Variable Pressure Support Ventilation vs. Biphasic Positive Airway Pressure/Airway Pressure Release Ventilation in experimental acute respiratory failure

Variable Pressure Support Ventilation vs. Biphasic Positive Airway Pressure/Airway Pressure Release Ventilation in experimental acute respiratory failure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Variable Pressure Support Ventilation vs. Biphasic Positive Airway Pressure/Airway Pressure Release Ventilation in experimental acute respiratory failure Thomas Bluth, Maren Fritzsche, Dirk Haufe, Thomas Kiss, Thea Koch, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8914906/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Background Spontaneous breathing during mechanical ventilation (MV) can improve cardiorespiratory function and lung protection. Biphasic Positive Airway Pressure (BIPAP) and Airway Pressure Release Ventilation (APRV) are common MV modes that combine spontaneous breathing with controlled ventilation. Variable pressure support ventilation (PSV), which varies breath-by-breath pressure support randomly, has been shown to improve gas exchange and reduce lung injury compared to conventional MV modes. This study aimed to compare the short-term effects of variable PSV with BIPAP in a model of acute respiratory failure, hypothesizing that variable PSV would improve lung function without increasing lung damage or inflammation. Methods In an exploratory randomized study with 18 pigs, lung injury was induced by lung lavage. Over 4 hours, two lung protective strategies were applied with individually optimized PEEP: 1) BIPAP with non-assisted spontaneous breathing and 2) variable PSV, maintaining a mean tidal volume of 6 ml/kg body weight while varying pressure support. Plasma and bronchoalveolar lavage fluid samples were collected for inflammation markers, and lung damage was assessed histologically. Gene expression of inflammatory cytokines was also measured. Results Variable PSV resulted in slightly improved gas exchange with higher mean tidal volumes and minute ventilation compared to BIPAP, as well as reduced work of breathing. Histopathological analysis showed alveolar damage to be mild, with no significant overall difference between the groups. However, variable PSV caused more alveolar edema, especially in gravity-dependent lung regions, and increased the wet-to-dry ratio than BIPAP. Despite these differences, there were no significant changes in systemic or pulmonary inflammatory cytokines or gene expression between the two groups. Conclusion In this model of acute respiratory failure, variable PSV with a protective tidal volume of 6 ml/kg resulted in marginal, but clinically insignificant improvements in gas exchange and reduced work of breathing compared to BIPAP with non-assisted spontaneous breathing. Overall lung damage and inflammatory responses were similar between groups. However, the consequent assistance and its variation of spontaneous breaths with variable PSV may have contributed to increased alveolar edema in this study. mechanical ventilation BIPAP variable ventilation randomized trial animal lung injury Figures Figure 1 Figure 2 Figure 3 Background Maintaining or restoring spontaneous breathing early during mechanical ventilation in patients suffering from acute respiratory failure can improve gas exchange and respiratory mechanics, reduce the need for sedatives and cardiovascular support and is finally able to reduce the total time of mechanical ventilation (1–4). Reduced time of ventilatory support may reduce the risk of ventilator induced diaphragmatic dysfunction (5) and the development of other ventilator associated complications. Another approach to improving mechanical ventilation is to continuously vary mandatory ventilation parameters. It has been shown that variable tidal volumes can improve gas exchange and respiratory mechanics in different experimental settings (6–13). Based on some of these initial findings variable pressure support ventilation (variable PSV) had been developed (14), which theoretically combines the positive effects of spontaneous breathing modes and the restored physiological breathing pattern variability. Experimental evidence suggests that application of extrinsic variability in pressure support as with variable PSV is associated with beneficial effects in experimental lung injury (9,11,14,15), and was well tolerated during short term application in patients with acute respiratory failure (16). Most studies showing positive effects of spontaneous breathing in acute respiratory distress syndrome (ARDS) were performed with biphasic positive airway pressure / airway pressure release ventilation (BIPAP/APRV), favoring BIPAP/APRV as the standard ventilatory mode for maintenance of spontaneous breathing (2). The present study based on findings that BIPAP with maintained non assisted spontaneous breathing and PSV, a completely assisted spontaneous breathing mode, are associated with distinct short term effects on pulmonary aeration and perfusion (17,18). Using a porcine model of acute lung injury induced by surfactant depletion we aimed at comparing variable PSV with BIPAP regarding gas exchange, pulmonary mechanics and inflammatory response. We hypothesized that the application of variable pressure support improves gas exchange and respiratory mechanics without causing increased pulmonary inflammatory response. Methods Ethics and consent to participate The institutional animal care and welfare committee and the government of the state of Saxony, Germany, approved all animal procedures following federal law (Landesdirektion Dresden, Germany, File AZ 24D-9168.11-1/2006-18). Animals were purchased from a private owner (Agrar Service GmbH Schweinemast Horka, Germany). This company provided an informed consent statement to use the animals in the current study. Animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the US National Academy of Sciences Guide for the Care and Use of Laboratory Animals and reported according to the Animal Research: Reporting In Vivo Experiments statements. Trial design and primary endpoint This was an explorative randomized controlled experimental study. For structure and clarity of the manuscript, a primary endpoint was defined, which was the ratio between arterial partial pressure of oxygen and fraction of inspired oxygen (PaO 2 /F I O 2 , Horovitz index). Relevant secondary endpoints included parameters of respiratory mechanics, as well as systemic and pulmonary inflammation and alveolar damage. Animal preparation and mechanical ventilation settings Eighteen juvenile pigs (22 – 30 kg; German landrace) were intramuscularly premedicated with ketamine (10 mg/kg) and midazolam (1 mg/kg). Anesthesia was induced by intravenous boli of ketamine and midazolam and maintained by continuous infusion (12-18 mg/kg/h ketamine and 2 mg/kg/h midazolam). Muscle paralysis was achieved by infusion of atracurium (1 mg/kg/h). Animals were orotracheally intubated with an 8.0 ID endotracheal tube and ventilated in volume controlled mode using an EVITA XL ventilator (Dräger Medical, Lübeck, Germany). Initial ventilator settings were as follows: tidal volume (V T ) 10 ml/kg of actual body weight, F I O 2 1.0, positive endexpiratory pressure (PEEP) 5 cm H 2 O, inspiratory:expiratory ratio (I:E) 1:1 and respiratory rate to achieve arterial carbon dioxide (PaCO 2 ) of 35-45 mmHg at fixed inspiratory flow of 35 l/min. Fluid uptake was maintained by infusion of a balanced crystalloid solution (10 ml/kg/h). After right lateral neck incision a 5 Fr. catheter was placed into the internal carotid artery and a 7.5 Fr. Swan-Ganz catheter was advanced via an 8.5 Fr. sheath into the pulmonal artery. Urine drainage was performed by invasive catheterization of the urinary bladder via mini laparotomy. Animals were kept in supine position during the entire experiment. Experimental respiratory failure was induced by repetitive saline lung lavage (30 ml/kg) in supine position until PaO 2 /F I O 2 fell constantly below 200 mmHg for 30 minutes (19). Following injury, lung recruitment by means of a continuous pressure of 50 cm H 2 O during 30 s and a consecutive decremental PEEP trial was conducted in order to set PEEP according to optimal respiratory system mechanics as described earlier (20). Briefly, PEEP was set at 20 cm H 2 O and reduced in steps of 2 cm H 2 O after each 2 minutes while keeping other respiratory parameters unchanged. After this, lung recruitment was repeated, and PEEP was set at the level corresponding to the minimal elastance of the respiratory system (E RS ) . Prior to resuming of spontaneous breathing, atracurium was stopped and ketamine and midazolam infusion was reduced. Animals were randomly assigned to variable PSV or BIPAP. During BIPAP spontaneous breathing was facilitated and considered sufficient, if the amount of minute ventilation (MV) of spontaneous breaths reached minimum 20% of total MV according to the algorithm implemented in the ventilator. In order to apply unassisted spontaneous breathing and therefore avoid synchronization of the pressure changes and the subject’s effort, as implemented in BiPAP ventilation mode, BIPAP was performed using the APRV mode embedded in the ventilator. However, because APRV is commonly regarded in clinical practice as a mode employing inverse ratio ventilation, the term BIPAP is used in this study to clarify the ventilatory settings applied. Variable PSV was applied via external remote control of the ventilator as previously described (14). Ventilator settings are summarized in Table 1. After 4 hours of study intervention had been completed, animals were sacrificed by intravenous injection of 1 M-potassium chloride (50 ml) following deepening of general anesthesia with thiopental (2 g). The lungs were removed at continuous airway pressures equal to PEEP. After separation, the middle lobe of the right lung was weighed (wet weight) and then rinsed two times with 50ml with saline solution to obtain bronchoalveolar lavage fluid (BALF). After standardized drying by microwave heating the middle lobe was weighed again (dry weight), and the ratio between wet and dry weight calculated (wet-to-dry ratio) (21). Tissue samples were taken from dependent and nondependent areas of both lungs according to a fixed protocol. Data Acquisition and Measurements Airway flow was measured using a heated pneumotachograph (Fleisch No. 2; Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (PXL12X5DN; Sensortechnics, Troy, NY) and airway pressures were obtained using a pressure transducer (SCX01DNC; SenSym ICT, Milpitas, CA.) at the endotracheal tube. After advancing an esophageal balloon catheter (Erich