Comparative effects of variable versus conventional volume-controlled one-lung ventilation on gas exchange and respiratory system mechanics in thoracic surgery patients: A randomized controlled clinical trial.

BACKGROUND: Mechanical ventilation with variable tidal volumes (V-VCV) has the potential to improve lung function during general anesthesia. We tested the hypothesis that V-VCV compared to conventional volume-controlled ventilation (C-VCV) would improve intraoperative arterial oxygenation and respiratory system mechanics in patients undergoing thoracic surgery under one-lung ventilation (OLV). METHODS: Patients were randomized to V-VCV (n = 39) or C-VCV (n = 39). During OLV tidal volume of 5 mL/kg predicted body weight (PBW) was used. Both groups were ventilated with a positive end-expiratory pressure (PEEP) of 5 cm H2O, inspiration to expiration ratio (I:E) of 1:1 (during OLV) and 1:2 during two-lung ventilation, the respiratory rate (RR) titrated to arterial pH, inspiratory peak-pressure ≤ 40 cm H2O and an inspiratory oxygen fraction of 1.0. RESULTS: Seventy-five out of 78 Patients completed the trial and were analyzed (dropouts were excluded). The partial pressure of arterial oxygen (PaO2) 20 min after the start of OLV did not differ among groups (V-VCV: 25.8 ± 14.6 kPa vs C-VCV: 27.2 ± 15.3 kPa; mean difference [95% CI]: 1.3 [-8.2, 5.5], P = 0.700). Furthermore, intraoperative gas exchange, intraoperative adverse events, need for rescue maneuvers due to desaturation and hypercapnia, incidence of postoperative pulmonary and extra-pulmonary complications, and hospital free days at day 30 after surgery did not differ between groups. CONCLUSIONS: In thoracic surgery patients under OLV, V-VCV did not improve oxygenation or respiratory system mechanics compared to C-VCV. Ethical Committee: EK 420092019. TRIAL REGISTRATION: at the German Clinical Trials Register: DRKS00022202 (16.06.2020).

Effects of positive end-expiratory pressure on pulmonary perfusion distribution and intrapulmonary shunt during one-lung ventilation in pigs A randomized crossover study.

BACKGROUND: During one-lung ventilation (OLV), positive end-expiratory pressure (PEEP) can improve lung aeration, but might over-distend lung units and increase intrapulmonary shunt. We hypothesized that higher PEEP shifts pulmonary perfusion from the ventilated to the non-ventilated lung, resulting in a U-shaped relationship with intrapulmonary shunt during OLV. METHODS: In nine anesthetized female pigs, a thoracotomy was performed and intravenous lipopolysaccharide infused to mimic the inflammatory response of thoracic surgery. Animals underwent OLV in supine position with PEEP of 0 cmH2O, 5 cmH2O, titrated to best respiratory system compliance, and 15 cmH2O (PEEP0, PEEP5, PEEPtitr, and PEEP15, respectively, 45 min each, Latin square sequence). Respiratory, hemodynamic, and gas exchange variables were measured. The distributions of perfusion and ventilation were determined by i.v. fluorescent microspheres and computed tomography, respectively. RESULTS: Compared to two lung ventilation, the driving pressure increased with OLV, irrespective of the PEEP level. During OLV, cardiac output was lower at PEEP15 (5.5 ± 1.5 l/min) than PEEP0 (7.6 ± 3 l/min) and PEEP5 (7.4 ± 2.9 l/min; P=0.004), while the intrapulmonary shunt was highest at PEEP0 (PEEP0: 48.1 ± 14.4 %; PEEP5: 42.4 ± 14.8 %; PEEPtitr: 37.8 ± 11.0 %; PEEP15: 39.0 ± 10.7 %; P=0.027). The relative perfusion of the ventilated lung did not differ among PEEP levels (PEEP0: 65.0 ± 10.6 %; PEEP5:68.7 ± 8.7 %; PEEPtitr: 68.2 ± 10.5 %; PEEP15: 58.4 ± 12.8%; P=0.096), but the centers of relative perfusion and ventilation in the ventilated lung shifted from ventral to dorsal, and from cranial to caudal zones with increasing PEEP. CONCLUSION: In this experimental model of thoracic surgery, higher PEEP during OLV did not shift the perfusion from the ventilated to the non-ventilated lung, thus not increasing intrapulmonary shunt. TRIAL REGISTRATION: This study was registered and approved by the Landesdirektion Dresden, Germany (25-5131/496/33).

Respiratory mechanics and mechanical power during low vs. high positive end-expiratory pressure in obese surgical patients - A sub-study of the PROBESE randomized controlled trial.

