEEP, the median difference between ΔCVP and ΔPES (bias) was -0.2 mmHg, and the 95% limits of agreement (LoA) were -3.9 and +5.5 mmHg. With CPAP, bias was -0.1 mmHg, and 95%-LoA were -5.8 and +4.5 mmHg. In both cases, ΔCVP correlated with ΔPES (rs 0.81 and 0.67; P<0.001 for both). CONCLUSIONS: In critically-ill subjects breathing spontaneously, ΔCVP recognized strong inspiratory efforts with acceptable accuracy. Even so, it sometimes largely differed from ∆PES.

Patterns of Use of Adjunctive Therapies in Patients With Early Moderate to Severe ARDS: Insights From the LUNG SAFE Study.

BACKGROUND: Adjunctive strategies are an important part of the management of ARDS. However, their application in clinical practice remains inconsistent. RESEARCH QUESTION: We wished to determine the frequency and patterns of use of adjunctive strategies in patients with moderate to severe ARDS (Pao2/Fio2 [P/F ratio] < 150) enrolled into the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. STUDY DESIGN AND METHODS: The LUNG SAFE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in 2014 in 459 ICUs from 50 countries. The primary objective of this substudy was to determine the frequency of use of widely available (neuromuscular blockade, prone position) adjuncts vs adjuncts requiring specialized equipment (extracorporeal membrane oxygenation, inhaled vasodilators, high-frequency ventilation) in patients in the first 48 h of moderate to severe ARDS (P/F ratio < 150). RESULTS: Of 1,146 patients on invasive ventilation with moderate to severe ARDS, 811 patients (71%) received no adjunct within 48 h of ARDS onset. Of 335 (29%) that received adjunctive strategies, 252 (75%) received a single strategy, and 83 (25%) receiving more than one adjunct. Of ARDS nonsurvivors, 67% did not receive any adjunctive strategy in the first 48 h. Most patients (67%) receiving specialized adjuncts did not receive prone positioning or neuromuscular blockade. Patients that received adjuncts were more likely to have their ARDS recognized, be younger and sicker, have pneumonia, be more difficult to ventilate, and be in a European high-income country than those that did not receive adjuncts. INTERPRETATION: Three in 10 patients with moderate to severe ARDS, and only one-third of nonsurvivors, received adjunctive strategies over the first 48 h of ARDS. A more consistent and evidence-driven approach to adjunct use may reduce costs and improve outcomes in patients with moderate to severe ARDS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02010073; URL: www.clinicaltrials.gov.

Continuous Renal Replacement Therapy in Venovenous Extracorporeal Membrane Oxygenation: A Retrospective Study on Regional Citrate Anticoagulation.

Systemic infusion of unfractionated heparin (UFH) is the standard anticoagulation technique for continuous renal replacement therapy (CRRT) during extracorporeal membrane oxygenation (ECMO), but often fails to avoid CRRT circuit clotting. The aim of this study was to assess, in patients undergoing CRRT during venovenous ECMO (vv-ECMO), the efficacy and safety of adding regional citrate anticoagulation (RCA) for CRRT circuit anticoagulation (RCA + UFH group) compared with the sole systemic heparin anticoagulation (UFH group). We performed a retrospective chart review (2009-2018) of patients treated with CRRT during ECMO. We evaluated filter life span, rate of CRRT circuit clotting, and coagulation parameters. The incidence of citrate anticoagulation-related complications was recorded. Forty-eight consecutive adult patients underwent CRRT during vv-ECMO in the study period. The incidence of CRRT circuit clotting was lower in the RCA + UFH group (11% vs. 38% in the UFH group, p < 0.001). Log-rank survival analysis demonstrated longer circuit lifetime for RCA + UFH group. No complication ascribable to citrate anticoagulation was recorded. Regional citrate anticoagulation resulted a feasible, safe, and effective technique as additional anticoagulation for CRRT circuits during ECMO. Compared with systemic heparinization only, this technique allowed to reduce the rate of CRRT circuit clotting.

Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design.

