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The Effects of Anesthesia, Muscle Paralysis, and Ventilation on the Lung Evaluated by Lung Diffusion for Carbon Monoxide and Pulmonary Surfactant Protein B

Di Marco, Fabiano MD, PhD*; Bonacina, Daniele MD; Vassena, Emanuele MD; Arisi, Erik MD; Apostolo, Anna MD; Banfi, Cristina PhD; Centanni, Stefano MD, PhD*; Agostoni, Piergiuseppe MD, PhD§∥; Fumagalli, Roberto MD, PhD†¶

doi: 10.1213/ANE.0000000000000496
Critical Care, Trauma, and Resuscitation: Research Report

BACKGROUND: An increased alveolar-arterial oxygen tension difference is frequent in anesthetized patients. In this study, we evaluated the effect on the lung of anesthesia, muscle paralysis, and a brief course of mechanical ventilation.

METHODS: Lung diffusion for carbon monoxide (DLCO), including pulmonary capillary blood volume (Vc) and conductance of the alveolar-capillary membrane (DM), and pulmonary surfactant protein type B (a marker of alveolar damage) were measured in 45 patients without pulmonary disease undergoing extrathoracic surgery.

RESULTS: Anesthesia, muscle paralysis, and mechanical ventilation led to impairment of gas exchange, with a reduction of DLCO values immediately after anesthetic induction due to a concomitant reduction of both DM and Vc. While changes in DM were due to the reduction of lung volume, changes in Vc were not limited to volume loss, since the Vc/alveolar volume ratio decreased significantly. Although DLCO and its components decreased immediately after induction, none of the values decreased further at 1 and 3 hours. Surfactant protein type B, however, was unchanged immediately after anesthesia but increased at 1 hour after induction and further increased after 3 hours of anesthesia. The level of alveolar damage correlated with the reduction of lung perfusion and lung dynamic strain (i.e., ratio between tidal volume and end-expiratory lung volume).

CONCLUSIONS: A brief course of anesthesia and controlled ventilation leads to: (1) alveolar damage, which is correlated with lung strain and perfusion, and (2) impaired gas exchange mainly due to volume loss but also to reduced aerated lung perfusion.

Published ahead of print October 30, 2014.

From the *Pneumologia, Ospedale San Paolo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy; Department of Experimental Medicine, University of Milano-Bicocca, Italy; Centro Cardiologico Monzino IRCCS, Milano, Italy; §Centro Cardiologico Monzino IRCCS, Dipartimento di Scienze Cliniche e di Comunità, Sezione cardiovascolare, Università di Milano, Milan, Italy; Division of Pulmonary and Critical Care and Medicine, Department of Medicine, University of Washington, Seattle, Washington; and Anesthesia and Intensive Care, Ospedale Niguarda Ca’ Granda, Milano, Italy.

Accepted for publication September 1, 2014.

Published ahead of print October 30, 2014.

Funding: None source of support (costs were supported by the University of Milano-Bicocca).

The authors declare no conflicts of interest.

This report was previously presented, in part, at the European Respiratory Society, Italian Congress of Respiratory Disease.

Reprints will not be available from the authors.

Address correspondence to Fabiano Di Marco, MD, PhD, Pneumologia, Ospedale San Paolo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, via A. di Rudinì 8, 20142 Milano, Italy. Address e-mail to fabiano.dimarco@unimi.it.