STUDY OBJECTIVE: We aimed to characterize intra-operative mechanical ventilation with low or high positive end-expiratory pressure (PEEP) and recruitment manoeuvres (RM) regarding intra-tidal recruitment/derecruitment and overdistension using non-linear respiratory mechanics, and mechanical power in obese surgical patients enrolled in the PROBESE trial. DESIGN: Prospective, two-centre substudy of the international, multicentre, two-arm, randomized-controlled PROBESE trial. SETTING: Operating rooms of two European University Hospitals. PATIENTS: Forty-eight adult obese patients undergoing abdominal surgery. INTERVENTIONS: Intra-operative protective ventilation with either PEEP of 12 cmH2O and repeated RM (HighPEEP+RM) or 4 cmH2O without RM (LowPEEP). MEASUREMENTS: The index of intra-tidal recruitment/de-recruitment and overdistension (%E2) as well as airway pressure, tidal volume (VT), respiratory rate (RR), resistance, elastance, and mechanical power (MP) were calculated from respiratory signals recorded after anesthesia induction, 1 h thereafter, and end of surgery (EOS). MAIN RESULTS: Twenty-four patients were analyzed in each group. PEEP was higher (mean ± SD, 11.7 ± 0.4 vs. 3.7 ± 0.6 cmH2O, P < 0.001) and driving pressure lower (12.8 ± 3.5 vs. 21.7 ± 6.8 cmH2O, P < 0.001) during HighPEEP+RM than LowPEEP, while VT and RR did not differ significantly (7.3 ± 0.6 vs. 7.4 ± 0.8 ml∙kg-1, P = 0.835; and 14.6 ± 2.5 vs. 15.7 ± 2.0 min-1, P = 0.150, respectively). %E2 was higher in HighPEEP+RM than in LowPEEP following induction (-3.1 ± 7.2 vs. -12.4 ± 10.2%; P < 0.001) and subsequent timepoints. Total resistance and elastance (13.3 ± 3.8 vs. 17.7 ± 6.8 cmH2O∙l∙s-2, P = 0.009; and 15.7 ± 5.5 vs. 28.5 ± 8.4 cmH2O∙l, P < 0.001, respectively) were lower during HighPEEP+RM than LowPEEP. Additionally, MP was lower in HighPEEP+RM than LowPEEP group (5.0 ± 2.2 vs. 10.4 ± 4.7 J∙min-1, P < 0.001). CONCLUSIONS: In this sub-cohort of PROBESE, intra-operative ventilation with high PEEP and RM reduced intra-tidal recruitment/de-recruitment as well as driving pressure, elastance, resistance, and mechanical power, as compared with low PEEP. TRIAL REGISTRATION: The PROBESE study was registered at www. CLINICALTRIALS: gov, identifier: NCT02148692 (submission for registration on May 23, 2014).

Modulation of the hippo-YAP pathway by cyclic stretch in rat type 2 alveolar epithelial cells-a proof-of-concept study.

Background: Mechanical ventilation (MV) is a life supporting therapy but may also cause lung damage. This phenomenon is known as ventilator-induced lung injury (VILI). A potential pathomechanisms of ventilator-induced lung injury may be the stretch-induced production and release of cytokines and pro-inflammatory molecules from the alveolar epithelium. Yes-associated protein (YAP) might be regulated by mechanical forces and involved in the inflammation cascade. However, its role in stretch-induced damage of alveolar cells remains poorly understood. In this study, we explored the role of YAP in the response of alveolar epithelial type II cells (AEC II) to elevated cyclic stretch in vitro. We hypothesize that Yes-associated protein activates its downstream targets and regulates the interleukin-6 (IL-6) expression in response to 30% cyclic stretch in AEC II. Methods: The rat lung L2 cell line was exposed to 30% cyclic equibiaxial stretch for 1 or 4 h. Non-stretched conditions served as controls. The cytoskeleton remodeling and cell junction integrity were evaluated by F-actin and Pan-cadherin immunofluorescence, respectively. The gene expression and protein levels of IL-6, Yes-associated protein, Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and connective tissue growth factor (CTGF/CCN2) were studied by real-time polymerase chain reaction (RT-qPCR) and Western blot, respectively. Verteporfin (VP) was used to inhibit Yes-associated protein activation. The effects of 30% cyclic stretch were assessed by two-way ANOVA. Statistical significance as accepted at p < 0.05. Results: Cyclic stretch of 30% induced YAP nuclear accumulation, activated the transcription of Yes-associated protein downstream targets Cyr61/CCN1 and CTGF/CCN2 and elevated IL-6 expression in AEC II after 1 hour, compared to static control. VP (2 µM) inhibited Yes-associated protein activation in response to 30% cyclic stretch and reduced IL-6 protein levels. Conclusion: In rat lung L2 AEC II, 30% cyclic stretch activated YAP, and its downstream targets Cyr61/CCN1 and CTGF/CCN2 and proinflammatory IL-6 expression. Target activation was blocked by a Yes-associated protein inhibitor. This novel YAP-dependent pathway could be involved in stretch-induced damage of alveolar cells.

Distribution of transpulmonary pressure during one-lung ventilation in pigs at different body positions.

