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The present study examined the contributions of the lungs and chest wall to respiratory complications in a rat model of diabetes and clarified the effects of metformin on these changes. At low positive end-expiratory pressure, type 2 diabetes was linked to dysfunctional airway and lung tissue mechanics in relation with gas-exchange defects and collagen overexpression, whereas decreased tissue hysteresivity was manifested in the chest wall abnormalities. Metformin treated all adverse respiratory consequences of diabetes.

Background Although high-frequency percussive ventilation (HFPV) improves gas exchange, concerns remain about tissue overdistension caused by the oscillations and consequent lung damage. We compared a modified percussive ventilation modality created by superimposing high-frequency oscillations to the conventional ventilation waveform during expiration only (eHFPV) with conventional mechanical ventilation (CMV) and standard HFPV. Methods Hypoxia and hypercapnia were induced by decreasing the frequency of CMV in New Zealand White rabbits (n = 10). Following steady-state CMV periods, percussive modalities with oscillations randomly introduced to the entire breathing cycle (HFPV) or to the expiratory phase alone (eHFPV) with varying amplitudes (2 or 4 cmH2O) and frequencies were used (5 or 10 Hz). The arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were determined. Volumetric capnography was used to evaluate the ventilation dead space fraction, phase 2 slope, and minute elimination of CO2. Respiratory mechanics were characterized by forced oscillations. Results The use of eHFPV with 5 Hz superimposed oscillation frequency and an amplitude of 4 cmH2O enhanced gas exchange similar to those observed after HFPV. These improvements in PaO2 (47.3 ± 5.5 vs. 58.6 ± 7.2 mmHg) and PaCO2 (54.7 ± 2.3 vs. 50.1 ± 2.9 mmHg) were associated with lower ventilation dead space and capnogram phase 2 slope, as well as enhanced minute CO2 elimination without altering respiratory mechanics. Conclusions These findings demonstrated improved gas exchange using eHFPV as a novel mechanical ventilation modality that combines the benefits of conventional and small-amplitude high-frequency oscillatory ventilation, owing to improved longitudinal gas transport rather than increased lung surface area available for gas exchange.

Although ventilator-induced lung injury (VILI) often develops after prolonged mechanical ventilation in normal lungs, pulmonary disorders may aggravate the development of adverse symptoms. VILI exaggeration can be anticipated in type 2 diabetes mellitus (T2DM) due to its adverse pulmonary consequences. Therefore, we determined whether T2DM modulates VILI and evaluated how T2DM therapy affects adverse pulmonary changes. Rats were randomly assigned into the untreated T2DM group receiving low-dose streptozotocin with high-fat diet (T2DM, n = 8), T2DM group supplemented with metformin therapy (MET, n = 8), and control group (CTRL, n = 8). In each animal, VILI was induced by mechanical ventilation for 4 h with high tidal volume (23 ml/kg) and low positive end-expiratory pressure (0 cmH2O). Arterial and venous blood samples were analyzed to measure the arterial partial pressure of oxygen (PaO2), oxygen saturation (SaO2), and the intrapulmonary shunt fraction (Qs/Qt). Airway and respiratory tissue mechanics were evaluated by forced oscillations. Lung histology samples were analyzed to determine injury level. Significant worsening of VILI, in terms of PaO2, SaO2, and Qs/Qt, was observed in the T2DM group, without differences in the respiratory mechanics. These functional changes were also reflected in lung injury score. The MET group showed no difference compared with the CTRL group. Gas exchange impairment without significant mechanical changes suggests that untreated diabetes exaggerates VILI by augmenting the damage of the alveolar–capillary barrier. Controlled hyperglycemia with metformin may reduce the manifestations of respiratory defects during prolonged mechanical ventilation.

Additional file 1: Details of the simulation study and additional data for respiratory mechanics.

Objective To investigate the effects of dopamine on the adverse pulmonary changes after cardiopulmonary bypass. Design A prospective, nonrandomized clinical investigation. Setting A university hospital. Participants One hundred fifty-seven patients who underwent elective cardiac surgery that required cardiopulmonary bypass. Interventions Fifty-two patients were administered intravenous infusion of dopamine (3 µg/kg/min) for five minutes after weaning from cardiopulmonary bypass; no intervention was applied in the other 105 patients. Measurements and Main Results Measurements were performed under general anesthesia and mechanical ventilation before cardiopulmonary bypass, after cardiopulmonary bypass, and after the intervention. In each protocol stage, forced oscillatory lung impedance was measured to assess airway and tissue mechanical changes. Mainstream capnography was performed to assess ventilation- and/or perfusion-matching by calculating the normalized phase-3 slopes of the time and volumetric capnograms and the physiologic deadspace. Arterial and central venous blood samples were analyzed to characterize lung oxygenation and intrapulmonary shunt. After cardiopulmonary bypass, dopamineinduced marked improvements in airway resistance and tissue damping, with relatively small decreases in lung tissue elastance. These changes were associated with decreases in the normalized phase-3 slopes of the time and volumetric capnograms. The inotrope had no effect on physiologic deadspace, intrapulmonary shunt, or lung oxygenation. Conclusion Dopamine reversed the complex detrimental lung mechanical changes induced by cardiopulmonary bypass and alleviated ventilation heterogeneities without affecting the physiologic deadspace or intrapulmonary shunt. Therefore, dopamine has a potential benefit on the gas exchange abnormalities after weaning from cardiopulmonary bypass.