A frequent finding during anesthesia is impaired oxygenation, with an increased alveolar-arterial oxygen tension difference (PA-aO2) in up to 90% of anesthetized patients. This impairment holds true for both IV and inhaled anesthetic regimes.1,2 Postoperative pulmonary complications occur in 3% and 10% of patients undergoing elective abdominal surgery, with a higher incidence of pulmonary complications in case of emergency surgery. A proposed mechanism for the rapid collapse of alveoli on induction of anesthesia and more widespread closure of airways is loss of respiratory muscle tone and gas reabsorption.1

Measurement of PaO2 or other oxygenation indices may have a low sensitivity for assessing lung gas exchange because factors such as mixed venous oxygen tension may influence arterial oxygenation.3,4 The diffusing capacity of the lung for carbon monoxide (DLCO), a routine test used in clinical practice, reflects total lung conductance for gas exchange.5 Technical difficulties have limited the study of DLCO in patients receiving mechanical ventilation.6,7 DLCO is the product of 2 factors (i.e., lung volume and alveolar uptake of carbon monoxide, KCO) and reflects the conductance of the overall respiratory system. Importantly, DLCO depends on both pulmonary capillary blood volume (Vc) and conductance of the alveolar-capillary membrane (DM), which can both be measured.8 A previous study that evaluated the effect of positive end-expiratory pressure (PEEP) on DLCO in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients demonstrated that after 24 hours of mechanical ventilation, patients with no evident pulmonary disease developed inadequate pulmonary gas exchange as measured by DLCO, with values of KCO similar to those of ALI/ARDS patients.9 A possible reason is impairment of the alveolar-capillary membrane detected by a very sensitive method such as DLCO, when compared with PaO2 or PaO2/FiO2 ratio. This hypothesis is supported by animal studies finding that mechanical ventilation, including low tidal volume (Vt) ventilation, causes lung injury in the absence of preexisting lung disease.10,11

Finally, pulmonary surfactant protein type B (SPB), a membrane-based lipid–protein complex, has been proposed as a biological marker of damage to the alveolar-capillary membrane. SPB is synthesized only by type II pneumocytes and secreted into the alveolar space12 via a gradient across the alveolar-capillary membrane and has been proposed as a biological marker of damage to the alveolar-capillary membrane. A high level of plasma SPB has been reported in acute pulmonary edema,13 ARDS,14,15 and chronic heart failure.16,17

Our hypothesis was that anesthesia and positive-pressure mechanical ventilation, even if administered for a few hours, can damage the alveolar-capillary membrane and contribute to the negative effects of anesthesia on lung function. We thus designed a study to evaluate the effects of anesthesia, muscle paralysis, and a brief course of invasive positive-pressure ventilation on gas exchange, DLCO, and SPB in patients with normal preoperative lung function.

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METHODS

The protocol was approved by the appropriate ethics committee (San Gerardo Hospital, Monza, Italy). Written informed consent was obtained from each patient, and the study was registered at www.ClinicalTrials.gov with the number NCT01503879.

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Population

We enrolled 45 consecutive patients with scheduled extrathoracic surgery, with the exclusion of laparoscopy, needing general anesthesia. All patients without significant pulmonary disease (no history of pulmonary diseases, normal chest examination, normal chest radiograph, and spirometry) were considered. Exclusion criteria were age <18 years, cardiovascular disease conditioning cardiac failure, chronic renal failure, and obesity (body mass index [BMI] ≥30 kg/m2).

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Experimental Protocol

Before the study, patients underwent an exhaustive clinical evaluation, chest radiograph, blood test, and spirometry to assess the presence of a significant pulmonary disease. Eligible patients who were enrolled underwent DLCO and SPB measurement the day before surgery (see below). Then, immediately after general anesthesia and tracheal intubation (all patients), and at 1 and 3 hours after anesthetic induction (subgroup), patients underwent DLCO and SPB measurement and arterial blood gas analysis.

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Anesthetic Plan and Mechanical Ventilation

Anesthesiologists were advised to ventilate patients’ lungs in volume-controlled mode with a Vt = 6 to 8 mL/kg of predicted body weight using a total IV approach to avoid interference between the gas analyzers for methane (CH4) and carbon monoxide (CO) and volatile anesthetics. Patients were premedicated with a benzodiazepine. Anesthesia was induced with IV propofol, and tracheal intubation was facilitated with either cisatracurium or rocuronium. Anesthesia was maintained with propofol. Analgesia was administered either by boluses of fentanyl or by an infusion of remifentanil. This anesthetic strategy is commonly used in current clinical practice at the study site. Anesthesiologists decided whether to use PEEP and to what extent, which however did not change during surgery.