Background. Global and regional transpulmonary pressure (PL) during one-lung ventilation (OLV) is poorly characterized. We hypothesized that global and regional PL and driving PL (ΔPL) increase during protective low tidal volume OLV compared to two-lung ventilation (TLV), and vary with body position. Methods. In sixteen anesthetized juvenile pigs, intra-pleural pressure sensors were placed in ventral, dorsal, and caudal zones of the left hemithorax by video-assisted thoracoscopy. A right thoracotomy was performed and lipopolysaccharide administered intravenously to mimic the inflammatory response due to thoracic surgery. Animals were ventilated in a volume-controlled mode with a tidal volume (VT) of 6 mL kg-1 during TLV and of 5 mL kg-1 during OLV and a positive end-expiratory pressure (PEEP) of 5 cmH2O. Global and local transpulmonary pressures were calculated. Lung instability was defined as end-expiratory PL<2.9 cmH2O according to previous investigations. Variables were acquired during TLV (TLVsupine), left lung ventilation in supine (OLVsupine), semilateral (OLVsemilateral), lateral (OLVlateral) and prone (OLVprone) positions randomized according to Latin-square sequence. Effects of position were tested using repeated measures ANOVA. Results. End-expiratory PL and ΔPL were higher during OLVsupine than TLVsupine. During OLV, regional end-inspiratory PL and ΔPL did not differ significantly among body positions. Yet, end-expiratory PL was lower in semilateral (ventral: 4.8 ± 2.9 cmH2O; caudal: 3.1 ± 2.6 cmH2O) and lateral (ventral: 1.9 ± 3.3 cmH2O; caudal: 2.7 ± 1.7 cmH2O) compared to supine (ventral: 4.8 ± 2.9 cmH2O; caudal: 3.1 ± 2.6 cmH2O) and prone position (ventral: 1.7 ± 2.5 cmH2O; caudal: 3.3 ± 1.6 cmH2O), mainly in ventral (p ≤ 0.001) and caudal (p = 0.007) regions. Lung instability was detected more often in semilateral (26 out of 48 measurements; p = 0.012) and lateral (29 out of 48 measurements, p < 0.001) as compared to supine position (15 out of 48 measurements), and more often in lateral as compared to prone position (19 out of 48 measurements, p = 0.027). Conclusion. Compared to TLV, OLV increased lung stress. Body position did not affect stress of the ventilated lung during OLV, but lung stability was lowest in semilateral and lateral decubitus position.

Variable ventilation versus stepwise lung recruitment manoeuvres for lung recruitment: A comparative study in an experimental model of atelectasis.

BACKGROUND: Variable ventilation recruits alveoli in atelectatic lungs, but it is unknown how it compares with conventional recruitment manoeuvres. OBJECTIVES: To test whether mechanical ventilation with variable tidal volumes and conventional recruitment manoeuvres have comparable effects on lung function. DESIGN: Randomised crossover study. SETTING: University hospital research facility. ANIMALS: Eleven juvenile mechanically ventilated pigs with atelectasis created by saline lung lavage. INTERVENTIONS: Lung recruitment was performed using two strategies, both with an individualised optimal positive-end expiratory pressure (PEEP) associated with the best respiratory system elastance during a decremental PEEP trial: conventional recruitment manoeuvres (stepwise increase of PEEP) in pressure-controlled mode) followed by 50 min of volume-controlled ventilation (VCV) with constant tidal volume, and variable ventilation, consisting of 50 min of VCV with random variation in tidal volume. MAIN OUTCOME MEASURES: Before and 50 min after each recruitment manoeuvre strategy, lung aeration was assessed by computed tomography, and relative lung perfusion and ventilation (0% = dorsal, 100% = ventral) were determined by electrical impedance tomography. RESULTS: After 50 min, variable ventilation and stepwise recruitment manoeuvres decreased the relative mass of poorly and nonaerated lung tissue (percent lung mass: 35.3 ±â€Š6.2 versus 34.2 ±â€Š6.6, P  = 0.303); reduced poorly aerated lung mass compared with baseline (-3.5 ±â€Š4.0%, P  = 0.016, and -5.2 ±â€Š2.8%, P  < 0.001, respectively), and reduced nonaerated lung mass compared with baseline (-7.2 ±â€Š2.5%, P  < 0.001; and -4.7 ±â€Š2.8%, P  < 0.001 respectively), while the distribution of relative perfusion was barely affected (variable ventilation: -0.8 ±â€Š1.1%, P  = 0.044; stepwise recruitment manoeuvres: -0.4 ±â€Š0.9%, P  = 0.167). Compared with baseline, variable ventilation and stepwise recruitment manoeuvres increased Pa O 2 (172 ±â€Š85mmHg, P  = 0.001; and 213 ±â€Š73 mmHg, P  < 0.001, respectively), reduced Pa CO 2 (-9.6 ±â€Š8.1 mmHg, P  = 0.003; and -6.7 ±â€Š4.6 mmHg, P  < 0.001, respectively), and decreased elastance (-11.4 ±â€Š6.3 cmH 2 O, P  < 0.001; and -14.1 ±â€Š3.3 cmH 2 O, P  < 0.001, respectively). Mean arterial pressure decreased during stepwise recruitment manoeuvres (-24 ±â€Š8 mmHg, P  = 0.006), but not variable ventilation. CONCLUSION: In this model of lung atelectasis, variable ventilation and stepwise recruitment manoeuvres effectively recruited lungs, but only variable ventilation did not adversely affect haemodynamics. TRIAL REGISTRATION: This study was registered and approved by Landesdirektion Dresden, Germany (DD24-5131/354/64).

Effect of patient-ventilator asynchrony on lung and diaphragmatic injury in experimental acute respiratory distress syndrome in a porcine model.