Background: Laboratory skills training is an essential step before conducting minimally invasive surgery in clinical practice. Our main aim was to develop an animal model for training in clinically highly challenging laparoscopic duodenal atresia repair that could be useful in establishing a minimum number of repetitions to indicate safe performance of similar interventions on humans. Materials and methods: A rabbit model of laparoscopic duodenum atresia surgery involving a diamond-shaped duodeno-duodenostomy was designed. This approach was tested in two groups of surgeons: in a beginner group without any previous clinical laparoscopic experience (but having undergone previous standardized dry-lab training, n = 8) and in an advanced group comprising pediatric surgery fellows with previous clinical experience of laparoscopy (n = 7). Each participant performed eight interventions. Surgical time, expert assessment using the Global Operative Assessment of Laparoscopic Skills (GOALS) score, anastomosis quality (leakage) and results from participant feedback questionnaires were analyzed. Results: Participants in both groups successfully completed all eight surgeries. The surgical time gradually improved in both groups, but it was typically shorter in the advanced group than in the beginner group. The leakage rate was significantly lower in the advanced group in the first two interventions, and it reached its optimal level after five operations in both groups. The GOALS and participant feedback scores showed gradual increases, evident even after the fifth surgery. Conclusions: Our data confirm the feasibility of this advanced pediatric laparoscopic model. Surgical time, anastomosis quality, GOALS score and self-assessment parameters adequately quantify technical improvement among the participants. Anastomosis quality reaches its optimal value after the fifth operation even in novice, but uniformly trained surgeons. A minimum number of wet-lab operations can be determined before surgery can be safely conducted in a clinical setting, where the development of further non-technical skills is also required. Open access funding provided by University of Szeged. This study has been funded by FEDER funds through the Competitiveness Factors Operational Program (COMPETE) and by national funds through the Foundation for Science and Technology (FCT) within the scope of project No. POCI-01–0145-FEDER-007038, as well as by project No. NORTE-01–0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020) under the Portugal 2020 Partnership Agreement through the European Regional Development Fund (FEDER).

BACKGROUND Capnoperitoneum during laparoscopy leads to cranial shift of the diaphragm, loss in lung volume, and risk of impaired gas exchange. Infants are susceptible to these changes and bedside assessment of lung volume during laparoscopy might assist with optimizing the ventilation. Thus, the primary aim was to investigate the monitoring value of a continuous end-expiratory lung volume (EELV) assessment method based on CO2 dynamics ( EELVCO2 ) in a pediatric capnoperitoneum model by evaluating the correlation and trending ability against helium washout (EELVHe ). METHODS Intra-abdominal pressure (IAP) was randomly varied between 0, 6, and 12 mm Hg with CO2 insufflation, while positive end-expiratory pressure (PEEP) levels of 3, 6, and 9 cm H2 O were randomly applied in eight anesthetized and mechanically ventilated chinchilla rabbits. Concomitant EELVCO2 and EELVHe and lung clearance index (LCI) were obtained under each experimental condition. RESULTS Significant correlations were found between EELVCO2 and EELVHe before capnoperitoneum (r = .85, P

Introduction: Prolonged mechanical ventilation may lead to the onset of ventilator-induced lung injury (VILI). While type two diabetes (T2DM) reduces airway patency and facilitates atelectasis development, exaggeration of VILI can be anticipated. Thus, we aimed at characterizing whether T2DM modulates VILI, and we also characterized how T2DM therapy affects adverse pulmonary changes. Methods: Rats were randomly assigned into three groups: a model of untreated T2DM received a low dose of streptozotocin with high-fat diet (T2DM, n=8); a model of T2DM where this treatment was supplemented by metformin therapy (MET, n=8); and a control group (CTRL, n=8). VILI in each animal was induced by ventilating the rats with high tidal volume (VT=23 ml/kg) for four hours. Blood samples were analyzed to measure the arterial oxygen tension (PaO2), oxygen saturation (SaO2) and the intrapulmonary shunt fraction (Qs/Qt) in every two hours. Airway and respiratory tissue mechanics were assessed by forced oscillations. The level of injury and the oxidative stress were determined by lung histology. Results: Significant worsening of VILI was observed in PaO2, SaO2 and Qs/Qt in T2DM group, without differences in the respiratory mechanics. These functional defects were also reflected in the lung injury score. Animals in the MET group showed no difference to rats in the CTRL group. Conclusion: Impairment of the gas exchange without significant mechanical changes suggests that untreated diabetes exaggerates VILI via destructing the alveolar-capillary barrier. Metformin therapy reduces the manifestations of respiratory defects in diabetes during prolonged mechanical ventilation. Supported by UNKP-20-3

Changes in lung mechanics are frequently inferred from intact-chest measures of total respiratory system mechanics without consideration of the chest wall contribution. The participation of lungs and chest wall in respiratory mechanics has not been evaluated systematically in small animals commonly used in respiratory research. Thus, we compared these contributions in intact-chest mice, rats, and rabbits and further characterized the influence of positive end-expiratory pressure (PEEP). Forced oscillation technique was applied to anesthetized mechanically ventilated healthy animals to obtain total respiratory system impedance (Zrs) at 0, 3, and 6 cmH2O PEEP levels. Esophageal pressure was measured by a catheter-tip micromanometer to separate Zrs into pulmonary (ZL) and chest wall (Zcw) components. A model containing a frequency-independent Newtonian resistance (RN), inertance, and a constant-phase tissue damping (G) and elastance (H) was fitted to Zrs, ZL, and Zcw spectra. The contribution of Zcw to RN was negligible in all species and PEEP levels studied. However, the participation of Zcw in G and H was significant in all species and increased significantly with increasing PEEP and animal size (rabbit > rat > mice). Even in mice, the chest wall contribution to G and H was still considerable, reaching 47.0 ± 4.0(SE)% and 32.9 ± 5.9% for G and H, respectively. These findings demonstrate that airway parameters can be assessed from respiratory system mechanical measurements. However, the contribution from the chest wall should be considered when intact-chest measurements are used to estimate lung parenchymal mechanics in small laboratory models (even in mice), particularly at elevated PEEP levels. NEW & NOTEWORTHY In species commonly used in respiratory research (rabbits, rats, mice), esophageal pressure-based estimates revealed negligible contribution from the chest wall to the Newtonian resistance. Conversely, chest wall participation in the viscoelastic tissue mechanical parameters increased with body size (rabbit > rat > mice) and positive end-expiratory pressure, with contribution varying between 30 and 50%, even in mice. These findings demonstrate the potential biasing effects of the chest wall when lung tissue mechanics are inferred from intact-chest measurements in small laboratory animals.