Jaeger, Höchberg, Germany) into mid-chest level, esophageal pressure was measured by a third pressure transducer (SCX01DNC, SenSym ICT). The signals of airway pressure, esophageal pressure, and airway flow were recorded using a LabView (National Instruments, Austin, TX) based data acquisition system as described previously (20). Continuous recordings (5 min) of respiratory mechanics, gas exchange, hemodynamics and blood samples for plasma cytokine analysis were assessed at baseline, injury, after titration of individual PEEP and resuming of spontaneous breathing (baseline 2) and 1-hour-intervals during the study intervention thereafter (Time 1 to 4). Parameters of respiratory mechanics were calculated offline as described elsewhere (20). Airway pressure at 100 ms after beginning of inspiration (P 0.1 ) was determined and used as surrogate of the central respiratory drive. Transpulmonary right-to-left shunt was calculated using standard formula, as previously described (20). Using the recorded respiratory signals, tidal volumes were semiautomatically (algorithm-based detection and visually supervision of correct identification) classified as mandatory, assisted spontaneous and non-assisted spontaneous. Scoring of Diffuse alveolar damage, which includes typical histopathological features of the early exudative phase of ARDS, was performed in tissue samples from gravity dependent and non-dependent regions of the left lung as described before (22). mRNA expression of Interleukin (IL)-6, IL-8 and Amphiregulin in right lung tissue samples was analyzed using quantitative real-time polymerase chain reaction as previously described (10). Protein levels of IL-6 and IL-8 were measured in plasma at all time points and in BALF supernatant using commercially available enzyme linked immunosorbent assay kits according to the manufacturer’s instructions. Statistical analysis Data are presented as mean ± standard deviation unless stated otherwise. Student´s t-test, one-way analysis of variance or repeated measures analysis of variance were used for normal distributed data as appropriate, Mann-Whitney-U-test and Wilcoxon-test were used in case of non-normal distributed data or nominal scaled variables. All tests were performed using the SPSS software package (Vers. 15.0, SPSS Inc., Chicago, IL). Multiple comparisons were adjusted according to Sidak or Bonferroni-Holm procedure as appropriate. The global significance level was defined as P<0.05 and, despite the exploratory nature of the study, is indicated in the text and tables for improved clarity. Results Groups did not differ significantly regarding bodyweight (mean [min-max]; variable PSV 27 [25-31]; BIPAP 27 [22-30]; p = 0.64) and number of lavages (mean [min-max]; variable PSV 8 [2-14]; BIPAP 8 [1-12]; p = 0.90). Typical recordings of airway flow, airway and esophageal pressure are depicted in Figure 1. Gas Exchange Data on gas exchange are presented in Figure 2 and Table 2. Induction of lung injury significantly decreased PaO 2 /F I O 2 and pH and increased PaCO 2 and Shunt in both groups (Baseline 1 vs. Injury). Optimized PEEP and resuming of spontaneous breathing (Injury vs. Baseline 2) led to significantly increased PaO 2 /F I O 2 and PaCO 2 and decreased pH and Shunt. The primary endpoint, PaO 2 /F I O 2 , and pH were significantly increased with variable PSV as compared to BIPAP. PaCO 2 were significantly lower with variable PSV as compared to BIPAP, whereas Shunt did not differ significantly between groups. Respiratory Variables Respiratory data are presented in Figures 2 and Table 2. Lung injury led to increased peak and mean airway pressures (P peak , P mean ) without affecting other respiratory variables. Individually adjusted PEEP level did not relevantly differ in both groups (variable PSV 16 ± 1; BIPAP 15 ± 2 cm H 2 O; p = 0.36). Reduction of tidal volumes during resuming of spontaneous breathing was associated with a consecutive decrease in minute ventilation and increased respiratory rate as well as increased, but not relevant intrinsic PEEP. Total and spontaneous tidal volume and minute ventilation were significantly increased with variable PSV compared to BIPAP (Figure 3). Total respiratory rate did not differ significantly between groups, but spontaneous respiratory rate was significantly increased with variable PSV. P peak was higher and P mean and pressure time product (PTP) were lower with variable PSV as compared to BIPAP. P 0.1 was significantly lower with variable PSV compared to BIPAP. Hemodynamics Hemodynamic data are shown in Table 2. Mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance increased with lung injury, whereas cardiac output decreased mainly by a reduced heart rate. Optimized PEEP and induction of spontaneous breathing led to a significant decrease of MPAP. Analysis of differences between groups revealed decreased cardiac output and increased systemic vascular resistance with variable PSV compared to BIPAP, whereas other variables did not differ. Histology and lung edema Cumulative alveolar damage scores did not differ significantly between the experimental groups, although lungs ventilated with noisy PSV showed significantly more alveolar oedema, particularly in gravity-dependent regions (Table 3). Other characteristics of the score showed no significant differences between the groups. Independent of group allocation, alveolar overdistension was more pronounced in non-dependent compared to dependent regions and achieved the highest scores among all features. The wet-to-dry weight ratio were higher in lungs ventilated with variable PSV compared to BIPAP (8.0 ± 0.8 versus 7.1 ± 0.4; p = 0.011). Biomarkers of lung injury mRNA expression of IL-6, IL-8 and Amphiregulin did not differ significantly between groups, independent from lung region (Table 4). Protein levels of IL-6 and IL-8 in plasma did not differ significantly between groups at any time point (Table 5), nor did IL-6 (variable PSV 877 [213 - 1712]; BIPAP 356 [232 - 661]; p = 0.55) and IL-8 (variable PSV 170 [116 - 272]; BIPAP 99 [97 - 198]; p = 0.45) in bronchoalveolar lavage fluid. Discussion The main results of this study could be summarized as follows: 1) Variable PSV was associated with marginally improved gas exchange and decreased respiratory effort when compared to BIPAP. 2) Ventilation with Variable PSV may have favored development of pulmonary edema, but did not relevantly increase overall alveolar damage and systemic or pulmonary inflammation. In contrast to our preliminary studies (14,17,18,23) ventilator settings in the present trial were chosen according to clinical standard without trying to match mean airway pressure and/or tidal volume. Effects of cardiorespiratory function Early induction of spontaneous breathing has been repeatedly shown to improve pulmonary function and attenuate pulmonary inflammation in the experimental as well as in the clinical setting (1,11). As a possible mechanism behind improvement of gas exchange increased pulmonary aeration especially in juxtadiaphragmal regions was discussed (24). Our group demonstrated that redistribution of pulmonary blood flow towards better aerated lung regions, resulting in improved ventilation/perfusion matching, but not alveolar recruitment and/or increase in pulmonary aeration alone improve pulmonary gas exchange during spontaneous breathing (23). The excellent functional variables of the respiratory system in both groups of the current study support such assumptions. However, oxygenation was probably driven to a relevant degree by the high PEEP levels used here. The approach to setting individual PEEP according to minimal elastance was chosen, as a previous study suggested spontaneous breathing with higher PEEP in experimental ARDS to better stabilize dependent lung segments and more effectively prevent from pulmonary inflammation (25). Due to the effective lung recruitment absolute differences of gas exchange variables between experimental groups remained smaller than in our previous study (14). However, the significant higher PaO 2 /F I O 2 ratio and the better pH in combination with the lower PaCO 2 seen with variable PSV indicate improved alveolar ventilation and gas exchange compared to BIPAP. The improved alveolar ventilation can largely be explained by the higher mean tidal volume and total minute ventilation generated by the assistance of breathing, while unassisted spontaneous breaths remained relatively low under BIPAP. Conceptually, some researchers consider unassisted spontaneous breaths during BIPAP to be generally irrelevant in increasing minute volume, instead emphasize their overall potential to improve cardiorespiratory function (26). However, this view has been recently challenged by the finding, that excessive inspiratory efforts might result in lung damage and spontaneous tidal volumes and pressures need to be closely observed during respiratory therapy, instead (27). In addition to differences in ventilation, lower mean airway pressure in the variable PSV group may have favored a redistribution of pulmonary blood flow towards better ventilated areas especially in the setting of higher PEEP, which finally resulted in an improved ventilation/perfusion matching as indicated by previous published studies (14,17,23). It is worth noting that higher mean airway and lower peak airway pressures found in the BIPAP group are related to the different I:E settings (1:1 with BIPAP vs. app. 1:4 with variable PSV) because airway pressures were calculated as mean values over time. When compared to our previous study with lower PEEP and F I O 2 settings, spontaneous respiratory rate in BIPAP was markedly lower and no signs of discomfort could be observed (14). PTP and P 0.1 as surrogates for respiratory workload were obviously higher with BIPAP compared to the fully assisted breaths with variable PSV. The decision if a reduction of respiratory workload in mechanically ventilated patients is desirable or not should be made in the context of each individual case. Patients running into muscle fatigue could benefit from relief of the work of breathing through fully assisted spontaneous breathing, whereas a certain amount of respiratory work by non- or partially supported spontaneous breathing could be helpful to prevent disuse atrophy of respiratory muscles in other scenarios (5). The increase in cardiac output with BIPAP may be due to increased muscle activity also expressed by the markedly increased inspiratory effort. On the other hand, increased venous return due to a more pronounced cyclic reduction in intrathoracic pressure with BIPAP could lead to an increase in left ventricular stroke volume (SV). Left ventricular output could also be enhanced