BACKGROUND: Patient-ventilator asynchrony during mechanical ventilation may exacerbate lung and diaphragm injury in spontaneously breathing subjects. We investigated whether subject-ventilator asynchrony increases lung or diaphragmatic injury in a porcine model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced in adult female pigs by lung lavage and injurious ventilation before mechanical ventilation by pressure assist-control for 12 h. Mechanically ventilated pigs were randomised to breathe spontaneously with or without induced subject-ventilator asynchrony or neuromuscular block (n=7 per group). Subject-ventilator asynchrony was produced by ineffective, auto-, or double-triggering of spontaneous breaths. The primary outcome was mean alveolar septal thickness (where thickening of the alveolar wall indicates worse lung injury). Secondary outcomes included distribution of ventilation (electrical impedance tomography), lung morphometric analysis, inflammatory biomarkers (gene expression), lung wet-to-dry weight ratio, and diaphragmatic muscle fibre thickness. RESULTS: Subject-ventilator asynchrony (median [interquartile range] 28.8% [10.4] asynchronous breaths of total breaths; n=7) did not increase mean alveolar septal thickness compared with synchronous spontaneous breathing (asynchronous breaths 1.0% [1.6] of total breaths; n=7). There was no difference in mean alveolar septal thickness throughout upper and lower lung lobes between pigs randomised to subject-ventilator asynchrony vs synchronous spontaneous breathing (87.3-92.2 µm after subject-ventilator asynchrony, compared with 84.1-95.0 µm in synchronised spontaneous breathing;). There were also no differences between groups in wet-to-dry weight ratio, diaphragmatic muscle fibre thickness, atelectasis, lung aeration, or mRNA expression levels for inflammatory cytokines pivotal in ARDS pathogenesis. CONCLUSIONS: Subject-ventilator asynchrony during spontaneous breathing did not exacerbate lung injury and dysfunction in experimental porcine ARDS.

Changes in lung aeration and respiratory function after open abdominal surgery: A quantitative magnetic resonance imaging study.

BACKGROUND: Atelectasis is one of the most common respiratory complications in patients undergoing open abdominal surgery. Peripheral oxygen saturation (SpO2 ) and forced vital capacity (FVC) are bedside indicators of postoperative respiratory dysfunction. The aim of this study was to describe the changes in lung aeration, using quantitative analysis of magnetic resonance imaging (MRI) and the diagnostic accuracy of SpO2 and FVC to detect postoperative atelectasis. METHODS: Post-hoc analysis of a randomized trial conducted at a University Hospital in Dresden, Germany. Patients undergoing pre- and postoperative lung MRI were included. MRI signal intensity was analyzed quantitatively to define poorly and nonaerated lung compartments. Postoperative atelectasis was defined as nonaerated lung volume above 2% of the total lung volume in the respective MRI investigation. RESULTS: This study included 45 patients, 27 with and 18 patients without postoperative atelectasis. Patients with atelectasis had higher body mass index (p = .024), had more preoperative poorly aerated lung volume (p = .049), a lower preoperative SpO2 (p = .009), and a lower preoperative FVC (p = .029). The amount of atelectasis correlated with preoperative SpO2 (Spearman's ρ = -.51, p < .001) and postoperative SpO2 (ρ = -.60, p < .001), and with preoperative FVC (ρ = -.29, p = .047) and postoperative FVC (ρ = -.40, p = .006). A postoperative SpO2 ≤ 94% had 74% sensitivity and 78% specificity to detect atelectasis, while postoperative FVC ≤ 50% had 56% sensitivity and 100% specificity to detect atelectasis. CONCLUSION: SpO2 and FVC correlated with the amount of postoperative non-aerated lung volume, showing acceptable diagnostic accuracy in bedside detection of postoperative atelectasis.

Static Stretch Increases the Pro-Inflammatory Response of Rat Type 2 Alveolar Epithelial Cells to Dynamic Stretch.

Background: Mechanical ventilation (MV) inflicts stress on the lungs, initiating or increasing lung inflammation, so-called ventilator-induced lung injury (VILI). Besides overdistention, cyclic opening-and-closing of alveoli (atelectrauma) is recognized as a potential mechanism of VILI. The dynamic stretch may be reduced by positive end-expiratory pressure (PEEP), which in turn increases the static stretch. We investigated whether static stretch modulates the inflammatory response of rat type 2 alveolar epithelial cells (AECs) at different levels of dynamic stretch and hypothesized that static stretch increases pro-inflammatory response of AECs at given dynamic stretch. Methods: AECs, stimulated and not stimulated with lipopolysaccharide (LPS), were subjected to combinations of static (10, 20, and 30%) and dynamic stretch (15, 20, and 30%), for 1 and 4 h. Non-stretched AECs served as control. The gene expression and secreted protein levels of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein 2 (MIP-2) were studied by real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The effects of static and dynamic stretch were assessed by two-factorial ANOVA with planned effects post-hoc comparison according to Sidák. Statistical significance was considered for p < 0.05. Results: In LPS-stimulated, but not in non-stimulated rat type 2 AECs, compared to non-stretched cells: 1) dynamic stretch increased the expression of amphiregulin (AREG) (p < 0.05), MCP-1 (p < 0.001), and MIP-2 (<0.05), respectively, as well as the protein secretion of IL-6 (p < 0.001) and MCP-1 (p < 0.05); 2) static stretch increased the gene expression of MCP-1 (p < 0.001) and MIP-2, but not AREG, and resulted in higher secretion of IL-6 (p < 0.001), but not MCP-1, while MIP-2 was not detectable in the medium. Conclusion: In rat type 2 AECs stimulated with LPS, static stretch increased the pro-inflammatory response to dynamic stretch, suggesting a potential pro-inflammatory effect of PEEP during mechanical ventilation at the cellular level.