Background Crystalloids are first line in fluid resuscitation therapy, however there is a lack of evidence-based recommendations on the volume to be administered. Therefore, we aimed at comparing the systemic hemodynamic and respiratory effects of volume replacement therapy with a 1:1 ratio to the historical 1:3 ratio. Methods Anesthetized, ventilated rats randomly included in 3 groups: blood withdrawal and replacement with crystalloid in 1:1 ratio (Group 1, n = 11), traditional 1:3 ratio (Group 3, n = 12) and a control group with no interventions (Group C, n = 9). Arterial blood of 5% of the total blood volume was withdrawn 7 times, and replaced stepwise with different volume rations of Ringer’s acetate, according to group assignments. Airway resistance (Raw), respiratory tissue damping (G) and tissue elastance (H), mean arterial pressure (MAP) and heart rate (HR) were assessed following each step of fluid replacement with a crystalloid (CR1-CR6). Lung edema index was measured from histological samples. Results Raw decreased in Groups 1 and 3 following CR3 (p

To clarify the potential of dopamine to alter airway tone in the presence of different bronchoconstrictor stimuli, changes in airway function following dopamine administrations were characterized when the bronchial tone was elevated by stimulating the histaminic or cholinergic pathway. Airway resistance, tissue damping and tissue elastance were measured in anesthetized mechanically ventilated rabbits under baseline conditions, during steady-state bronchoconstriction induced by methacholine or histamine, and following intravenous dopamine (5 and 15 μg/kg/min). Bronchoconstriction induced by methacholine and histamine was significantly ameliorated by dopamine (14.8 ± 2.9% and 14.9 ± 2.9%; p 0.05 for both), with no difference between the mode of stimuli. Dopamine had no effect on the tissue mechanics. These findings indicate that dopamine relaxes the elevated airway smooth muscle tone without affecting the lung periphery, and this effect is independent of the mode of constrictor stimuli. This profile of dopamine suggests its ability to treat effectively cholinergic and histaminergic bronchoconstriction, besides its positive inotropic effects on the myocardial contractility.

Highlights • Acute shortage of ventilators may emerge during outbreak of pandemic with severe pulmonary consequences, such as COVID-19. • To avoid inevitable triage, use of ventilator splitting as a lifesaving concept was assessed to reveal whether shared ventilation risks uneven ventilation with a potential cross-breathing. • This alternative may have importance during the exacerbation of the current or next epidemic wave, when intensive care specialists may be faced with a shortage of ventilators, particularly in less developed or developing countries., Exacerbation of COVID-19 pandemic may lead to acute shortage of ventilators, which may require shared use of ventilator as a lifesaving concept. Two model lungs were ventilated with one ventilator to i) test the adequacy of individual tidal volumes via capnography, ii) assess cross-breathing between lungs, and iii) offer a simulation-based algorithm for ensuring equal tidal volumes. Ventilation asymmetry was induced by placing rubber band around one model lung, and the uneven distribution of tidal volumes (VT) was counterbalanced by elevating airflow resistance (HR) contralaterally. VT, end-tidal CO2 concentration (ETCO2), and peak inspiratory pressure (Ppi) were measured. Unilateral LC reduced VT and elevated ETCO2 on the affected side. Under HR, VT and ETCO2 were re-equilibrated. In conclusion, capnography serves as simple, bedside method for controlling the adequacy of split ventilation in each patient. No collateral gas flow was observed between the two lungs with different time constants. Ventilator sharing may play a role in emergency situations.

Diabetes mellitus increases smooth muscle tone and causes tissue remodeling, affecting elastin and collagen. Although the lung is dominated by these elements, diabetes is expected to modify the airway function and respiratory tissue mechanics. Therefore, we characterized the respiratory function in patients with diabetes with and without associated obesity. Mechanically ventilated patients with normal body shapes were divided into the control nondiabetic ( n = 73) and diabetic ( n = 31) groups. The other two groups included obese patients without diabetes ( n = 43) or with diabetes ( n = 30). The mechanical properties of the respiratory system were determined by forced oscillation technique. Airway resistance (Raw), tissue damping (G), and tissue elastance (H) were assessed by forced oscillation. Capnography was applied to determine phase 3 slopes and dead space indices. The intrapulmonary shunt fraction (Qs/Qt) and the lung oxygenation index (PaO2/FIO2) were estimated from arterial and central venous blood samples. Compared with the corresponding control groups, diabetes alone increased the Raw (7.6 ± 6 cmH2O.s/l vs. 3.1 ± 1.9 cmH2O.s/l), G (11.7 ± 5.5 cmH2O/l vs. 6.5 ± 2.8 cmH2O/l), and H (31.5 ± 11.8 cmH2O/l vs. 24.2 ± 7.2 cmH2O/l ( P < 0.001 for all). Diabetes increased the capnographic phase 3 slope, whereas PaO2/FIO2 or Qs/Qt was not affected. Obesity alone caused similar detrimental changes in respiratory mechanics and alveolar heterogeneity, but these alterations also compromised gas exchange. We conclude that diabetes-induced intrinsic mechanical abnormalities are counterbalanced by hypoxic pulmonary vasoconstriction, which maintained intrapulmonary shunt fraction and oxygenation ability of the lungs.