through reduction in systemic vascular resistance due to decreased pH and permissive hypercapnia with BIPAP. However, this effect is not supposed to play a major role. Effects on lung protection In recent years, possible adverse side effects of spontaneous breathing in the acute phase of respiratory failure became more apparent. Excessive efforts resulting in high transpulmonary driving pressures can exacerbate lung damage, a phenomenon called patient self-inflicted lung injury (28). Synchronized spontaneous breaths are more likely to result in such higher transpulmonary pressures, as negative intrapleural pressure amplitudes during spontaneous inspiration add to positive pressure assistance provided by the ventilator. In contrast, non-assisted breaths such as those occurring during ventilation with BIPAP/APRV lack the ventilator component and may be even more lung protective, as long as the respiratory workload remains in a physiological range (29). Indeed, a more detailed analysis of pulmonary aeration by means of dynamic computed tomography in pigs ventilated with PSV or BIPAP observed a reduction of tidal reaeration and hyperaeration during BIPAP, suggesting an overall increased risk of ventilator induced lung injury during PSV and possibly during variable PSV (18). This finding rather resulted from lower tidal volumes during unassisted spontaneous breaths in BIPAP than from decreased nonaerated areas at end-expiration or different distribution of ventilation. In contrast, tidal reaeration and hyperinflation during controlled respiratory cycles in BIPAP were increased compared to PSV cycles. Based on the above considerations, PSV has an inherent, at least theoretical disadvantage over BIPAP with unassisted spontaneous breathing in terms of lung protection, which exists independently of the addition of variability. As of yet, this disadvantage has not been found in clinically relevant outcomes in the few clinical studies performed (30). Our group has already shown that optimizing PSV by varying the pressures support level does not lead to an increase in pulmonary inflammation (25). (Variable) PSV could therefore be equivalent to BIPAP in terms of lung protection if the vulnerability of the lungs is relatively low or if an improved lung function under PSV helps to reduce the invasiveness of ventilation in general. The data from this study seem to reflect these considerations. We clearly aimed to test variable PSV and BIPAP in a clinical setting with optimized lung protection. Indeed, the overall level of pulmonary inflammatory response in plasma, bronchoalveolar lavage fluid and lung tissue in our study was rather low and did not reveal many differences between groups. The lavage model is known to be well recruitable and high PEEP/F i O 2 in this setting might have effectively stabilized lung units. If one of the two modes would have introduced relevant injury to the vulnerably changed lungs, this should be reflected by histologic or inflammatory findings. As discussed above, the BIPAP group has been even favored with regard to lung parenchymal stress due to a lower rate of respiratory cycles with 6 ml/kg (controlled cycles) or to a lower mean Vt compared with variable PSV. Increased minute ventilation as a consequence of increased tidal volume or respiratory rate has been shown to influence ventilator induced lung injury (31). This explanation could also account for the difference in lung edema seen in the present study. An alternative explanation lies in the exploratory nature of this study: We cannot rule out the possibility that multiple testing has led to an overestimation of the net effect, i.e. to the detection of significant differences that are purely random. The probability that the difference in alveolar edema results from such an error appears moderate, as other characteristics of the Diffuse alveolar damage score and the cumulative score itself, as well as biochemical markers of inflammation, show no significant differences between the experimental groups. Although one could question the selective choice of parameters to determine lung parenchymal stress and inflammatory response in this study, the same methods yielded significant differences in previous studies employing the same experimental model (10,11). Further study limitations First, the lavage model represents a very well standardized experimental model that by far not necessarily reflects the complex clinical features of acute respiratory failure/ARDS, which limits the transferability of our data to the clinical setting, especially to clinical manifestation of severe ARDS. Second, since minute ventilation was not controlled in this protocol, we cannot exclude that improvement of gas exchange was affected by higher minute ventilation in the variable PSV group. Finally, the low level of pulmonary inflammatory response and lung parenchymal stress as well as the absence of relevant differences between groups could be due to the relatively short observational period of just four hours. Conclusions In this experimental model of acute respiratory failure in pigs, variable PSV and BIPAP with non-assisted spontaneous breathing improved respiratory function. Variable PSV was marginally superior to BIPAP regarding gas exchange and was associated with reduced respiratory workload. Although inflammatory markers did not differ between modes, variable PSV led to increased alveolar oedema compared to BIPAP. Abbreviations APRV airway pressure release ventilation ARDS acute respiratory distress syndrome BALF bronchoalveolar lavage fluid BIPAP biphasic positive airway pressure E RS elastance of the respiratory system F I O 2 fraction of inspired oxygen I:E inspiratory:expiratory ratio IL Interleukin MPAP mean pulmonary arterial pressure mRNA messenger ribonucleic acid MV minute ventilation P 0.1 airway pressure at 100 ms after beginning of inspiration P a O 2 arterial partial pressure of oxygen P a CO 2 arterial partial pressure of carbon dioxide PEEP positive endexpiratory pressure P mean mean airway pressure P peak peak airway pressure PSV pressure support ventilation PTP pressure time product V T tidal volume Declarations Ethics approval and consent to participate The experiments were approved by the institutional animal care and welfare committee and the government of the state of Saxony, Germany (Landesdirektion Dresden, Germany, File AZ 24D-9168.11-1/2006-18). Consent for publication Not applicable Availability of data and materials The complete dataset of the current trial is available from the corresponding author upon reasonable request. Competing interests Drs. Gama de Abreu, Spieth and Koch were granted a patent on the variable pressure support ventilation mode of assisted ventilation. The remaining authors have not disclosed any potential conflicts of interest. Funding This work was supported, in part, by a research grant of the Medical Faculty, Technical University of Dresden, Germany (MeDDrive Programm). Authors' contributions Conception and design: TB, DH, MGdA, PMS, AG; Data acquisition: TB, MF, TKi, MGdA, PMS, AG; Data analysis and interpretation: TB, MGdA, PMS, AG; Manuscript preparation: TB, PMS, AG; Manuscript revision: TB, MF, DH, TKi, TKo, MGdA, PMS, AG. All authors approved the final version to be published and agreed to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. Acknowledgements The authors are indebted to the students of the Pulmonary Engineering Group and the staff of the Anatomical Institute of the Medical Faculty TU Dresden. Especially Professor Michael Kasper deserves our sincere thanks for his commitment to assessing the diffuse alveolar damage score, Professor Alysson Roncally Carvalho for his support with the technical part of the experiments and Professor Stefan Uhlig and his lab staff for measurement of inflammatory markers. The mechanical ventilator used in this study was kindly provided by Dräger Medical, Lübeck, Germany. References Putensen C, Zech S, Wrigge H, Zinserling J, Stüber F, Von Spiegel T. u. a. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med 1 Juli. 2001;164(1):43–9. Putensen C, Muders T, Varelmann D, Wrigge H. The impact of spontaneous breathing during mechanical ventilation. Curr Opin Crit Care Februar. 2006;12(1):13–8. Zhou Y, Jin X, Lv Y, Wang P, Yang Y, Liang G. u. a. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med November. 2017;43(11):1648–59. Richard JCM, Beloncle FM, Béduneau G, Mortaza S, Ehrmann S, Diehl JL. u. a. Pressure control plus spontaneous ventilation versus volume assist-control ventilation in acute respiratory distress syndrome. A randomised clinical trial. Intensive Care Med Oktober. 2024;50(10):1647–56. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P. u. a. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. März 2008;27(13):1327–35. Suki B, Alencar AM, Sujeer MK, Lutchen KR, Collins JJ, Andrade JS. Jr, u. a. Life-support system benefits from noise. Nat 14 Mai. 1998;393(6681):127–8. Lefevre GR, Kowalski SE, Girling LG, Thiessen DB, Mutch WA. Improved arterial oxygenation after oleic acid lung injury in the pig using a computer-controlled mechanical ventilator. Am J Respir Crit Care Med November. 1996;154(5):1567–72. McMullen MC, Girling LG, Graham MR, Mutch WAC. Biologically variable ventilation improves oxygenation and respiratory mechanics during one-lung ventilation. Anesthesiology Juli. 2006;105(1):91–7. Spieth PM, Carvalho AR, Güldner A, Pelosi P, Kirichuk O, Koch T. u. a. Effects of different levels of pressure support variability in experimental lung injury. Anesthesiology Februar. 2009;110(2):342–50. Spieth PM, Carvalho AR, Pelosi P, Hoehn C, Meissner C, Kasper M. u. a. Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury. Am J Respir Crit Care Med 15 April. 2009;179(8):684–93. Spieth PM, Carvalho AR, Güldner A, Kasper M, Schubert R, Carvalho NC. u. a. Pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support. Crit Care Med April. 2011;39(4):746–55. Dos Santos Rocha A, Südy R, Bizzotto D, Kassai M, Carvalho T, Dellacà. RL, u. a. Benefit of Physiologically Variable Over Pressure-Controlled Ventilation in a Model of Chronic Obstructive Pulmonary Disease: A Randomized Study. Front Physiol. 2020;11:625777. Dos Santos Rocha A, Peták F, Carvalho T, Habre W, Balogh AL. Physiologically variable ventilation prevents lung function deterioration in a model of pulmonary fibrosis. J Appl Physiol Bethesda Md 1985 1 April. 2022;132(4):915–24. Gama de Abreu M, Spieth PM, Pelosi P, Carvalho AR, Walter C, Schreiber-Ferstl. A, u. a. Noisy pressure support ventilation: a pilot study on a new assisted ventilation mode in experimental lung injury. Crit Care Med März. 2008;36(3):818–27. Spieth PM, Güldner A, Beda A, Carvalho N, Nowack T, Krause A. u. a. Comparative effects of proportional assist and variable pressure support ventilation on lung function and damage in experimental lung injury. Crit Care Med September. 