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DLCO, Lung Volume, and Dynamic Strain Measurement

DLCO was measured by 2 expert operators using the previously described rebreathing technique.9,18 All DLCO measurements, including those performed on the day before surgery, were performed with patients in supine position and at functional residual capacity for spontaneously breathing patients and at end-expiratory lung volume (EELV) for ventilated patients. In spontaneously breathing patients, a 3-way valve (patient–bag–air) of the previously described bag-in-box system was used.19 For intubated patients, a flexible tube was inserted between circuit Y and the patient’s endotracheal tube and clamped during an end-expiratory pause. A balloon was filled by means of a 1-L calibrated syringe (Hans Rudolph, Kansas City, KS) with a volume of 6 to 8 mL/kg of the predicted body weight of 1 of 3 mixtures (in random order, with the same volume for each patient for all measurements) containing 0.3% CH4 and CO with either 30%, 50%, or 70% O2 (balanced with N2). Before each measurement, patients breathed the same fractional inspired oxygen concentration (FiO2) of the gas mixture for 2 minutes. CO and CH4 concentrations at the mouth were then measured simultaneously in side-stream mode using a fast infrared gas analyzer (Cosmed Quark PFT, Rome, Italy). The infrared analyzer was part of the closed rebreathing system to allow the analyzed gas to be reinjected into the circuit by the pump used for sampling. DLCO was calculated as the product of alveolar volume (Volalv, the lung volume available for gas exchange during the rebreathing maneuver, i.e., the addition of EELV, measured by the CH4 dilution method,19 and the volume of the balloon used for DLCO measurement) and KCO (computed on the basis of the semilogarithmic disappearance of CO normalized for the corresponding CH4 concentration).20 Adjustments for hemoglobin (Hb), measured at every DLCO evaluation and COHb back pressure, were applied.5,21 DM and Vc were calculated from DLCO measured at 3 alveolar PO2 as described by Roughton and Forster8:

CV

CV

where θCO, the rate of CO uptake by blood, was computed according to the following equation: θCO = 0.73 + 0.0058·[(713·FiO2) − (PaCO2·0.8)]. Moreover, we evaluated the specific values of the conductance of the overall respiratory system (DLCO), DM, and Vc, by the ratio of these values to alveolar volume (i.e., DLCO/Volalv, DM/Volalv, and Vc/Volalv). This shows whether or not changes in DLCO, DM, and Vc are merely due to a variation of lung volume.

Dynamic lung strain was calculated as the ratio of the Vt to the EELV measured by CH4 dilution.22

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SPB Measurement

Fresh blood (5 mL) was drawn into Vacutainer tubes containing citrate 0.129 mol·L−1 as an anticoagulant. Plasma was immediately prepared by means of centrifugation at 1500 g for 10 minutes at 4°C, divided into aliquots and frozen at −80°C until assayed. The analysis of the immature form of SPB (~40 kDa) was performed by Western blotting on plasma samples, as previously described.17 To precisely resolve low-molecular-weight proteins, equal amounts of plasma proteins (50 mg) were separated by 1-dimensional SDS-PAGE on 15% polyacrylamide gels using a Tris-Tricine buffer system in nonreducing conditions.23 The protein concentration was evaluated by the Bradford method.24 Gels were electrophoretically transferred to nitrocellulose at 60 V for 2 hours. Immunoblotting on transferred samples was performed as follows: blocking in 5% (weight/volume) non-fat milk in Tris-buffered saline (100 mmol mol·L−1 Tris-HCl, pH 7.5, 150 mmol mol·L−1 NaCl) containing 0.1% Tween 20 (TBS-T) for 1 hour at room temperature; overnight incubation at 4°C with primary antibody against SPB (rabbit anti-human SPB H300; Santa Cruz Biotechnology, Santa Cruz, CA) diluted at 1:200 in 5% (w/v) non-fat milk in TBS-T; incubation with secondary goat anti-rabbit antibody conjugated to horseradish peroxidase (Bio-Rad, Milan, Italy) at 1:1000 for 1 hour. Bands were visualized by enhanced chemiluminescence using the enhanced chemiluminescence (ECL) kit (GE Healthcare, Milan, Italy) and acquired by a densitometer (GS800; Bio-Rad, Hercules, CA). Bands at 40 kDa detected by ECL were quantified by densitometry of exposed film using image analysis software (QuantityOne version 4.5.2; Bio-Rad). After transfer, membranes were stained with MemCode™ reversible protein stain (Pierce Biotechnology, Cramlington, UK) according to the manufacturer’s instructions to ensure equivalent loading of protein. For each subject, data are reported as the ratio of band volume after anesthesia versus the volume of the sample before surgery after local background subtraction, and they are expressed as arbitrary units.