Byssinosis is a nonspecific, chronic occupational respiratory disorder of textile workers. Long-term exposure to cotton and organic dust induces a chronic inflammation of the lower airways with predominantly obstructive pathological characteristics and symptoms. While declines in spirometric outcomes have been demonstrated in earlier studies, the effects of byssinosis on the airway and tissue mechanics have not been investigated. Thus, we aimed at characterizing the respiratory mechanical impairment of textile workers undergoing cardiac surgery. Data were collected after anesthesia induction in cardiac surgery patients with positive occupational anamnesis of long-term textile particle exposure (n=9), and were compared with a matched control group (n=18). Airway resistance (Raw) and respiratory tissue elastance (H) were obtained from impedance spectra measured by forced oscillations. Systemic oxygenation (PaO2/FiO2) was determined from arterial blood gas samples. Compared to control, the exposed group had an increased Raw (13.9±4.3[SE] vs. 5.3±1.1 cmH2O∙s/l, p The impaired airway mechanics of textile workers reflects the dominance of the obstructive trait of byssinosis. However, the tendency for a deteriorated respiratory tissue mechanics and the compromised gas exchange indicate small airway closures. These characteristics highlight the imperative need for improvements in personal protection and environmental hygiene as prevention of this occupational respiratory disorder. Supported by OTKA 115253, UNKP-19-3

Background: Monitoring of intrapulmonary shunt is essential in mechanically ventilated patients to detect gas exchange abnormalities. The standard calculation utilizes arterial and central venous blood gas assessments, however, blood samples cannot be easily taken repeatedly. While volumetric capnography can serve as a surrogate measure of intrapulmonary shunt, an arterial blood sample is still required for the assessment of perfused but not ventilated alveolar compartments. The value of transcutaneous measurement of CO2 has been proved in newborns to replace the arterial sample. Our aim is to assess the validity of the transcutaneous method for bedside assessment of intrapulmonary shunting in adults. Methods: We have compared transcutaneous CO2 (TcCO2) with simultaneously taken arterial (PaCO2) and central venous (PvCO2) samples in adults undergoing elective cardiac surgeries (n=22). Correlation and Bland-Altman analyses were performed on data obtained after anaesthesia induction and instrumentation. Results: Significant linear relationship was found between TcCO2 and PaCO2 (r=0.63, p Conclusion: Transcutaneous CO2 measurements have the potential to surrogate arterial blood gas parameters. Further comparative studies are required to confirm that TcCO2 combined with volumetric capnography is suitable to calculate intrapulmonary shunting, thereby providing a valuable tool for online monitoring. Supported by OTKA 115253

BACKGROUND Capnoperitoneum provides a ventilatory challenge due to reduction in end-expiratory lung volume and peritoneal carbon dioxide absorption in both children and adults. The primary aim of this controlled interventional trial was to determine the positive end-expiratory pressure (PEEP) level needed to ensure for adequate carbon dioxide clearance and preservation of carbon dioxide homeostasis in an experimental model of infant laparoscopy. The secondary aim was to evaluate potential effects on cardiac output of PEEP and abdominal pressure level variations in the same setting. METHODS Eight chinchilla bastard rabbits were anesthetized and mechanically ventilated. Intra-abdominal pressures were randomly set to 0, 6, and 12 mm Hg by carbon dioxide insufflation. Carbon dioxide clearance using volumetric capnography, arterial blood gas data, and cardiac output was recorded, while PEEP 3, 6, and 9 cmH2 O were applied in a random order. RESULTS A PEEP of 9 cmH2 O showed restoration of carbon dioxide clearance without causing changes in arterial partial pressure of carbon dioxide and bicarbonate and with no associated deterioration in cardiac output. CONCLUSION The results promote a PEEP level of 9 cmH2 O in this model of infant capnoperitoneum to allow for adequate carbon dioxide removal with subsequent preservation of carbon dioxide homeostasis. The use of high PEEP was not associated with any decrease in cardiac output.

Background Benefits of variable mechanical ventilation based on the physiological breathing pattern have been observed both in healthy and injured lungs. These benefits have not been characterized in pediatric models and the effect of this ventilation mode on regional distribution of lung inflammation also remains controversial. Here, we compare structural, molecular and functional outcomes reflecting regional inflammation between PVV and conventional pressure-controlled ventilation (PCV) in a pediatric model of healthy lungs and acute respiratory distress syndrome (ARDS). Methods New-Zealand White rabbit pups (n = 36, 670 ± 20 g [half-width 95% confidence interval]), with healthy lungs or after induction of ARDS, were randomized to five hours of mechanical ventilation with PCV or PVV. Regional lung aeration, inflammation and perfusion were assessed using x-ray computed tomography, positron-emission tomography and single-photon emission computed tomography, respectively. Ventilation parameters, blood gases and respiratory tissue elastance were recorded hourly. Results Mechanical ventilation worsened respiratory elastance in healthy and ARDS animals ventilated with PCV (11 ± 8%, 6 ± 3%, p 18F]fluorodeoxyglucose uptake in healthy (1.49 ± 0.62 standardized uptake value, SUV) and ARDS animals (1.86 ± 0.47 SUV) compared to PCV (2.33 ± 0.775 and 2.28 ± 0.3 SUV, respectively, p Conclusions Variable ventilation based on a physiological respiratory pattern, compared to conventional pressure-controlled ventilation, reduced global and regional inflammation in both healthy and injured lungs of juvenile rabbits.

Background Diabetes mellitus causes the deterioration of smooth muscle cells and interstitial matrix proteins, including collagen. Collagen and smooth muscle cells are abundant in the lungs, but the effect of diabetes on airway function and viscoelastic respiratory tissue mechanics has not been characterized. This study investigated the impact of diabetes on respiratory function, bronchial responsiveness, and gas exchange parameters. Methods Rats were allocated randomly to three groups: a model of type 1 diabetes that received a high dose of streptozotocin (DM1, n = 13); a model of type 2 diabetes that received a low dose of streptozotocin with a high-fat diet (DM2, n = 14); and a control group with no treatment (C, n = 14). Forced oscillations were applied to assess airway resistance (Raw), respiratory tissue damping (G), and elastance (H). The arterial partial pressure of oxygen to the inspired oxygen fraction (PaO2/FiO2) and intrapulmonary shunt fraction (Qs/Qt) were determined from blood gas samples at positive end-expiratory pressures (PEEPs) of 0, 3, and 6 cmH2O. Lung responsiveness to methacholine was also assessed. Collagen fibers in lung tissue were quantified by histology. Results The rats in groups DM1 and DM2 exhibited elevated Raw, G, H, and Qs/Qt, compromised PaO2/FiO2, and diminished airway responsiveness. The severity of adverse tissue mechanical change correlated with excessive lung collagen expression. Increased PEEP normalized the respiratory mechanics, but the gas exchange abnormalities remained. Conclusions These findings indicate that diabetes reduces airway and lung tissue viscoelasticity, resulting in alveolar collapsibility that can be compensated by increasing PEEP. Diabetes also induces persistent alveolo-capillary dysfunction and abnormal adaptation ability of the airways to exogenous constrictor stimuli.