2012;40(9):2654–61. Spieth PM, Güldner A, Huhle R, Beda A, Bluth T, Schreiter D. u. a. Short-term effects of noisy pressure support ventilation in patients with acute hypoxemic respiratory failure. Crit Care Lond Engl 31 Oktober. 2013;17(5):R261. Carvalho AR, Spieth PM, Pelosi P, Beda A, Lopes AJ, Neykova B. u. a. Pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow. Anesth Analg September. 2009;109(3):856–65. Gama de Abreu M, Cuevas M, Spieth PM, Carvalho AR, Hietschold V, Stroszczynski C. u. a. Regional lung aeration and ventilation during pressure support and biphasic positive airway pressure ventilation in experimental lung injury. Crit Care Lond Engl. 2010;14(2):R34. Lachmann B, Robertson B, Vogel J. In vivo lung lavage as an experimental model of the respiratory distress syndrome. Acta Anaesthesiol Scand Juni. 1980;24(3):231–6. de Abreu MG, Quelhas AD, Spieth P, Bräuer G, Knels L, Kasper M. u. a. Comparative effects of vaporized perfluorohexane and partial liquid ventilation in oleic acid-induced lung injury. Anesthesiology Februar. 2006;104(2):278–89. Peterson BT, Brooks JA, Zack AG. Use of microwave oven for determination of postmortem water volume of lungs. J Appl Physiol Juni. 1982;52(6):1661–3. Spieth PM, Knels L, Kasper M, Domingues Quelhas A, Wiedemann B, Lupp A. u. a. Effects of vaporized perfluorohexane and partial liquid ventilation on regional distribution of alveolar damage in experimental lung injury. Intensive Care Med Februar. 2007;33(2):308–14. Carvalho AR, Spieth PM, Güldner A, Cuevas M, Carvalho NC, Beda A. u. a. Distribution of regional lung aeration and perfusion during conventional and noisy pressure support ventilation in experimental lung injury. J Appl Physiol Bethesda Md 1985 April. 2011;110(4):1083–92. Neumann P, Wrigge H, Zinserling J, Hinz J, Maripuu E, Andersson LG. u. a. Spontaneous breathing affects the spatial ventilation and perfusion distribution during mechanical ventilatory support. Crit Care Med Mai. 2005;33(5):1090–5. Kiss T, Bluth T, Braune A, Huhle R, Denz A, Herzog M. u. a. Effects of positive end-expiratory pressure and spontaneous breathing activity on regional lung inflammation in experimental acute respiratory distress syndrome. Crit Care Med April. 2019;47(4):e358–65. Putensen C, Wrigge H. Clinical review: Biphasic positive airway pressure and airway pressure release ventilation. Crit Care. 2004;8(6):492–7. Yoshida T, Uchiyama A, Matsuura N, Mashimo T, Fujino Y. Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury. Crit Care Med Mai. 2012;40(5):1578–85. Brochard L, Slutsky AS, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med [Internet]. 15. Februar 2017 [zitiert 10. Januar 2026];195(4). Verfügbar unter: https://pubmed.ncbi.nlm.nih.gov/27626833/ Richard JCM, Lyazidi A, Akoumianaki E, Mortaza S, Cordioli RL, Lefebvre JC. u. a. Potentially harmful effects of inspiratory synchronization during pressure preset ventilation. Intensive Care Med November. 2013;39(11):2003–10. Maxwell RA, Green JM, Waldrop J, Dart BW, Smith PW, Brooks D. u. a. A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. J Trauma September. 2010;69(3):501–10. discussion 511. Simbruner G, Mittal RA, Smith J, Maritz G, van Rensberg J, Simbruner B. u. a. Effects of duration and amount of lung stretch at biophysical, biochemical, histological, and transcriptional levels in an in vivo rabbit model of mild lung injury. Am J Perinatol März. 2007;24(3):149–59. Tables Tables are available in the Supplementary Files section. Additional Declarations Competing interest reported. Drs. Gama de Abreu, Spieth and Koch were granted a patent on the variable pressure support ventilation mode of assisted ventilation. The remaining authors have not disclosed any potential conflicts of interest. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 19 May, 2026 Reviews received at journal 13 May, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviews received at journal 07 Apr, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviewers agreed at journal 11 Mar, 2026 Reviewers invited by journal 09 Mar, 2026 Editor assigned by journal 26 Feb, 2026 Editor invited by journal 25 Feb, 2026 Submission checks completed at journal 25 Feb, 2026 First submitted to journal 25 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8914906","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":606679956,"identity":"8397cf8c-4d1a-4b2c-9713-a1a6c51fd866","order_by":0,"name":"Thomas Bluth","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Bluth","suffix":""},{"id":606679957,"identity":"cba6d8f9-8603-4f41-acd5-c7b4baf73fac","order_by":1,"name":"Maren Fritzsche","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Maren","middleName":"","lastName":"Fritzsche","suffix":""},{"id":606679958,"identity":"1c856540-7e09-4983-9861-6a95f3e66d8d","order_by":2,"name":"Dirk Haufe","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Dirk","middleName":"","lastName":"Haufe","suffix":""},{"id":606679961,"identity":"4b89f29f-b707-49e6-879d-c50d466e8eec","order_by":3,"name":"Thomas Kiss","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Kiss","suffix":""},{"id":606679962,"identity":"21b4b8a5-2ea7-4b2d-9db7-3532f5c82bf1","order_by":4,"name":"Thea Koch","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Thea","middleName":"","lastName":"Koch","suffix":""},{"id":606679963,"identity":"1ffcc047-71dd-4ea1-95db-40ab7dc248fb","order_by":5,"name":"Marcelo Gama Abreu","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Marcelo","middleName":"Gama","lastName":"Abreu","suffix":""},{"id":606679964,"identity":"37747b38-fc96-454b-96ba-1b048859bf87","order_by":6,"name":"Peter Markus Spieth","email":"","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"Markus","lastName":"Spieth","suffix":""},{"id":606679965,"identity":"4bd4ad37-3cce-4396-a6a9-509b6808f7b7","order_by":7,"name":"Andreas Güldner","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYHACAxiD8QAPkORnYGOQ4GFgJkoLA1iLZAPJWgwOENDCP7t524cPNXUM8hHJBw683WGTb3wjLfHGGwZrOVxaJO4cK54549hhBsMbaQkH555Js9x2I+2w5RyGdGOc1tzIMWbmYTvAYDgjx+Awb9thA7Mb6W3SPAyHExtw6JAHafnzrw6oJf8DUMt/A+MZEC31uLQYgLQwtjEzyEvkMAC1HDAwkEg7BtKSgMtdQC8UM/b2HeYx4HlmcHBuW7KBxJlnyZZzDNINcdkidyN5M8OPb3Vy8u3JDx+8bbMz4G9PM7zxpsJaHqf3oYDH4ACqgwlpAAJ5XO4YBaNgFIyCUQAAd7VYuc4b6foAAAAASUVORK5CYII=","orcid":"","institution":"University Hospital Carl Gustav Carus, TUD Dresden University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Güldner","suffix":""}],"badges":[],"createdAt":"2026-02-19 07:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8914906/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8914906/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104713606,"identity":"7b7d5932-a02a-4368-bd5a-5f9e837a5b7d","added_by":"auto","created_at":"2026-03-16 10:50:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":90775,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTypical Recordings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTypical recordings of airway flow (Flow), airway (P\u003csub\u003eaw\u003c/sub\u003e) and esophageal (P\u003csub\u003eeso\u003c/sub\u003e) pressure over time. Variable PSV (Panel A) = variable Pressure Support Ventilation; BIPAP (Panel B) biphasic positive airway pressure ventilation.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8914906/v1/9f57e291348659457a168cbe.jpg"},{"id":104713604,"identity":"07dd462c-27eb-46c3-9790-cd673141c225","added_by":"auto","created_at":"2026-03-16 10:50:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100668,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGas Exchange and Airway Pressures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRatio of arterial partial pressure of oxygen and inspired oxygen fraction (PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e – Panel A); arterial partial pressure of carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e – Panel B); peak airway pressure (P\u003csub\u003epeak\u003c/sub\u003e – Panel C) and mean airway pressure (P\u003csub\u003emean\u003c/sub\u003e – Panel D). Variable PSV = variable Pressure Support Ventilation; BIPAP biphasic positive airway pressure ventilation.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8914906/v1/89a8db7021c09ddcd8367937.jpg"},{"id":104783001,"identity":"bdf28530-187f-4f83-947f-8043d39eff10","added_by":"auto","created_at":"2026-03-17 07:58:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":54948,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMean tidal volumes during study intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVariable PSV = variable Pressure Support Ventilation; BIPAP biphasic positive airway pressure ventilation. V\u003csub\u003eT\u003c/sub\u003e = tidal volume. a = p\u0026lt;.05 vs. variable PSV.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8914906/v1/4bef953dad60ca137200d1d5.jpg"},{"id":104835563,"identity":"e0b4544b-4deb-47c8-8098-52491447f16e","added_by":"auto","created_at":"2026-03-17 17:46:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":772271,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8914906/v1/c1dfbd66-f5d1-4fef-9fb5-15610dd9a94a.pdf"},{"id":104782968,"identity":"a13f2203-9ffb-430f-b479-a8bbf94ee39b","added_by":"auto","created_at":"2026-03-17 07:58:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38391,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8914906/v1/746ba8bb684b71209d3b360c.docx"}],"financialInterests":"Competing interest reported. Drs. Gama de Abreu, Spieth and Koch were granted a patent on the variable pressure support ventilation mode of assisted ventilation. The remaining authors have not disclosed any potential conflicts of interest.","formattedTitle":"Variable Pressure Support Ventilation vs. Biphasic Positive Airway Pressure/Airway Pressure Release Ventilation in experimental acute respiratory failure","fulltext":[{"header":"Background","content":"\u003cp\u003eMaintaining or restoring spontaneous breathing early during mechanical ventilation in patients suffering from acute respiratory failure can improve gas exchange and respiratory mechanics, reduce the need for sedatives and cardiovascular support and is finally able to reduce the total time of mechanical ventilation (1\u0026ndash;4). Reduced time of ventilatory support may reduce the risk of ventilator induced diaphragmatic dysfunction (5) and the development of other ventilator associated complications.