Mechanical Power Correlates With Lung Inflammation Assessed by Positron-Emission Tomography in Experimental Acute Lung Injury in Pigs.

Background: Mechanical ventilation (MV) may initiate or worsen lung injury, so-called ventilator-induced lung injury (VILI). Although different mechanisms of VILI have been identified, research mainly focused on single ventilator parameters. The mechanical power (MP) summarizes the potentially damaging effects of different parameters in one single variable and has been shown to be associated with lung damage. However, to date, the association of MP with pulmonary neutrophilic inflammation, as assessed by positron-emission tomography (PET), has not been prospectively investigated in a model of clinically relevant ventilation settings yet. We hypothesized that the degree of neutrophilic inflammation correlates with MP. Methods: Eight female juvenile pigs were anesthetized and mechanically ventilated. Lung injury was induced by repetitive lung lavages followed by initial PET and computed tomography (CT) scans. Animals were then ventilated according to the acute respiratory distress syndrome (ARDS) network recommendations, using the lowest combinations of positive end-expiratory pressure and inspiratory oxygen fraction that allowed adequate oxygenation. Ventilator settings were checked and adjusted hourly. Physiological measurements were conducted every 6 h. Lung imaging was repeated 24 h after first PET/CT before animals were killed. Pulmonary neutrophilic inflammation was assessed by normalized uptake rate of 2-deoxy-2-[18F]fluoro-D-glucose (KiS), and its difference between the two PET/CT was calculated (ΔKiS). Lung aeration was assessed by lung CT scan. MP was calculated from the recorded pressure-volume curve. Statistics included the Wilcoxon tests and non-parametric Spearman correlation. Results: Normalized 18F-FDG uptake rate increased significantly from first to second PET/CT (p = 0.012). ΔKiS significantly correlated with median MP (ρ = 0.738, p = 0.037) and its elastic and resistive components, but neither with median peak, plateau, end-expiratory, driving, and transpulmonary driving pressures, nor respiratory rate (RR), elastance, or resistance. Lung mass and volume significantly decreased, whereas relative mass of hyper-aerated lung compartment increased after 24 h (p = 0.012, p = 0.036, and p = 0.025, respectively). Resistance and PaCO2 were significantly higher (p = 0.012 and p = 0.017, respectively), whereas RR, end-expiratory pressure, and MP were lower at 18 h compared to start of intervention. Conclusions: In this model of experimental acute lung injury in pigs, pulmonary neutrophilic inflammation evaluated by PET/CT increased after 24 h of MV, and correlated with MP.

Effects of Different Levels of Variability and Pressure Support Ventilation on Lung Function in Patients With Mild-Moderate Acute Respiratory Distress Syndrome.

Background: Variable pressure support ventilation (vPSV) is an assisted ventilation mode that varies the level of pressure support on a breath-by-breath basis to restore the physiological variability of breathing activity. We aimed to compare the effects of vPSV at different levels of variability and pressure support (ΔP S) in patients with acute respiratory distress syndrome (ARDS). Methods: This study was a crossover randomized clinical trial. We included patients with mild to moderate ARDS already ventilated in conventional pressure support ventilation (PSV). The study consisted of two blocks of interventions, and variability during vPSV was set as the coefficient of variation of the ΔP S level. In the first block, the effects of three levels of variability were tested at constant ΔP S: 0% (PSV0%, conventional PSV), 15% (vPSV15%), and 30% (vPSV30%). In the second block, two levels of variability (0% and variability set to achieve ±5 cmH2O variability) were tested at two ΔPS levels (baseline ΔP S and ΔP S reduced by 5 cmH2O from baseline). The following four ventilation strategies were tested in the second block: PSV with baseline ΔP S and 0% variability (PSVBL) or ±5 cmH2O variability (vPSVBL), PSV with ΔPS reduced by 5 cmH2O and 0% variability (PSV-5) or ±5 cmH2O variability (vPSV-5). Outcomes included gas exchange, respiratory mechanics, and patient-ventilator asynchronies. Results: The study enrolled 20 patients. In the first block of interventions, oxygenation and respiratory mechanics parameters did not differ between vPSV15% and vPSV30% compared with PSV0%. The variability of tidal volume (V T) was higher with vPSV15% and vPSV30% compared with PSV0%. The incidence of asynchronies and the variability of transpulmonary pressure (P L) were higher with vPSV30% compared with PSV0%. In the second block of interventions, different levels of pressure support with and without variability did not change oxygenation. The variability of V T and P L was higher with vPSV-5 compared with PSV-5, but not with vPSVBL compared with PSVBL. Conclusion: In patients with mild-moderate ARDS, the addition of variability did not improve oxygenation at different pressure support levels. Moreover, high variability levels were associated with worse patient-ventilator synchrony. Clinical Trial Registration: www.clinicaltrials.gov, identifier: NCT01683669.

Effects of Body Position and Hypovolemia on the Regional Distribution of Pulmonary Perfusion During One-Lung Ventilation in Endotoxemic Pigs.