Levosimendan has a calcium-sensitizing effect in the myocardium and opens ATP-sensitive potassium channels (KATP) in vascular smooth muscle. Because airway smooth muscle also expresses KATP, we characterized the protective potential of levosimendan against increased airway and respiratory tissue resistances. Animals were administered levosimendan alone ( group L), levosimendan after pretreatment with a KATPchannel blocker (glibenclamide, group LG), glibenclamide only ( group G), or solvent alone (dextrose, group C). Airway resistance (Raw), tissue damping, and elastance were determined by forced oscillations under baseline conditions and following provocation tests with intravenous methacholine (MCh). Cardiac output (CO) was assessed by transpulmonary thermodilution. The same sequence of measurements was then repeated during intravenous infusion of levosimendan in groups L and LG or glucose in groups G and C. Sham treatments in groups C and G had no effect on lung responsiveness. However, levosimendan treatment in group L elevated CO and inhibited the MCh-induced airway responses [Rawchanges of 87.8 ± 83% (SD) vs. 24.4 ± 16% at 4 μg·kg−1·min−1MCh, P < 0.001], and in G (35.2 ± 12.7 vs. 25.2 ± 12.9%, P < 0.05). The preventive affect of levosimendan against lung constriction vanished in the LG group. Levosimendan exerts a KATP-mediated potential to prevent bronchoconstriction and may prohibit adverse lung peripheral changes both in the small bronchi and the pulmonary parenchyma. The identification of a further pleiotropic property of levosimendan that is related to the pulmonary system is of particular importance for patients with decreased cardiorespiratory reserves for which simultaneous circulatory support is complemented with prevention of adverse respiratory events.

Mechanical ventilation (MV) can worsen lung injury, particularly in ARDS, both through atelectrauma and volutrauma. It is not clear how these mechanisms contribute to lung inflammation and worsening injury with prolonged MV. ARDS was induced in juvenile rabbits (4-5 weeks, n=9), by combining iv endotoxin (20µg/kg) and injurious MV, followed by 5 hours of protective MV (pressure-control, PEEP 6 cmH2O; Pplateau 20-22 cmH2O). CT and PET imaging were performed thereafter. Lung regions (ROI) were segmented and partitioned based on normalized CT density into Aerated, Poorly-aerated and Collapsed regions. Standardised uptake values (SUV) were calculated. Moderate ARDS was triggered (PaO2/FiO2 = 226 ± 91 [SD]). Representative images are shown in Figure 1. ROI volumes were 16.6±3.4; 6.8±1.7; 5.4±1.2 mL in Aerated, Poorly-aerated and Collapsed lung regions, respectively. SUV was significantly higher within collapsed (0.84±0.29, p Significantly higher SUV in Poorly-aerated and Collapsed lung regions suggest that atelectrauma may contribute to lung inflammation, despite a protective ventilation strategy. Further study is underway to compare this outcome with normal lung and alternative ventilation strategies in ARDS. Grant: FNRS32003B_169334

Background Introducing mathematically derived variability (MVV) into the otherwise monotonous conventional mechanical ventilation has been suggested to improve lung recruitment and gas exchange. Although the application of a ventilation pattern based on variations in physiological breathing (PVV) is beneficial for healthy lungs, its value in the presence of acute respiratory distress syndrome (ARDS) has not been characterized. We therefore aimed at comparing conventional pressure-controlled ventilation with (PCS) or without regular sighs (PCV) to MVV and PVV at two levels of positive end-expiratory pressure (PEEP) in a model of severe ARDS. Methods Anesthetised rabbits (n = 54) were mechanically ventilated and severe ARDS (PaO2/FiO2 ≤ 150 mmHg) was induced by combining whole lung lavage, i.v. endotoxin and injurious ventilation. Rabbits were then randomly assigned to be ventilated with PVV, MVV, PCV, or PCS for 5 h while maintaining either 6 or 9 cmH2O PEEP. Ventilation parameters, blood gas indices and respiratory mechanics (tissue damping, G, and elastance, H) were recorded hourly. Serum cytokine levels were assessed with ELISA and lung histology was analyzed. Results Although no progression of lung injury was observed after 5 h of ventilation at PEEP 6 cmH2O with PVV and PCV, values for G (58.8 ± 71.1[half-width of 95% CI]% and 40.8 ± 39.0%, respectively), H (54.5 ± 57.2%, 50.7 ± 28.3%), partial pressure of carbon-dioxide (PaCO2, 43.9 ± 23.8%, 46.2 ± 35.4%) and pH (-4.6 ± 3.3%, -4.6 ± 2.2%) worsened with PCS and MVV. Regardless of ventilation pattern, application of a higher PEEP improved lung function and precluded progression of lung injury and inflammation. Histology lung injury scores were elevated in all groups with no difference between groups at either PEEP level. Conclusion At moderate PEEP, variable ventilation based on a pre-recorded physiological breathing pattern protected against progression of lung injury equally to the conventional pressure-controlled mode, whereas mathematical variability or application of regular sighs caused worsening in lung mechanics. This outcome may be related to the excessive increases in peak inspiratory pressure with the latter ventilation modes. However, a greater benefit on respiratory mechanics and gas exchange could be obtained by elevating PEEP, compared to the ventilation mode in severe ARDS.