\u003c/p\u003e \u003cp\u003eAnother approach to improving mechanical ventilation is to continuously vary mandatory ventilation parameters. It has been shown that variable tidal volumes can improve gas exchange and respiratory mechanics in different experimental settings (6\u0026ndash;13). Based on some of these initial findings variable pressure support ventilation (variable PSV) had been developed (14), which theoretically combines the positive effects of spontaneous breathing modes and the restored physiological breathing pattern variability. Experimental evidence suggests that application of extrinsic variability in pressure support as with variable PSV is associated with beneficial effects in experimental lung injury (9,11,14,15), and was well tolerated during short term application in patients with acute respiratory failure (16).\u003c/p\u003e \u003cp\u003eMost studies showing positive effects of spontaneous breathing in acute respiratory distress syndrome (ARDS) were performed with biphasic positive airway pressure / airway pressure release ventilation (BIPAP/APRV), favoring BIPAP/APRV as the standard ventilatory mode for maintenance of spontaneous breathing (2).\u003c/p\u003e \u003cp\u003eThe present study based on findings that BIPAP with maintained non assisted spontaneous breathing and PSV, a completely assisted spontaneous breathing mode, are associated with distinct short term effects on pulmonary aeration and perfusion (17,18). Using a porcine model of acute lung injury induced by surfactant depletion we aimed at comparing variable PSV with BIPAP regarding gas exchange, pulmonary mechanics and inflammatory response. We hypothesized that the application of variable pressure support improves gas exchange and respiratory mechanics without causing increased pulmonary inflammatory response.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eEthics and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe institutional animal care and welfare committee and the government of the state of Saxony, Germany, approved all animal procedures following federal law (Landesdirektion Dresden, Germany, File AZ 24D-9168.11-1/2006-18). Animals were purchased from a private owner (Agrar Service GmbH \u0026nbsp; Schweinemast Horka, Germany). This company provided an informed consent statement to use the animals in the current study. Animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the US National Academy of Sciences Guide for the Care and Use of Laboratory Animals and reported according to the Animal Research: Reporting In Vivo Experiments statements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTrial design and primary endpoint\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis was an explorative randomized controlled experimental study. For structure and clarity of the manuscript, a primary endpoint was defined, which was the ratio between arterial partial pressure of oxygen and fraction of inspired oxygen (PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, Horovitz index). Relevant secondary endpoints included parameters of respiratory mechanics, as well as systemic and pulmonary inflammation and alveolar damage. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnimal preparation and mechanical ventilation settings\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEighteen juvenile pigs (22 – 30 kg; German landrace) were intramuscularly premedicated with ketamine (10 mg/kg) and midazolam (1 mg/kg). Anesthesia was induced by intravenous boli of ketamine and midazolam and maintained by continuous infusion (12-18 mg/kg/h ketamine and 2 mg/kg/h midazolam). Muscle paralysis was achieved by infusion of atracurium (1 mg/kg/h). Animals were orotracheally intubated with an 8.0 ID endotracheal tube and ventilated in volume controlled mode using an EVITA XL ventilator (Dräger Medical, Lübeck, Germany). Initial ventilator settings were as follows: tidal volume (V\u003csub\u003eT\u003c/sub\u003e) 10 ml/kg of actual body weight, F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e 1.0, positive endexpiratory pressure (PEEP) 5 cm H\u003csub\u003e2\u003c/sub\u003eO, inspiratory:expiratory ratio (I:E) 1:1 and respiratory rate to achieve arterial carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e) of 35-45 mmHg at fixed inspiratory flow of 35 l/min. Fluid uptake was maintained by infusion of a balanced crystalloid solution (10 ml/kg/h). After right lateral neck incision a 5 Fr. catheter was placed into the internal carotid artery and a 7.5 Fr. Swan-Ganz catheter was advanced via an 8.5 Fr. sheath into the pulmonal artery. Urine drainage was performed by invasive catheterization of the urinary bladder via mini laparotomy. Animals were kept in supine position during the entire experiment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExperimental respiratory failure was induced by repetitive saline lung lavage (30 ml/kg) in supine position until PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e fell constantly below 200 mmHg for 30 minutes (19).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing injury, lung recruitment by means of a continuous pressure of 50 cm H\u003csub\u003e2\u003c/sub\u003eO during 30 s and a consecutive decremental PEEP trial was conducted in order to set PEEP according to optimal respiratory system mechanics as described earlier (20). Briefly, PEEP was set at 20 cm H\u003csub\u003e2\u003c/sub\u003eO and reduced in steps of 2 cm H\u003csub\u003e2\u003c/sub\u003eO after each 2 minutes while keeping other respiratory parameters unchanged. After this, lung recruitment was repeated, and PEEP was set at the level corresponding to the minimal elastance of the respiratory system (E\u003csub\u003eRS\u003c/sub\u003e)\u003csub\u003e.\u003c/sub\u003e Prior to resuming of spontaneous breathing, atracurium was stopped and ketamine and midazolam infusion was reduced.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnimals were randomly assigned to variable PSV or BIPAP. During BIPAP spontaneous breathing was facilitated and considered sufficient, if the amount of minute ventilation (MV) of spontaneous breaths reached minimum 20% of total MV according to the algorithm implemented in the ventilator. In order to apply unassisted spontaneous breathing and therefore avoid synchronization of the pressure changes and the subject’s effort, as implemented in BiPAP ventilation mode, BIPAP was performed using the APRV mode embedded in the ventilator. However, because APRV is commonly regarded in clinical practice as a mode employing inverse ratio ventilation, the term BIPAP is used in this study to clarify the ventilatory settings applied. Variable PSV was applied via external remote control of the ventilator as previously described (14). Ventilator settings are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter 4 hours of study intervention had been completed, animals were sacrificed by intravenous injection of 1 M-potassium chloride (50 ml) following deepening of general anesthesia with thiopental (2 g). The lungs were removed at continuous airway pressures equal to PEEP. After separation, the middle lobe of the right lung was weighed (wet weight) and then rinsed two times with 50ml with saline solution to obtain bronchoalveolar lavage fluid (BALF). After standardized drying by microwave heating the middle lobe was weighed again (dry weight), and the ratio between wet and dry weight calculated (wet-to-dry ratio) (21). Tissue samples were taken from dependent and nondependent areas of both lungs according to a fixed protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData\u0026nbsp;\u003c/em\u003e\u003cem\u003eAcquisition and Measurements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAirway flow was measured using a heated pneumotachograph (Fleisch No. 2; Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (PXL12X5DN; Sensortechnics, Troy, NY) and airway pressures were obtained using a pressure transducer (SCX01DNC; SenSym ICT, Milpitas, CA.) at the endotracheal tube. After advancing an esophageal balloon catheter (Erich Jaeger, Höchberg, Germany) into mid-chest level, esophageal pressure was measured by a third pressure transducer (SCX01DNC, SenSym ICT). The signals of airway pressure, esophageal pressure, and airway flow were recorded using a LabView (National Instruments, Austin, TX) based data acquisition system as described previously (20).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eContinuous recordings (5 min) of respiratory mechanics, gas exchange, hemodynamics and blood samples for plasma cytokine analysis were assessed at baseline, injury, after titration of individual PEEP and resuming of spontaneous breathing (baseline 2) and 1-hour-intervals during the study intervention thereafter (Time 1 to 4). Parameters of respiratory mechanics were calculated offline as described elsewhere (20).\u0026nbsp;Airway pressure at 100 ms after beginning of inspiration (P\u003csub\u003e0.1\u003c/sub\u003e) was determined and used as surrogate of the central respiratory drive. Transpulmonary right-to-left shunt was calculated using standard formula, as previously described\u0026nbsp;(20). Using the recorded respiratory signals, tidal volumes were semiautomatically (algorithm-based detection and visually supervision of correct identification) classified as mandatory, assisted spontaneous and non-assisted spontaneous.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eScoring of Diffuse alveolar damage, which includes typical histopathological features of the early exudative phase of ARDS, was performed in tissue samples from gravity dependent and non-dependent regions of the left lung as described before (22). mRNA expression of Interleukin (IL)-6, IL-8 and Amphiregulin in right lung tissue samples was analyzed using quantitative real-time polymerase chain reaction as previously described (10). Protein levels of IL-6 and IL-8 were measured in plasma at all time points and in BALF supernatant using commercially available enzyme linked immunosorbent assay kits according to the manufacturer’s instructions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData are presented as mean ± standard deviation unless stated otherwise. Student´s t-test, one-way analysis of variance or repeated measures analysis of variance were used for normal distributed data as appropriate, Mann-Whitney-U-test and Wilcoxon-test were used in case of non-normal distributed data or nominal scaled variables. All tests were performed using the SPSS software package (Vers. 15.0, SPSS Inc., Chicago, IL). Multiple comparisons were adjusted according to Sidak or Bonferroni-Holm procedure as appropriate. The global significance level was defined as P\u0026lt;0.05 and, despite the exploratory nature of the study, is indicated in the text and tables for improved clarity.