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Power Analysis

Due to an absence of published data on changes in DLCO during anesthesia, we were not able to directly predict a sample size. Even if the minimum clinically important difference for DLCO has not yet been solidly established for all categories of patients, in chronic obstructive pulmonary disease patients its level has been estimated as 1.1 mL·min−1·mm Hg−1 and 11% of baseline values.25 With our repeated measures study design, and using a power of 80% and an α of 5%, 18 patients were adequate to detect a difference in DLCO of 2.0 mL·mm Hg−1·min−1, expected standard deviation (SD) of 2.8 mL·mm Hg−1·min−1.6 However, we enrolled a sizable group of patients (i.e., 45) to have greater statistical power comparing 2 DLCO components (i.e., DM and Vc) between basal measurements and data collected immediately after anesthesia and paralysis, since their variability is expected to be greater.9,18

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Statistical Analysis

All results are shown as mean ± SD, unless otherwise stated. The data on DLCO and KCO reported in text and tables refer to the measurement at FiO2 = 50%, while data at 30% and 70% of FiO2 were used to calculate DM and Vc. According to the number of enrolled patients, the Lilliefors corrected K-S test was performed before data analysis to examine the distribution of the residuals of the parametric tests. The residuals of the 12 variables each followed a normal distribution (all P > 0.096), therefore permitting the use of parametric tests. Intrapatient comparisons of changes were performed by paired t-test with Bonferroni correction (i.e., all such P values have been multiplied by 6, the number of comparisons). For interpatient comparisons (smokers versus nonsmokers and patients with high versus low lung strain), unpaired Student t test analysis was used (test for equal variances was performed, all P > 0.113). Relationships between variables were evaluated using Pearson product moment correlation coefficients. The Spearman rho and P values were provided. All tests were two-sided, and P values lower than 0.05 were considered statistically significant. Statistical tests were performed using the Statistical Package for Social Sciences (version 21.0; SPSS, Chicago, IL).

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RESULTS

We enrolled 45 patients (71% females, 69% nonsmokers, aged 48 ± 14 years, BMI 24.0 ± 3.0 kg/m2, forced expiratory volume in the first second 94 ± 9% of predicted values), 18 of whom (61% females, 67% non smokers, aged 57 ± 12 years, BMI 24.8 ± 2.0 kg/m2, forced expiratory volume in the first second 95 ± 11% of predicted values) underwent long surgery (evaluation up to 3 hours). The means level of PEEP and Vt/predicted body weight ratio during surgery were 4 ± 1 cm H2O (range 0–6 cm H2O) and 8.3 ± 1.2, respectively. The discrepancy between the ventilation strategy suggested and the real Vt used was mainly due to the use of higher Vt in patient with a significant difference between the actual body weight and the predicted body weight.