OBJECTIVES The forced oscillation technique (FOT) is the method of choice for assessment of respiratory tissue mechanics. A laryngeal mask airway (LMA) is increasingly used to secure the airways in subjects under sedation or general anesthesia. While FOT is routinely performed using an endotracheal tube (ETT), the accuracy of information about airway and tissue mechanics obtained with FOT using a LMA has not been characterized. Therefore, we compared the mechanical parameters obtained with FOT using LMA and ETT in rabbits. APPROACH FOT was performed through a LMA at normal and reduced oscillatory amplitudes in anesthetized and mechanically ventilated rabbits (n = 9) at positive end-expiratory pressures (PEEP) of 3 and 6 cmH2O. These measurements were repeated at normal amplitude for the same animal using an ETT. Airway resistance, inertance, respiratory tissue damping (G) and elastance (H) were measured under each condition by FOT. The potential bias of the distensible upper airways when FOT was applied using LMA was assessed with a simulation study. MAIN RESULTS Values of parameters reflecting airway mechanics were significantly higher when measured using LMA at both PEEPs and oscillatory amplitudes than with ETT. Conversely, regardless of the condition, there was a correlation (r = 0.89 both at normal and reduced amplitudes; p

Background Although PEEP and inversed I:E ratio have been shown to improve gas exchange in ARDS, both can adversely affect systemic hemodynamics and cerebral perfusion. The goal of this study was to assess how changes in PEEP and I:E ratio affect systemic and cerebral oxygenation and perfusion in normal and injured lung. Methods Eight anesthetized Chinchilla-Bastard rabbits were ventilated at baseline with pressure-regulated volume control mode, VT = 6 ml/kg, PEEP = 6 cmH2O, FIO2 = 0.4; respiratory rate set for ETCO2 = 5.5%, and I:E = 1:2, 1:1 or 2:1 in random order. Ultrasonic carotid artery flow (CF), arterial (PaO2), jugular venous blood gases and near infrared spectroscopic cerebral oxygenation (∆HBO2) were recorded for each experimental condition. After induced lung injury, the animals were ventilated with PEEP = 9 followed by 6 cmH2O. Results At baseline, inverse-ratio ventilation (IRV) significantly reduced cerebral oxygenation (∆O2HB; − 27 at 1:2; − 15 at 1:1 vs. 0.27 μmol/L at 2:1; p

The contribution of the hematocrit (Hct) of the blood in the pulmonary vasculature to the overall lung mechanics has not been characterized. We therefore set out to establish how changes of the Hct level in the pulmonary circulation affect the airway and lung tissue viscoelastic properties. The Hct level of the blood in an isolated perfused rat lung model was randomly altered. Intermediate (26.5%), followed by low (6.6%) or normal (43.7%), Hct was set in two consecutive sequences. The pulmonary capillary pressure was maintained constant throughout the experiment, and the pulmonary hemodynamic parameters were monitored continuously. The airway resistance (Raw), the viscous (G) and elastic (H) parameters, and the hysteresivity (η = G/H) of the lung tissues were obtained from measurements of forced oscillatory input impedance data. Raw was not affected by the alterations of the Hct levels. As concerns the lung tissues, the decrease of Hct to intermediate or low levels resulted in close to proportional decreases in the viscoelastic parameters G [16.5 ± 7.7% (SD), 12.1 ± 9.5%, P < 0.005] and H (13.2 ± 8.6%, 10.8 ± 4.7%, P < 0.001). No significant changes in η were detected in a wide range of Hct, which indicates that coupled processes cause alterations in the resistive and elastic properties of the lungs following Hct changes in the pulmonary circulation. The diminishment of the viscous and elastic parameters of the pulmonary parenchyma following a reduction of blood Hct demonstrates the significant contribution of the red blood cells to the overall lung viscoelasticity.

BACKGROUNDFluid replacement with blood products, colloids and crystalloids is associated with morbidity and mortality. Despite this, the consequences of fluid administration on airway and respiratory tissue properties are not fully understood.OBJECTIVEComparison of respiratory effects of fluid repla

Changes in lung mechanics are in the centre of interest in rat models of respiratory diseases; however, they are frequently inferred from total respiratory system indices that are biased by chest wall properties. Thus, we assessed the separate contribution of the lung and chest wall compartments to the total respiratory system mechanics in rats, and we also evaluated the influence of altered lung volume on these estimates. The forced oscillation technique was applied in anesthetized, mechanically ventilated rats (n=14) to obtain mechanical impedance of the total respiratory system (Zrs) at 0, 3 and 6 cmH2O positive end-expiratory pressure (PEEP) levels. Oesophageal pressure was measured by a self-made balloon to separate Zrs into pulmonary (ZL) and chest wall (Zw) components. A model containing a frequency-independent Newtonian resistance (R), inertance (I) and a constant-phase tissue damping (G) and elastance (H), was fitted to Zrs, ZL, and Zw spectra. The contribution of Zw to the total respiratory R and I was negligible (3.8±5.6[SD]% and 5.5±23%) at all PEEP levels. However, the participation of Zw in G and H was significant at PEEP0 (17±10% and 12±6%, p These findings demonstrate that airway parameters can be accurately assessed from respiratory system mechanical assessments. However, the contribution of the chest wall to the viscoelastic parameters of the total respiratory tissues should be taken into account when these indices are used to estimate lung parenchymal mechanics, particularly at high PEEP levels. Grant support: NKFIH K115253 and GINOP-2.3.2-15-2016-00006