Background: The incidence of hypoxemia during one-lung ventilation (OLV) is as high as 10%. It is also partially determined by the distribution of perfusion. During thoracic surgery, different body positions are used, such as the supine, semilateral, lateral, and prone positions, with such positions potentially influencing the distribution of perfusion. Furthermore, hypovolemia can impair hypoxic vasoconstriction. However, the effects of body position and hypovolemia on the distribution of perfusion remain poorly defined. We hypothesized that, during OLV, the relative perfusion of the ventilated lung is higher in the lateral decubitus position and that hypovolemia impairs the redistribution of pulmonary blood flow. Methods: Sixteen juvenile pigs were anesthetized, mechanically ventilated, submitted to a right-sided thoracotomy, and randomly assigned to one of two groups: (1) intravascular normovolemia or (2) intravascular hypovolemia, as achieved by drawing ~25% of the estimated blood volume (n = 8/group). Furthermore, to mimic thoracic surgery inflammatory conditions, Escherichia coli lipopolysaccharide was continuously infused at 0.5 µg kg-1 h-1. Under left-sided OLV conditions, the animals were further randomized to one of the four sequences of supine, left semilateral, left lateral, and prone positioning. Measurements of pulmonary perfusion distribution with fluorescence-marked microspheres, ventilation distribution by electrical impedance tomography, and gas exchange were then performed during two-lung ventilation in a supine position and after 30 min in each position and intravascular volume status during OLV. Results: During one-lung ventilation, the relative perfusion of the ventilated lung was higher in the lateral than the supine position. The relative perfusion of the non-ventilated lung was lower in the lateral than the supine and prone positions and in semilateral compared with the prone position. During OLV, the highest arterial partial pressure of oxygen/inspiratory fraction of oxygen (PaO2/F I O 2) was achieved in the lateral position as compared with all the other positions. The distribution of perfusion, ventilation, and oxygenation did not differ significantly between normovolemia and hypovolemia. Conclusions: During one-lung ventilation in endotoxemic pigs, the relative perfusion of the ventilated lung and oxygenation were higher in the lateral than in the supine position and not impaired by hypovolemia.

Effects of two stepwise lung recruitment strategies on respiratory function and haemodynamics in anaesthetised pigs: A randomised crossover study.

BACKGROUND: Lung recruitment manoeuvres and positive end-expiratory pressure (PEEP) can improve lung function during general anaesthesia. Different recruitment manoeuvre strategies have been described in large international trials: in the protective ventilation using high vs. low PEEP (PROVHILO) strategy, tidal volume (VT) was increased during volume-controlled ventilation; in the individualised peri-operative open-lung approach vs. standard protective ventilation in abdominal surgery (iPROVE) strategy, PEEP was increased during pressure-controlled ventilation. OBJECTIVES: To compare the effects of the PROVHILO strategy and the iPROVE strategy on respiratory and haemodynamic variables. DESIGN: Randomised crossover study. SETTING: University hospital research facility. ANIMALS: A total of 20 juvenile anaesthetised pigs. INTERVENTIONS: Animals were assigned randomly to one of two sequences: PROVHILO strategy followed by iPROVE strategy or vice-versa (n = 10/sequence). In the PROVHILO strategy, VT was increased stepwise by 4 ml kg-1 at a fixed PEEP of 12 cmH2O until a plateau pressure of 30 to 35 cmH2O was reached. In the iPROVE strategy, at fixed driving pressure of 20 cmH2O, PEEP was increased up to 20 cmH2O followed by PEEP titration according to the lowest elastance of the respiratory system (ERS). MAIN OUTCOME MEASURES: We assessed regional transpulmonary pressure (Ptrans), respiratory system mechanics, gas exchange and haemodynamics, as well as the centre of ventilation (CoV) by electrical impedance tomography. RESULTS: During recruitment manoeuvres with the PROVHILO strategy compared with the iPROV strategy, dorsal Ptrans was lower at end-inspiration (16.3 ±â€Š2.7 vs. 18.6 ±â€Š3.1 cmH2O, P = 0.001) and end-expiration (4.8 ±â€Š2.6 vs. 8.8 ±â€Š3.4 cmH2O, P  < 0.001), and mean arterial pressure (MAP) was higher (77 ±â€Š11 vs. 60 ±â€Š14 mmHg, P < 0.001). At 1 and 15 min after recruitment manoeuvres, ERS was higher in the PROVHILO strategy than the iPROVE strategy (24.6 ±â€Š3.9 vs. 21.5 ±â€Š3.4 and 26.7 ±â€Š4.3 vs. 24.0 ±â€Š3.8 cmH2O l-1; P  < 0.001, respectively). At 1 min, PaO2 was lower in PROVHILO compared with iPROVE strategy (57.1 ±â€Š6.1 vs. 59.3 ±â€Š5.1 kPa, P = 0.013), but at 15 min, values did not differ. CoV did not differ between strategies. CONCLUSION: In anaesthetised pigs, the iPROVE strategy compared with the PROVHILO strategy increased dorsal Ptrans at the cost of lower MAP during recruitment manoeuvres, and decreased ERS thereafter, without consistent improvement of oxygenation or shift of the CoV. TRIAL REGISTRATION: This study was registered and approved by the Landesdirektion Dresden, Germany (DD24-5131/338/28).

Automatic Lung Segmentation and Quantification of Aeration in Computed Tomography of the Chest Using 3D Transfer Learning.