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eGroups did not differ significantly regarding bodyweight (mean [min-max]; variable PSV 27 [25-31]; BIPAP 27 [22-30]; p = 0.64) and number of lavages (mean [min-max]; variable PSV 8 [2-14]; BIPAP 8 [1-12]; p = 0.90). Typical recordings of airway flow, airway and esophageal pressure are depicted in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGas Exchange\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData on gas exchange are presented in Figure 2 and Table 2. Induction of lung injury significantly decreased PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u0026nbsp;\u003c/sub\u003eand pH and increased PaCO\u003csub\u003e2\u003c/sub\u003e and Shunt in both groups (Baseline 1 vs. Injury). Optimized PEEP and resuming of spontaneous breathing (Injury vs. Baseline 2) led to significantly increased PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e and PaCO\u003csub\u003e2\u003c/sub\u003e and decreased pH and Shunt. The primary endpoint, PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, and pH were significantly increased with variable PSV as compared to BIPAP. PaCO\u003csub\u003e2\u003c/sub\u003e were significantly lower with variable PSV as compared to BIPAP, whereas Shunt did not differ significantly between groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRespiratory Variables\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRespiratory data are presented in Figures 2 and Table 2. Lung injury led to increased peak and mean airway pressures (P\u003csub\u003epeak\u003c/sub\u003e, P\u003csub\u003emean\u003c/sub\u003e) without affecting other respiratory variables. Individually adjusted PEEP level did not relevantly differ in both groups (variable PSV 16 ± 1; BIPAP 15 ± 2 cm H\u003csub\u003e2\u003c/sub\u003eO; p = 0.36). Reduction of tidal volumes during resuming of spontaneous breathing was associated with a consecutive decrease in minute ventilation and increased respiratory rate as well as increased, but not relevant intrinsic PEEP. Total and spontaneous tidal volume and minute ventilation were significantly increased with variable PSV compared to BIPAP (Figure 3). Total respiratory rate did not differ significantly between groups, but spontaneous respiratory rate was significantly increased with variable PSV. P\u003csub\u003epeak\u0026nbsp;\u003c/sub\u003ewas higher and P\u003csub\u003emean\u003c/sub\u003e and pressure time product (PTP) were lower with variable PSV as compared to BIPAP. P\u003csub\u003e0.1\u003c/sub\u003e was significantly lower with variable PSV compared to BIPAP.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHemodynamics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHemodynamic data are shown in Table 2. Mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance increased with lung injury, whereas cardiac output decreased mainly by a reduced heart rate. Optimized PEEP and induction of spontaneous breathing led to a significant decrease of MPAP. Analysis of differences between groups revealed decreased cardiac output and increased systemic vascular resistance with variable PSV compared to BIPAP, whereas other variables did not differ.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHistology and lung edema\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCumulative alveolar damage scores did not differ significantly between the experimental groups, although lungs ventilated with noisy PSV showed significantly more alveolar oedema, particularly in gravity-dependent regions (Table 3). Other characteristics of the score showed no significant differences between the groups. Independent of group allocation, alveolar overdistension was more pronounced in non-dependent compared to dependent regions and achieved the highest scores among all features. The wet-to-dry weight ratio were higher in lungs ventilated with variable PSV compared to BIPAP (8.0 ± 0.8 versus 7.1 ± 0.4; p = 0.011).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBiomarkers of lung injury\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003emRNA expression of IL-6, IL-8 and Amphiregulin did not differ significantly between groups, independent from lung region (Table 4). Protein levels of IL-6 and IL-8 in plasma did not differ significantly between groups at any time point (Table 5), nor did IL-6 (variable PSV 877 [213 - 1712]; BIPAP 356 [232 - 661]; p = 0.55) and IL-8 (variable PSV 170 [116 - 272]; BIPAP 99 [97 - 198]; p = 0.45) in bronchoalveolar lavage fluid.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main results of this study could be summarized as follows: 1) Variable PSV was associated with marginally improved gas exchange and decreased respiratory effort when compared to BIPAP. 2) Ventilation with Variable PSV may have favored development of pulmonary edema, but did not relevantly increase overall alveolar damage and systemic or pulmonary inflammation. In contrast to our preliminary studies (14,17,18,23) ventilator settings in the present trial were chosen according to clinical standard without trying to match mean airway pressure and/or tidal volume.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eEffects of cardiorespiratory function\u003c/h2\u003e \u003cp\u003eEarly induction of spontaneous breathing has been repeatedly shown to improve pulmonary function and attenuate pulmonary inflammation in the experimental as well as in the clinical setting (1,11). As a possible mechanism behind improvement of gas exchange increased pulmonary aeration especially in juxtadiaphragmal regions was discussed (24). Our group demonstrated that redistribution of pulmonary blood flow towards better aerated lung regions, resulting in improved ventilation/perfusion matching, but not alveolar recruitment and/or increase in pulmonary aeration alone improve pulmonary gas exchange during spontaneous breathing (23). The excellent functional variables of the respiratory system in both groups of the current study support such assumptions. However, oxygenation was probably driven to a relevant degree by the high PEEP levels used here. The approach to setting individual PEEP according to minimal elastance was chosen, as a previous study suggested spontaneous breathing with higher PEEP in experimental ARDS to better stabilize dependent lung segments and more effectively prevent from pulmonary inflammation (25). Due to the effective lung recruitment absolute differences of gas exchange variables between experimental groups remained smaller than in our previous study (14). However, the significant higher PaO\u003csub\u003e2\u003c/sub\u003e/F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e ratio and the better pH in combination with the lower PaCO\u003csub\u003e2\u003c/sub\u003e seen with variable PSV indicate improved alveolar ventilation and gas exchange compared to BIPAP. The improved alveolar ventilation can largely be explained by the higher mean tidal volume and total minute ventilation generated by the assistance of breathing, while unassisted spontaneous breaths remained relatively low under BIPAP. Conceptually, some researchers consider unassisted spontaneous breaths during BIPAP to be generally irrelevant in increasing minute volume, instead emphasize their overall potential to improve cardiorespiratory function (26). However, this view has been recently challenged by the finding, that excessive inspiratory efforts might result in lung damage and spontaneous tidal volumes and pressures need to be closely observed during respiratory therapy, instead (27). In addition to differences in ventilation, lower mean airway pressure in the variable PSV group may have favored a redistribution of pulmonary blood flow towards better ventilated areas especially in the setting of higher PEEP, which finally resulted in an improved ventilation/perfusion matching as indicated by previous published studies (14,17,23).\u003c/p\u003e \u003cp\u003eIt is worth noting that higher mean airway and lower peak airway pressures found in the BIPAP group are related to the different I:E settings (1:1 with BIPAP vs. app. 1:4 with variable PSV) because airway pressures were calculated as mean values over time. When compared to our previous study with lower PEEP and F\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e settings, spontaneous respiratory rate in BIPAP was markedly lower and no signs of discomfort could be observed (14). PTP and P\u003csub\u003e0.1\u003c/sub\u003e as surrogates for respiratory workload were obviously higher with BIPAP compared to the fully assisted breaths with variable PSV. The decision if a reduction of respiratory workload in mechanically ventilated patients is desirable or not should be made in the context of each individual case. Patients running into muscle fatigue could benefit from relief of the work of breathing through fully assisted spontaneous breathing, whereas a certain amount of respiratory work by non- or partially supported spontaneous breathing could be helpful to prevent disuse atrophy of respiratory muscles in other scenarios (5).\u003c/p\u003e \u003cp\u003eThe increase in cardiac output with BIPAP may be due to increased muscle activity also expressed by the markedly increased inspiratory effort. On the other hand, increased venous return due to a more pronounced cyclic reduction in intrathoracic pressure with BIPAP could lead to an increase in left ventricular stroke volume (SV). Left ventricular output could also be enhanced through reduction in systemic vascular resistance due to decreased pH and permissive hypercapnia with BIPAP. However, this effect is not supposed to play a major role.