Whereas time capnography (Tcap) is routinely displayed during mechanical ventilation, the volumetric representation (Vcap) is seldom used. We compared the diagnostic value of indices derived from Tcap and Vcap following ventilation to perfusion ratio () mismatch subsequent to experimentally induced acute respiratory distress syndrome (ARDS), and alveolar recruitment by elevating the positive end-expiratory pressure (PEEP). Lung injury was induced by iv lipopolysaccharide, whole lung lavage and injurious ventilation in anesthetized, mechanically ventilated rabbits (n = 26). Mainstream Tcap and Vcap were performed to assess normalized phase 2 (Sn2T, Sn2V) and phase 3 slopes (Sn3T, Sn3V) in the time and volumetric domains. Vcap was also used to estimate Enghoff’s physiological dead space (VDE). Lung oxygenation index (PaO2/FiO2) and intrapulmonary shunt (Qs/Qt) were derived from arterial and central venous blood gas samples. All measurements were made under baseline conditions, and, following lung injury, under moderate (6 cmH2O) and high PEEP levels (9 cmH2O). Lung injury deteriorated the PaO2/FiO2 (baseline vs. injured 466 ± 10.2 [95% confidence interval] vs. 77.3 ± 17.1 mmHg, p < 0.05) and compromised all mechanical parameters significantly, whereas Tcap parameters exhibited contradictory or inconsistent changes. Conversely, Vcap indices exhibited consistent changes and provided excellent diagnostic value in detecting lung-function deterioration subsequent to lung injury [area under the receiver operating characteristic (ROC) curve of 1.0 ± 0.0, 0.87 ± 0.22 and 0.86 ± 0.22 for VDE, Sn3V and Sn3V/Sn2V, respectively]. Elevated PEEP increased PaO2/FiO2 and decreased Qs/Qt, which was reflected only in the Vcap slope ratio (Sn3V/Sn2V, p < 0.05). Our findings demonstrate the limited value of Tcap to detect ventilation to perfusion ratio () mismatch, following severe lung injury. Conversely, indices derived from Vcap proved to be sensitive for detecting lung volume loss and alveolar recruitment. Therefore, promotion of Vcap is of paramount importance as a real-time, non-invasive, bedside monitoring modality to detect the development of and to follow-up the progression of lung injury in a model of ARDS.

To understand the determinants of inhaled aerosol particle distribution and targeting in the lung, knowledge of regional deposition, lung morphology and regional ventilation, is crucial. No single imaging modality allows the acquisition of all such data together. Here we assessed the feasibility of dual-energy synchrotron radiation imaging to this end in anesthetized rabbits; both in normal lung (n = 6) and following methacholine (MCH)-induced bronchoconstriction (n = 6), a model of asthma. We used K-edge subtraction CT (KES) imaging to quantitatively map the regional deposition of iodine-containing aerosol particles. Morphological and regional ventilation images were obtained, followed by quantitative regional iodine deposition maps, after 5 and 10 minutes of aerosol administration. Iodine deposition was markedly inhomogeneous both in normal lung and after induced bronchoconstrition. Deposition was significantly reduced in the MCH group at both time points, with a strong dependency on inspiratory flow in both conditions (R2 = 0.71; p

Positive inotropic drugs are routinely used to elevate cardiac output; however, their potential to diminish an elevated airway tone have not been fully characterized. Therefore, we aimed at comparing the bronchodilator properties of inotropes commonly used in clinical practice. To exclude confounding systemic and neurological bias due to cardiopulmonary interactions, experiments were performed on isolated perfused rat lungs. Airway resistance (Raw) was measured by forced oscillations under the baseline conditions, during steady-state bronchoconstriction induced by acetylcholine (ACh) alone, and following saline vehicle (n=8) or increasing doses of adrenaline (n=8), dopamine (n=7), dobutamine (n=7), milrinone (n=8) and levosimendan (n=6) added to the whole blood perfusate. No changes in Raw were evidenced after administering the saline vehicle (1.1±4.5[SE]%), and at any doses of milrinone (change at the highest dose of ‑0.2±12% relative to the ACh level) and dobutamine (-4.0±6.3%). Conversely, Raw decreased significantly following the highest two doses of dopamine (-23±4%, p These findings demonstrate the lack of effect of dobutamine and milrinone on an elevated bronchial smooth muscle tone. While different pathways are involved in the bronchodilation affinities of adrenaline, dopamine and levosimendan, this potential is of particular importance in patients with increased bronchial smooth muscle tone, where the choice of the circulatory support may be considered in view of the respiratory condition. Supported by OTKA-NKFI grant K115253

Capnogram phase II slope (S II ) is related to lung elastic recoil and phase III slope (S III ) reflects ventilation heterogeneities and ventilation/perfusion mismatch. Since increased lung stiffness and inhomogeneous ventilation/perfusion is one of the main characteristics of acute lung injury (ALI), we aimed at characterizing the ability of S II and S III to detect ALI. Adult NZW rabbits (n=8) were anaesthetised and mechanically ventilated. ALI (PaO 2 /FiO 2 ≤200 mmHg) was induced by applying iv lipopolysaccharide (300 µg/kg), whole lung lavage (100 ml/kg) and 30-min injurious ventilation (PEEP=0, VT=10 ml/kg). Arterial oxygen tension (PaO 2 ) was recorded, while mechanical changes were assessed by measuring forced oscillatory airway resistance (Raw), tissue damping (G) and elastance (H). Mainstream time capnography was performed to assess S II and S III normalized to the ETCO 2 (Sn IIT , Sn IIIT ). The PaO 2 /FiO 2 (ALI vs baseline 74.3±9.3[SEM] vs 451.3±11.5, P 2 O.s/l, 182.4±11.9 vs 86.3±4 cmH 2 O/l and 713.9±60.3 vs 248±15.3 cmH 2 O/l for Raw, G and H, respectively, P IIT increased (13±0.82 vs 10.6±0.21 1/s, P IIIT (0.07±0.024 vs 0.04±0.01 1/s, P=0.29). These findings indicate that the capnograph may only reflect the lung areas participating in the gas exchange. The elevated S II may be related to the increased respiratory elastance of the ventilated lung units associated with ALI. The invariable S III in the presence of ALI demonstrates the fairly homogeneous emptying of the communicating alveoli. Grant: TAMOP 4.2.4.A/2-11-1-2012-0001, OTKA K115253, FNRS 32003B_169334