BACKGROUND: Identification of lung parenchyma on computer tomographic (CT) scans in the research setting is done semi-automatically and requires cumbersome manual correction. This is especially true in pathological conditions, hindering the clinical application of aeration compartment (AC) analysis. Deep learning based algorithms have lately been shown to be reliable and time-efficient in segmenting pathologic lungs. In this contribution, we thus propose a novel 3D transfer learning based approach to quantify lung volumes, aeration compartments and lung recruitability. METHODS: Two convolutional neural networks developed for biomedical image segmentation (uNet), with different resolutions and fields of view, were implemented using Matlab. Training and evaluation was done on 180 scans of 18 pigs in experimental ARDS (u2Net Pig ) and on a clinical data set of 150 scans from 58 ICU patients with lung conditions varying from healthy, to COPD, to ARDS and COVID-19 (u2Net Human ). One manual segmentations (MS) was available for each scan, being a consensus by two experts. Transfer learning was then applied to train u2Net Pig on the clinical data set generating u2Net Transfer . General segmentation quality was quantified using the Jaccard index (JI) and the Boundary Function score (BF). The slope between JI or BF and relative volume of non-aerated compartment (S JI and S BF , respectively) was calculated over data sets to assess robustness toward non-aerated lung regions. Additionally, the relative volume of ACs and lung volumes (LV) were compared between automatic and MS. RESULTS: On the experimental data set, u2Net Pig resulted in JI = 0.892 [0.88 : 091] (median [inter-quartile range]), BF = 0.995 [0.98 : 1.0] and slopes S JI = -0.2 {95% conf. int. -0.23 : -0.16} and S BF = -0.1 {-0.5 : -0.06}. u2Net Human showed similar performance compared to u2Net Pig in JI, BF but with reduced robustness S JI = -0.29 {-0.36 : -0.22} and S BF = -0.43 {-0.54 : -0.31}. Transfer learning improved overall JI = 0.92 [0.88 : 0.94], P < 0.001, but reduced robustness S JI = -0.46 {-0.52 : -0.40}, and affected neither BF = 0.96 [0.91 : 0.98] nor S BF = -0.48 {-0.59 : -0.36}. u2Net Transfer improved JI compared to u2Net Human in segmenting healthy (P = 0.008), ARDS (P < 0.001) and COPD (P = 0.004) patients but not in COVID-19 patients (P = 0.298). ACs and LV determined using u2Net Transfer segmentations exhibited < 5% volume difference compared to MS. CONCLUSION: Compared to manual segmentations, automatic uNet based 3D lung segmentation provides acceptable quality for both clinical and scientific purposes in the quantification of lung volumes, aeration compartments, and recruitability.

Comparative effects of neurally adjusted ventilatory assist and variable pressure support on lung and diaphragmatic function in a model of acute respiratory distress syndrome: A randomised animal study.

BACKGROUND: Variable assisted mechanical ventilation has been shown to improve lung function and reduce lung injury. However, differences between extrinsic and intrinsic variability are unknown. OBJECTIVE: To investigate the effects of neurally adjusted ventilatory assist (NAVA, intrinsic variability), variable pressure support ventilation (Noisy PSV, extrinsic variability) and conventional pressure-controlled ventilation (PCV) on lung and diaphragmatic function and damage in experimental acute respiratory distress syndrome (ARDS). DESIGN: Randomised controlled animal study. SETTING: University Hospital Research Facility. SUBJECTS: A total of 24 juvenile female pigs. INTERVENTIONS: ARDS was induced by repetitive lung lavage and injurious ventilation. Animals were randomly assigned to 24 h of either: 1) NAVA, 2) Noisy PSV or 3) PCV (n=8 per group). Mechanical ventilation settings followed the ARDS Network recommendations. MEASUREMENTS: The primary outcome was histological lung damage. Secondary outcomes were respiratory variables and patterns, subject-ventilator asynchrony (SVA), pulmonary and diaphragmatic biomarkers, as well as diaphragmatic muscle atrophy and myosin isotypes. RESULTS: Global alveolar damage did not differ between groups, but NAVA resulted in less interstitial oedema in dorsal lung regions than Noisy PSV. Gas exchange and SVA incidence did not differ between groups. Compared with Noisy PSV, NAVA generated higher coefficients of variation of tidal volume and respiratory rate. During NAVA, only 40.4% of breaths were triggered by the electrical diaphragm signal. The IL-8 concentration in lung tissue was lower after NAVA compared with PCV and Noisy PSV, whereas Noisy PSV yielded lower type III procollagen mRNA expression than NAVA and PCV. Diaphragmatic muscle fibre diameters were smaller after PCV compared with assisted modes, whereas expression of myosin isotypes did not differ between groups. CONCLUSION: Noisy PSV and NAVA did not reduce global lung injury compared with PCV but affected different biomarkers and attenuated diaphragmatic atrophy. NAVA increased the respiratory variability; however, NAVA yielded a similar SVA incidence as Noisy PSV. TRIAL REGISTRATION: This trial was registered and approved by the Landesdirektion Dresden, Germany (AZ 24-9168.11-1/2012-2).

Continuous external negative pressure improves oxygenation and respiratory mechanics in Experimental Lung Injury in Pigs - A pilot proof-of-concept trial.