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eEffects on lung protection\u003c/h2\u003e \u003cp\u003eIn recent years, possible adverse side effects of spontaneous breathing in the acute phase of respiratory failure became more apparent. Excessive efforts resulting in high transpulmonary driving pressures can exacerbate lung damage, a phenomenon called patient self-inflicted lung injury (28). Synchronized spontaneous breaths are more likely to result in such higher transpulmonary pressures, as negative intrapleural pressure amplitudes during spontaneous inspiration add to positive pressure assistance provided by the ventilator. In contrast, non-assisted breaths such as those occurring during ventilation with BIPAP/APRV lack the ventilator component and may be even more lung protective, as long as the respiratory workload remains in a physiological range (29). Indeed, a more detailed analysis of pulmonary aeration by means of dynamic computed tomography in pigs ventilated with PSV or BIPAP observed a reduction of tidal reaeration and hyperaeration during BIPAP, suggesting an overall increased risk of ventilator induced lung injury during PSV and possibly during variable PSV (18). This finding rather resulted from lower tidal volumes during unassisted spontaneous breaths in BIPAP than from decreased nonaerated areas at end-expiration or different distribution of ventilation. In contrast, tidal reaeration and hyperinflation during controlled respiratory cycles in BIPAP were increased compared to PSV cycles. Based on the above considerations, PSV has an inherent, at least theoretical disadvantage over BIPAP with unassisted spontaneous breathing in terms of lung protection, which exists independently of the addition of variability. As of yet, this disadvantage has not been found in clinically relevant outcomes in the few clinical studies performed (30). Our group has already shown that optimizing PSV by varying the pressures support level does not lead to an increase in pulmonary inflammation (25). (Variable) PSV could therefore be equivalent to BIPAP in terms of lung protection if the vulnerability of the lungs is relatively low or if an improved lung function under PSV helps to reduce the invasiveness of ventilation in general. The data from this study seem to reflect these considerations.\u003c/p\u003e \u003cp\u003eWe clearly aimed to test variable PSV and BIPAP in a clinical setting with optimized lung protection. Indeed, the overall level of pulmonary inflammatory response in plasma, bronchoalveolar lavage fluid and lung tissue in our study was rather low and did not reveal many differences between groups. The lavage model is known to be well recruitable and high PEEP/F\u003csub\u003ei\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e in this setting might have effectively stabilized lung units. If one of the two modes would have introduced relevant injury to the vulnerably changed lungs, this should be reflected by histologic or inflammatory findings. As discussed above, the BIPAP group has been even favored with regard to lung parenchymal stress due to a lower rate of respiratory cycles with 6 ml/kg (controlled cycles) or to a lower mean Vt compared with variable PSV. Increased minute ventilation as a consequence of increased tidal volume or respiratory rate has been shown to influence ventilator induced lung injury (31). This explanation could also account for the difference in lung edema seen in the present study. An alternative explanation lies in the exploratory nature of this study: We cannot rule out the possibility that multiple testing has led to an overestimation of the net effect, i.e. to the detection of significant differences that are purely random. The probability that the difference in alveolar edema results from such an error appears moderate, as other characteristics of the Diffuse alveolar damage score and the cumulative score itself, as well as biochemical markers of inflammation, show no significant differences between the experimental groups. Although one could question the selective choice of parameters to determine lung parenchymal stress and inflammatory response in this study, the same methods yielded significant differences in previous studies employing the same experimental model (10,11).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eFurther study limitations\u003c/h2\u003e \u003cp\u003eFirst, the lavage model represents a very well standardized experimental model that by far not necessarily reflects the complex clinical features of acute respiratory failure/ARDS, which limits the transferability of our data to the clinical setting, especially to clinical manifestation of severe ARDS. Second, since minute ventilation was not controlled in this protocol, we cannot exclude that improvement of gas exchange was affected by higher minute ventilation in the variable PSV group. Finally, the low level of pulmonary inflammatory response and lung parenchymal stress as well as the absence of relevant differences between groups could be due to the relatively short observational period of just four hours.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this experimental model of acute respiratory failure in pigs, variable PSV and BIPAP with non-assisted spontaneous breathing improved respiratory function. Variable PSV was marginally superior to BIPAP regarding gas exchange and was associated with reduced respiratory workload. Although inflammatory markers did not differ between modes, variable PSV led to increased alveolar oedema compared to BIPAP.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAPRV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eairway pressure release ventilation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eARDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute respiratory distress syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBALF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebronchoalveolar lavage fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBIPAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebiphasic positive airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eE\u003csub\u003eRS\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelastance of the respiratory system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eF\u003csub\u003eI\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efraction of inspired oxygen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eI:E\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einspiratory:expiratory ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInterleukin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMPAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emean pulmonary arterial pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emRNA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emessenger ribonucleic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eminute ventilation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP\u003csub\u003e0.1\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eairway pressure at 100 ms after beginning of inspiration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP\u003csub\u003ea\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earterial partial pressure of oxygen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP\u003csub\u003ea\u003c/sub\u003eCO\u003csub\u003e2\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earterial partial pressure of carbon dioxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEEP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositive endexpiratory pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP\u003csub\u003emean\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emean airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP\u003csub\u003epeak\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epeak airway pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epressure support ventilation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epressure time product\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV\u003csub\u003eT\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etidal volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe experiments were approved by the institutional animal care and welfare committee and the government of the state of Saxony, Germany (Landesdirektion Dresden, Germany, File AZ 24D-9168.11-1/2006-18).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe complete dataset of the current trial is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDrs. Gama de Abreu, Spieth and Koch were granted a patent on the variable pressure support ventilation mode of assisted ventilation. The remaining authors have not disclosed any potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported, in part, by a research grant of the Medical Faculty, Technical University of Dresden, Germany (MeDDrive Programm).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: TB, DH, MGdA, PMS, AG; Data acquisition: TB, MF, TKi, MGdA, PMS, AG; Data analysis and interpretation: TB, MGdA, PMS, AG; Manuscript preparation: TB, PMS, AG; Manuscript revision: TB, MF, DH, TKi, TKo, MGdA, PMS, AG.\u0026nbsp;All authors approved the final version to be published and agreed to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are indebted to the students of the Pulmonary Engineering Group and the staff of the Anatomical Institute of the Medical Faculty TU Dresden. Especially Professor Michael Kasper deserves our sincere thanks for his commitment to assessing the diffuse alveolar damage score, Professor Alysson Roncally Carvalho for his support with the technical part of the experiments and Professor Stefan Uhlig and his lab staff for measurement of inflammatory markers. The mechanical ventilator used in this study was kindly provided by Dr\u0026auml;ger Medical, L\u0026uuml;beck, Germany.\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePutensen C, Zech S, Wrigge H, Zinserling J, St\u0026uuml;ber F, Von Spiegel T. u. a. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med 1 Juli. 2001;164(1):43\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePutensen C, Muders T, Varelmann D, Wrigge H. The impact of spontaneous breathing during mechanical ventilation. Curr Opin Crit Care Februar. 2006;12(1):13\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Jin X, Lv Y, Wang P, Yang Y, Liang G. u. a. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med November. 2017;43(11):1648\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichard JCM, Beloncle FM, B\u0026eacute;duneau G, Mortaza S, Ehrmann S, Diehl JL. u. a. Pressure control plus spontaneous ventilation versus volume assist-control ventilation in acute respiratory distress syndrome. A randomised clinical trial. Intensive Care Med Oktober. 2024;50(10):1647\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P. u. a. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. M\u0026auml;rz 2008;27(13):1327\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuki B, Alencar AM, Sujeer MK, Lutchen KR, Collins JJ, Andrade JS. Jr, u. a. Life-support system benefits from noise. Nat 14 Mai. 1998;393(6681):127\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLefevre GR, Kowalski SE, Girling LG, Thiessen DB, Mutch WA. Improved arterial oxygenation after oleic acid lung injury in the pig using a computer-controlled mechanical ventilator. Am J Respir Crit Care Med November. 1996;154(5):1567\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcMullen MC, Girling LG, Graham MR, Mutch WAC. Biologically variable ventilation improves oxygenation and respiratory mechanics during one-lung ventilation. Anesthesiology Juli. 2006;105(1):91\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, Carvalho AR, G\u0026uuml;ldner A, Pelosi P, Kirichuk O, Koch T. u. a. Effects of different levels of pressure support variability in experimental lung injury. Anesthesiology Februar. 