Objective To investigate sevoflurane’s potential to alleviate the detrimental pulmonary changes after cardiopulmonary bypass (CPB). Design Prospective, randomized clinical investigation. Setting University hospital. Participants One hundred ninety patients undergoing elective cardiac surgery. Interventions Ninety-nine patients under intravenous anesthesia were administered 1 minimal alveolar concentration of sevoflurane for 5 minutes after being weaned from CPB (group SEV); intravenous anesthesia was maintained in the other 91 patients (group CTRL). Measurements and Main Results Measurements were performed with open chest: before CPB, after CPB, and after intervention. The lungs’ mechanical impedance and capnogram traces were recorded, arterial and central venous blood samples were analyzed, and lung compliance was documented. Airway resistance, tissue damping, and elastance were obtained from the impedance spectra. The capnogram phase III slope was determined using linear regression. The partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and shunt fraction were calculated from blood gas parameters. After CPB, sevoflurane induced bronchodilation, reflected in marked drops in airway resistance and smaller improvements in lung tissue viscoelasticity indicated by decreases in tissue damping and elastance. These changes were reflected in a decreased capnogram phase III slope and shunt fraction and increased partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and lung compliance. The more severe deteriorations that occurred after CPB, the greater improvements by sevoflurane were observed. Conclusions Sevoflurane can alleviate CPB-induced bronchoconstriction, compromised lung tissue mechanics, and enhanced intrapulmonary shunt. This benefit has particular importance in patients with severe CPB-induced lung function deterioration.

Capnography, the non-invasive monitoring of the CO2 partial pressure in the exhaled gas provides information on lung ventilation and perfusion. The reference mainstream (MS) method measures CO2 directly at the airway opening. Sidestream (SS) devices analyse a gas sample aspirated through a tube, distorting the capnogram in an unclarified manner and degree. We investigated the influence of sampling rate on the shape factors of the SS capnogram. Measurements were made simultaneously with MS and SS capnographs, the latter being equipped with adjustable sampling flow in 6 anaesthetised, ventilated patients. Phase 2 and 3 slopes (S2 and S3) were derived from time capnograms. S2 describes the transition between the emptying of bronchial and alveolar gas, S3 reflects the heterogeneity of alveolar ventilation. To assess the effects of sampling flow on capnogram shape, we analysed correlations between the sampling flow and the difference of SS and MS parameters (S2diff, S3diff). By increasing sampling flow from 100 to 400 ml/min in 3 steps, S2diff exhibited monotonous, linear decrease (R2=0.47, p Our results highlight that changes in sampling flow rate bias the shape factors derived from SS capnogram. Increasing the sampling flow from 200 to 400-500 ml/min improves the accuracy of SS capnographic parameter estimations, approaching those obtained by the MS method. In clinical practice, however, the feasibility of increasing the sampling flow is limited by the loss of tidal volume, which is of great importance in paediatric patients. Supported by OTKA grant K115253.

Dopamine (DA) has been shown to exert a dopaminergic-receptor mediated bronchodilating potential in pre-constricted airways. However, its characteristic circulatory dose-dependent effects have not yet been evaluated on the airways. Further, bronchial effects of dobutamine (DX) as an alternative positive inotropic drug is unknown. Baseline respiratory mechanics were measured in 15 anaesthetized, ventilated rats by means of forced oscillations. The airway resistance (Raw) was approximately doubled with increasing doses of iv methacholine (MCh). In the presence of this elevated bronchial tone, iv infusion of DA or DX was started with a 10 and 5 µg/kg/min initial dose, respectively, followed by doubling the doses 3 times in every 10 min. Raw was also measured after stopping DA or DX while MCh was still administered. A 30-min MCh-free recovery period was then installed, and the protocol was repeated with the other inotropic drug in random sequence. Only the highest doses of DX and DA decreased Raw significantly (-23±7% and -21±6%, respectively, p Supported by OTKA grant K115253.

Although capnography is standard part of respiratory monitoring in mechanically ventilated patients, its diagnostic value has not been established. We aimed to reveal how changes in lung mechanics are reflected in the alterations in the capnogram curves after lung function deteriorations to cardiopulmonary bypass (CPB). Anaesthetized, mechanically ventilated patients (n=101) were studied under open-chest condition before and 5 min after CPB. Changes in airway resistance (dRaw), tissue damping (dG) and elastance (dH) were measured by forced oscillations. Time and volumetric capnography were performed to assess changes in the parameters reflecting the normalized phase II (dS nIIT , dS nIIV ) and III slopes (dS nIIIT , dS nIIIV ), and the dead-space indices according to Fowler (dVD F ), Bohr (dVD B ) and Enghoff (dVD E ). dRaw correlated best with dS nIIT , whereas dG displayed similar relationships with the alterations in the various capnographic indices after CPB. The changes in CPB-induced lung tissue stiffness revealed statistically significant correlations with phase-III slope parameters (dS nIIIT , dS nIIIV ). Complex adverse changes in the airway and lung tissue mechanical properties appear in different capnogram indices: (i) the bronchoconstriction is reflected the best in S nII and VD F (ii) the S nIII is affected by changes in both airway and tissue mechanics. Grant: TAMOP 4.2.4.A/2-11-1-2012-0001, OTKA K115253.

The lung function deterioration to cardiopulmonary bypass (CPB) can be alleviated by recruitment manoeuvres (RM), elevating the positive end-expiratory pressure (PEEP), and/or bronchodilator therapies. We aimed at comparing the efficiency of these treatment strategies. Airway resistance (Raw), respiratory compliance (C), capnogram phase III slope (S III ), and Horowitz coefficient (HQ) were measured in anaesthetized, mechanically ventilated patients undergoing cardiac surgeries. Five different therapeutic interventions were compared to the standard post-CPB lung management with 4 cmH 2 O PEEP: i) application of elevated PEEP (8 cmH 2 O), ii) administration of 1 MAC sevoflurane (SEV) during either PEEP4 or iii) PEEP8, iv) a RM followed by PEEP8, and v) concomitant use of a RM, PEEP8, and SEV. The Raw decreased significantly in all groups, with the greatest drop after the combined application of RM, PEEP and SEV (-60±21[SD]%, p III decreased in all patients; elevated PEEP and SEV induced the greatest changes (-32±16%, p Supported by OTKA grant K115253.