BACKGROUND: Continuous external negative pressure (CENP) during positive pressure ventilation can recruit dependent lung regions. We hypothesised that CENP applied regionally to the thorax or the abdomen only, increases the caudal end-expiratory transpulmonary pressure depending on positive end-expiratory pressure (PEEP) in lung-injured pigs. Eight pigs were anesthetised and mechanically ventilated in the supine position. Pressure sensors were placed in the left pleural space, and a lung injury was induced by saline lung lavages. A CENP shell was placed at the abdomen and thorax (randomised order), and animals were ventilated with PEEP 15, 7 and zero cmH2O (15 min each). On each PEEP level, CENP of - 40, - 30, - 20, - 10 and 0 cmH2O was applied (3 min each). Respiratory and haemodynamic variables were recorded. Electrical impedance tomography allowed assessment of centre of ventilation. RESULTS: Compared to positive pressure ventilation alone, the caudal transpulmonary pressure was significantly increased by CENP of ≤ 20 cmH2O at all PEEP levels. CENP of - 20 cmH2O reduced the mean airway pressure at zero PEEP (P = 0.025). The driving pressure decreased at CENP of ≤ 10 at PEEP of 0 and 7 cmH2O (P < 0.001 each) but increased at CENP of - 30 cmH2O during the highest PEEP (P = 0.001). CENP of - 30 cmH2O reduced the mechanical power during zero PEEP (P < 0.001). Both elastance (P < 0.001) and resistance (P < 0.001) were decreased at CENP ≤ 30 at PEEP of 0 and 7 cmH2O. Oxygenation increased at CENP of ≤ 20 at PEEP of 0 and 7 cmH2O (P < 0.001 each). Applying external negative pressure significantly shifted the centre of aeration towards dorsal lung regions irrespectively of the PEEP level. Cardiac output decreased significantly at CENP -20 cmH2O at all PEEP levels (P < 0.001). Effects on caudal transpulmonary pressure, elastance and cardiac output were more pronounced when CENP was applied to the abdomen compared with the thorax. CONCLUSIONS: In this lung injury model in pigs, CENP increased the end-expiratory caudal transpulmonary pressure. This lead to a shift of lung aeration towards dependent zones as well as improved respiratory mechanics and oxygenation, especially when CENP was applied to the abdomen as compared to the thorax. CENP values ≤ 20 cmH2O impaired the haemodynamics.

Comparative effects of flow vs. volume-controlled one-lung ventilation on gas exchange and respiratory system mechanics in pigs.

BACKGROUND: Flow-controlled ventilation (FCV) allows expiratory flow control, reducing the collapse of the airways during expiration. The performance of FCV during one-lung ventilation (OLV) under intravascular normo- and hypovolaemia is currently unknown. In this explorative study, we hypothesised that OLV with FCV improves PaO2 and reduces mechanical power compared to volume-controlled ventilation (VCV). Sixteen juvenile pigs were randomly assigned to one of two groups: (1) intravascular normovolaemia (n = 8) and (2) intravascular hypovolaemia (n = 8). To mimic inflammation due to major thoracic surgery, a thoracotomy was performed, and 0.5 µg/kg/h lipopolysaccharides from Escherichia coli continuously administered intravenously. Animals were randomly assigned to OLV with one of two sequences (60 min per mode): (1) VCV-FCV or (2) FCV-VCV. Variables of gas exchange, haemodynamics and respiratory signals were collected 20, 40 and 60 min after initiation of OLV with each mechanical ventilation mode. The distribution of ventilation was determined using electrical impedance tomography (EIT). RESULTS: Oxygenation did not differ significantly between modes (P = 0.881). In the normovolaemia group, the corrected expired minute volume (P = 0.022) and positive end-expiratory pressure (PEEP) were lower during FCV than VCV. The minute volume (P ≤ 0.001), respiratory rate (P ≤ 0.001), total PEEP (P ≤ 0.001), resistance of the respiratory system (P ≤ 0.001), mechanical power (P ≤ 0.001) and resistive mechanical power (P ≤ 0.001) were lower during FCV than VCV irrespective of the volaemia status. The distribution of ventilation did not differ between both ventilation modes (P = 0.103). CONCLUSIONS: In a model of OLV in normo- and hypovolemic pigs, mechanical power was lower during FCV compared to VCV, without significant differences in oxygenation. Furthermore, the efficacy of ventilation was higher during FCV compared to VCV during normovolaemia.

Association of remote imaging photoplethysmography and cutaneous perfusion in volunteers.

Remote imaging photoplethysmography (iPPG) senses the cardiac pulse in outer skin layers and is responsive to mean arterial pressure and pulse pressure in critically ill patients. Whether iPPG is sufficiently sensitive to monitor cutaneous perfusion is not known. This study aimed at determining the response of iPPG to changes in cutaneous perfusion measured by  Laser speckle imaging (LSI). Thirty-seven volunteers were engaged in a cognitive test known to evoke autonomic nervous activity and a Heat test. Simultaneous measurements of iPPG and LSI were taken at baseline and during cutaneous perfusion challenges. A perfusion index (PI) was calculated to assess iPPG signal strength. The response of iPPG to the challenges and its relation to LSI were determined. PI of iPPG significantly increased in response to autonomic nervous stimuli and to the Heat test by 5.8% (p = 0.005) and 11.1% (p < 0.001), respectively. PI was associated with LSI measures of cutaneous perfusion throughout experiments (p < 0.001). iPPG responses to study task correlated with those of LSI (r = 0.62, p < 0.001) and were comparable among subjects. iPPG is sensitive to autonomic nervous activity in volunteers and is closely associated with cutaneous perfusion.