2009;110(2):342\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, Carvalho AR, Pelosi P, Hoehn C, Meissner C, Kasper M. u. a. Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury. Am J Respir Crit Care Med 15 April. 2009;179(8):684\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, Carvalho AR, G\u0026uuml;ldner A, Kasper M, Schubert R, Carvalho NC. u. a. Pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support. Crit Care Med April. 2011;39(4):746\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDos Santos Rocha A, S\u0026uuml;dy R, Bizzotto D, Kassai M, Carvalho T, Dellac\u0026agrave;. RL, u. a. Benefit of Physiologically Variable Over Pressure-Controlled Ventilation in a Model of Chronic Obstructive Pulmonary Disease: A Randomized Study. Front Physiol. 2020;11:625777.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDos Santos Rocha A, Pet\u0026aacute;k F, Carvalho T, Habre W, Balogh AL. Physiologically variable ventilation prevents lung function deterioration in a model of pulmonary fibrosis. J Appl Physiol Bethesda Md 1985 1 April. 2022;132(4):915\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGama de Abreu M, Spieth PM, Pelosi P, Carvalho AR, Walter C, Schreiber-Ferstl. A, u. a. Noisy pressure support ventilation: a pilot study on a new assisted ventilation mode in experimental lung injury. Crit Care Med M\u0026auml;rz. 2008;36(3):818\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, G\u0026uuml;ldner A, Beda A, Carvalho N, Nowack T, Krause A. u. a. Comparative effects of proportional assist and variable pressure support ventilation on lung function and damage in experimental lung injury. Crit Care Med September. 2012;40(9):2654\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, G\u0026uuml;ldner A, Huhle R, Beda A, Bluth T, Schreiter D. u. a. Short-term effects of noisy pressure support ventilation in patients with acute hypoxemic respiratory failure. Crit Care Lond Engl 31 Oktober. 2013;17(5):R261.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarvalho AR, Spieth PM, Pelosi P, Beda A, Lopes AJ, Neykova B. u. a. Pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow. Anesth Analg September. 2009;109(3):856\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGama de Abreu M, Cuevas M, Spieth PM, Carvalho AR, Hietschold V, Stroszczynski C. u. a. Regional lung aeration and ventilation during pressure support and biphasic positive airway pressure ventilation in experimental lung injury. Crit Care Lond Engl. 2010;14(2):R34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLachmann B, Robertson B, Vogel J. In vivo lung lavage as an experimental model of the respiratory distress syndrome. Acta Anaesthesiol Scand Juni. 1980;24(3):231\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Abreu MG, Quelhas AD, Spieth P, Br\u0026auml;uer G, Knels L, Kasper M. u. a. Comparative effects of vaporized perfluorohexane and partial liquid ventilation in oleic acid-induced lung injury. Anesthesiology Februar. 2006;104(2):278\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeterson BT, Brooks JA, Zack AG. Use of microwave oven for determination of postmortem water volume of lungs. J Appl Physiol Juni. 1982;52(6):1661\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpieth PM, Knels L, Kasper M, Domingues Quelhas A, Wiedemann B, Lupp A. u. a. Effects of vaporized perfluorohexane and partial liquid ventilation on regional distribution of alveolar damage in experimental lung injury. Intensive Care Med Februar. 2007;33(2):308\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarvalho AR, Spieth PM, G\u0026uuml;ldner A, Cuevas M, Carvalho NC, Beda A. u. a. Distribution of regional lung aeration and perfusion during conventional and noisy pressure support ventilation in experimental lung injury. J Appl Physiol Bethesda Md 1985 April. 2011;110(4):1083\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeumann P, Wrigge H, Zinserling J, Hinz J, Maripuu E, Andersson LG. u. a. Spontaneous breathing affects the spatial ventilation and perfusion distribution during mechanical ventilatory support. Crit Care Med Mai. 2005;33(5):1090\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKiss T, Bluth T, Braune A, Huhle R, Denz A, Herzog M. u. a. Effects of positive end-expiratory pressure and spontaneous breathing activity on regional lung inflammation in experimental acute respiratory distress syndrome. Crit Care Med April. 2019;47(4):e358\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePutensen C, Wrigge H. Clinical review: Biphasic positive airway pressure and airway pressure release ventilation. Crit Care. 2004;8(6):492\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida T, Uchiyama A, Matsuura N, Mashimo T, Fujino Y. Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury. Crit Care Med Mai. 2012;40(5):1578\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrochard L, Slutsky AS, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med [Internet]. 15. Februar 2017 [zitiert 10. Januar 2026];195(4). Verf\u0026uuml;gbar unter: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/27626833/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/27626833/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichard JCM, Lyazidi A, Akoumianaki E, Mortaza S, Cordioli RL, Lefebvre JC. u. a. Potentially harmful effects of inspiratory synchronization during pressure preset ventilation. Intensive Care Med November. 2013;39(11):2003\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaxwell RA, Green JM, Waldrop J, Dart BW, Smith PW, Brooks D. u. a. A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. J Trauma September. 2010;69(3):501\u0026ndash;10. discussion 511.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimbruner G, Mittal RA, Smith J, Maritz G, van Rensberg J, Simbruner B. u. a. Effects of duration and amount of lung stretch at biophysical, biochemical, histological, and transcriptional levels in an in vivo rabbit model of mild lung injury. Am J Perinatol M\u0026auml;rz. 2007;24(3):149\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"mechanical ventilation, BIPAP, variable ventilation, randomized trial, animal, lung injury","lastPublishedDoi":"10.21203/rs.3.rs-8914906/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8914906/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpontaneous breathing during mechanical ventilation (MV) can improve cardiorespiratory function and lung protection. Biphasic Positive Airway Pressure (BIPAP) and Airway Pressure Release Ventilation (APRV) are common MV modes that combine spontaneous breathing with controlled ventilation. Variable pressure support ventilation (PSV), which varies breath-by-breath pressure support randomly, has been shown to improve gas exchange and reduce lung injury compared to conventional MV modes. This study aimed to compare the short-term effects of variable PSV with BIPAP in a model of acute respiratory failure, hypothesizing that variable PSV would improve lung function without increasing lung damage or inflammation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn an exploratory randomized study with 18 pigs, lung injury was induced by lung lavage. Over 4 hours, two lung protective strategies were applied with individually optimized PEEP: 1) BIPAP with non-assisted spontaneous breathing and 2) variable PSV, maintaining a mean tidal volume of 6 ml/kg body weight while varying pressure support. Plasma and bronchoalveolar lavage fluid samples were collected for inflammation markers, and lung damage was assessed histologically. Gene expression of inflammatory cytokines was also measured.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVariable PSV resulted in slightly improved gas exchange with higher mean tidal volumes and minute ventilation compared to BIPAP, as well as reduced work of breathing. Histopathological analysis showed alveolar damage to be mild, with no significant overall difference between the groups. However, variable PSV caused more alveolar edema, especially in gravity-dependent lung regions, and increased the wet-to-dry ratio than BIPAP. Despite these differences, there were no significant changes in systemic or pulmonary inflammatory cytokines or gene expression between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this model of acute respiratory failure, variable PSV with a protective tidal volume of 6 ml/kg resulted in marginal, but clinically insignificant improvements in gas exchange and reduced work of breathing compared to BIPAP with non-assisted spontaneous breathing. Overall lung damage and inflammatory responses were similar between groups. However, the consequent assistance and its variation of spontaneous breaths with variable PSV may have contributed to increased alveolar edema in this study.\u003c/p\u003e","manuscriptTitle":"Variable Pressure Support Ventilation vs. Biphasic Positive Airway Pressure/Airway Pressure Release Ventilation in experimental acute respiratory failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 10:50:16","doi":"10.21203/rs.3.rs-8914906/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-19T07:51:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-13T11:51:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"193459169223153002628482881919968858706","date":"2026-04-22T14:09:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-07T09:20:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266594794373689567510837857721140704685","date":"2026-03-16T07:25:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304484662720258895055734398844621635485","date":"2026-03-11T09:55:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-09T08:58:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-26T07:56:10+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-25T15:55:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-25T13:58:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2026-02-25T13:51:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b3ec9382-b609-480d-b877-6b1580d8b3b1","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-19T07:51:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-13T11:51:12+00:00","index":40,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-19T07:55:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 10:50:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8914906","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8914906","identity":"rs-8914906","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}