PURPOSE: To describe the variability and determinants of the effect of extracorporeal CO2 removal (ECCO2R) on tidal volume (Vt), driving pressure (ΔP), and mechanical power (PowerRS) and to determine whether highly responsive patients can be identified for the purpose of predictive enrichment in ECCO2R trial design. METHODS: Using data from the SUPERNOVA trial (95 patients with early moderate acute respiratory distress syndrome), the independent effects of alveolar dead space fraction (ADF), respiratory system compliance (Crs), hypoxemia (PaO2/FiO2), and device performance (higher vs lower CO2 extraction) on the magnitude of reduction in Vt, ΔP, and PowerRS permitted by ECCO2R were assessed by linear regression. Predicted and observed changes in ΔP were compared by Bland-Altman analysis. Hypothetical trials of ECCO2R, incorporating predictive enrichment and different target CO2 removal rates, were simulated in the SUPERNOVA study population. RESULTS: Changes in Vt permitted by ECCO2R were independently associated with ADF and device performance but not PaO2/FiO2. Changes in ΔP and PowerRS were independently associated with ADF, Crs, and device performance but not PaO2/FiO2. The change in ΔP predicted from ADF and Crs was moderately correlated with observed change in ΔP (R2 0.32, p < 0.001); limits of agreement between observed and predicted changes in ΔP were ± 3.9 cmH2O. In simulated trials, restricting enrollment to patients with a larger predicted decrease in ΔP enhanced the average reduction in ΔP, increased predicted mortality benefit, and reduced sample size and screening size requirements. The increase in statistical power obtained by restricting enrollment based on predicted ΔP response varied according to device performance as specified by the target CO2 removal rate. CONCLUSIONS: The lung-protective benefits of ECCO2R increase with higher alveolar dead space fraction, lower respiratory system compliance, and higher device performance. ADF and Crs, rather than severity of hypoxemia, should be the primary factors determining whether to enroll patients in clinical trials of ECCO2R.

Prevention of Lung Bacterial Colonization With a Leak-Proof Endotracheal Tube Cuff: An Experimental Animal Study.

BACKGROUND: Endotracheal tubes with standard polyvinyl chloride cuffs create folds on inflation into the trachea, which lead to potential leakage of subglottic secretions into the lower airways and cause lung colonization and pneumonia. The use of a double-layer prototype leak-proof cuff has shown effective prevention of the fluid leakage across the cuff. We hypothesized that the use of such a leak-proof cuff could prevent lung bacterial colonization in vivo. METHODS: To simulate patients in the ICU, 13 pigs were placed in the semirecumbent position, intubated, and mechanically ventilated for 72 h. Five animals were prospectively intubated with an endotracheal tube with a leak-proof cuff (leak-proof cuff group). Data from 8 animals previously intubated with an endotracheal tube with a standard polyvinyl chloride cuff (standard cuff group) were retrospectively analyzed. Leakage of tracheal secretions across the leak-proof cuff was tested by the macroscopic methylene blue evaluation. Arterial blood gas exchanges and microbiology were tested in all the pigs at necropsy. RESULTS: In the standard cuff group, all the pigs showed heavy bacterial colonization of the lungs after 72 h of mechanical ventilation, with an overall proportion of colonized lung lobes of 92% (44/48 lobes, 8/8 animals) compared with 27% (8/30 lobes, 5/5 animals) in the leak-proof cuff group (P < .001). These results were strengthened by the absence of methylene blue in the tracheal secretions below the leak-proof cuff. Furthermore, no hypoxemia was demonstrated in the pigs in the leak-proof cuff group after the 72-h experiment (PaO2 /FIO2 change from baseline, leak-proof cuff group vs standard cuff group; median difference 332, 95% CI 41-389 mm Hg; P = .030). CONCLUSIONS: A new leak-proof cuff for endotracheal intubation prevented macroscopic leakage of subglottic secretions along the airways. This mechanism led to the reduction of lung bacterial colonization, which could contribute to the prevention of hypoxemia in the pigs on mechanical ventilation while in the semirecumbent position.

An Artificial Cough Maneuver to Remove Secretions From Below the Endotracheal Tube Cuff.

BACKGROUND: Endotracheal suctioning is mandatory to prevent complications caused by the retention of tracheal secretions. Endotracheal suctioning is often performed late, when patients show signs of respiratory and hemodynamic alterations. We conceived a prototype device that, when synchronized with the ventilator, automatically removes secretions collected below the endotracheal tube (ETT) cuff, thus avoiding endotracheal suctioning. The aim of our investigation was to assess the performance of this novel prototype in vitro. METHODS: Three studies were performed to examine the characteristics of the prototype. We tested device's ability to generate an effective artificial cough flow (artificial cough maneuver) > 1 L/s by rapidly deflating the ETT cuff within the time of a sustained inflation (at 30 and at 40 cm H2O) (cough flow study). We also tested the prototype's ability to remove the fluid positioned below the ETT cuff using saline dye (fluid removal study), and to prevent the aspiration of saline dye from above the ETT cuff during the deflation phase of the ETT cuff (aspiration study). The trachea model was positioned at 45° in the aspiration study, and horizontally in the other two studies. RESULTS: In the cough flow study, the prototype provided an effective artificial cough maneuver, with a mean ± SD of 1.78 ± 0.19 L/s (range, 1.42-2.14 L/s). The tracheal pressure after ETT cuff deflation never decreased below the PEEP level. In the fluid removal study, the prototype cleared the fluid from below the ETT cuff and the experimental trachea. No fluid was aspirated from the area above the ETT cuff toward the lower airways. CONCLUSIONS: We conceived an system capable of automatically expelling fluid from below the ETT cuff outside an experimental trachea by generating an artificial cough maneuver. This system may decrease the use of endotracheal suctioning and its complications. Future in vivo studies are needed to confirm this first in vitro evaluation.