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Acute Effect of Anesthesia and Muscle Paralysis

The acute effect of anesthesia and muscle paralysis in 45 patients is depicted in Table 1. General anesthesia and muscle paralysis significantly impaired gas exchange, as demonstrated by a reduction of DLCO (P < 0.001). This impairment was mainly due to a reduction of lung volume (EELV, P < 0.001), but also to a reduction of gas exchange coefficient (KCO, P < 0.001). The reduction of DLCO was due to a concomitant and significant reduction of both DM (P < 0.001) and Vc (P < 0.001). The former, however, was merely due to the reduction of lung volume (DM/alveolar volume, Volalv, did not change significantly, P = 0.237), while the latter was not limited to volume loss, since the Vc/Volalv ratio decreased significantly (P = 0.001). Smoking history did not affect changes in DLCO and lung volumes (Table 2). SPB did not significantly change immediately after anesthesia (P = 0.668).

Table 1

Table 1

Table 2

Table 2

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Changes in Patients After 3 Hours of Anesthesia, Muscle Paralysis, and Ventilation

Mean changes after 3 hours of anesthesia, muscle paralysis, and positive-pressure mechanical ventilation are depicted in Table 3 and Figure 1. Despite the significant reduction of DLCO and its components immediately after induction, none of the values further decreased at 1 and 3 hours. However, SPB, which did not change immediately after induction, increased at 1 hour (P = 0.036) and increased further after 3 hours of anesthesia (P = 0.014, Fig. 1). PaO2/FiO2 ratio did not change significantly during anesthesia (P = 0.518).

Table 3

Table 3

Figure 1

Figure 1

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Correlation Between Changes in Gas Exchange, Lung Volume, and SPB

Mean dynamic lung strain during the protocol was 0.34 ± 0.11 and did not significantly change during the 3 hours of anesthesia (P = 0.616), since Vt was the same throughout the study and EELV did not change significantly at 1 and 3 hours. Changes in gas exchange and lung volume evaluated by DLCO and in SPB according to the level of lung dynamic strain are depicted in Table 4. We did not find any significant difference between the groups. Moreover, we found that changes of SPB were significantly inversely correlated with changes of Vc at 3 hours, and directly correlated with the mean level of lung dynamic strain during the 3 hours of surgery (Figs. 2 and 3, P = 0.023 and 0.031, respectively).

Table 4

Table 4

Figure 2

Figure 2

Figure 3

Figure 3

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DISCUSSION

The main findings of this study were that (1) gas exchange properties of the lung are impaired mainly by a loss of lung volume but also by a reduction of specific lung perfusion (i.e., Vc for unit of aerated volume); (2) this impairment occurs rapidly in smokers and nonsmokers after the induction of anesthesia and intubation, and did not change significantly after 1 and 3 hours; (3) a brief course of anesthesia, muscle paralysis, and positive-pressure ventilation led to alveolar damage, as shown by SPB increase, already present after 1 hour and further increased at 3 hours; and (4) the level of damage is directly correlated with the level of dynamic lung strain and reduced perfusion of aerated lung.

Anesthesia and muscle paralysis are associated with rapid alveolar collapse on anesthetic induction and more widespread closure of airways responsible for shunt and hypoxemia.26–28 Studies in animal models suggest that when normal lungs are mechanically ventilated without PEEP, progressive loss of aeration occurs for several hours and is preferentially localized to dorsal regions.29 In the present study, we used DLCO to measure lung volume and diffusion properties of the lung, including DM and Vc. We found a reduction of the total lung conductance for gas exchange (i.e., DLCO) mainly related to a reduction of lung volume (i.e., EELV). However, at a lower EELV, the coefficient of gas transfer for carbon monoxide (i.e., KCO) was also reduced, suggesting a smaller but also less efficient lung. Our data suggest that the mechanism underlying a low DLCO was a reduction of alveolar perfusion (i.e., Vc/alveolar volume) and not a physical impairment of the alveolar-capillary membrane, as suggested by its specific conductance (DM/EELV). Positive-pressure ventilation is associated with a reduction of lung perfusion, as also evaluated by DLCO in a previous study on healthy and ALI/ARDS patients, with a significant correlation between the level of Vc and that of PEEP.6,9 Moreover, recent studies in animal models contributed to better understanding the effect of positive-pressure ventilation on lung perfusion. Both Carvalho et al.30 and Vimlati et al.31 found that in contrast to positive-pressure mechanical ventilation, spontaneous breathing reduced intrapulmonary shunt and improved oxygenation, and this improvement was not caused by reduction of lung collapse. These studies indirectly confirm the deleterious effect of positive-pressure ventilation on lung perfusion, which may occur via an effect of high alveolar pressure on the resistance of perialveolar vessels, impeding the redistribution of blood flow from collapsed to ventilated lung areas. Although a reduction in cardiac output could also reduce lung perfusion, Vimlati et al.31 found an increase of cardiac output during mechanical ventilation.

Our study adds new interesting insights about the timing of changes in lung function after anesthesia. We found that impaired gas exchange on anesthetic induction was rapid (seen immediately after anesthesia, muscle paralysis, and intubation) and stable during the 3 hours of anesthesia. It is worth noting that our study confirmed the high sensitivity of DLCO in detecting changes in gas exchange, since the magnitude of the deterioration of gas exchange induced by anesthesia, muscle paralysis, and positive-pressure mechanical ventilation is often underestimated or even undetected on the basis of PaO2 or PaO2/FiO2 alone. It is noteworthy that the measurement of DLCO (alveolar volume and KCO) in clinical practice is technically feasible, while the measurement of Vc and DM is time-consuming and complex (a potential different approach would be the contemporary use of CO and nitric oxide, as already proposed in different fields).32 Knowledge of alveolar volume and KCO would be very useful both for understanding the physiological changes induced by anesthesia and invasive mechanical ventilation, and to judge the effect of PEEP increase or recruitment maneuvers, approaches very commonly used in clinical practice to improve oxygenation. An increase of alveolar volume with an increase in airway pressure accompanied by stability and KCO indicates an “effective” volume recruitment (alveolarization), while an increase of alveolar volume with a KCO reduction suggests that, on average, the recruitment has been characterized more by overdistension.9,33 This approach may be useful for selected patients at high risk (e.g., patients with underlying lung disease or obese).

In the present study, we found that anesthesia, muscle paralysis, and a brief course of positive-pressure ventilation are associated with a significant increase of SPB, even if the physical properties of the capillary-alveolar membrane (i.e., DM/Volalv and DM/Vc ratio) are not affected. We did not find an increase of SPB immediately after anesthesia but recorded an increase in SPB in the blood at 1 hour, with a further significant increase at 3 hours. The combination of SPB increase, preserved function of the ventilated and perfused alveolar-capillary unit, and reduction of alveolar volume suggests that the increased SPB we observed is generated from underperfused alveolar cells. The negative effect of sedation and positive-pressure ventilation on lung function due to an impairment of the alveolar-capillary membrane has been confirmed both in animal models10,11 and in vivo.34,35 One of the possible mechanisms for ventilator-induced lung injury is increased pulmonary inflammation in response to repeated mechanical stimuli, which is mediated at least in part by proinflammatory cytokines.36,37 Our results agree with those of Agostoni et al.,38 who studied changes of SPB during cardiopulmonary bypass. However, we found evidence that even greater alveolar damage is expected in this model, observing a 3.8-fold increase of SPB in patients with normal lungs exposed to a brief course of mechanical ventilation using low tidal Vts. The dissociation between the results of SPB and DM/Volalv was surprising, since a correlation was expected between them. One possible explanation is that SPB is more sensitive to a biological membrane dysfunction that does not correspond to a physical impairment.

A number of technical points deserve discussion. First, computed values of Vc and DM depend on the overall specific transfer resistance from the red cell membrane to the Hb molecule for CO (θCO), at a given FiO2, for which 3 equations have been proposed.39 However, this issue does not bias within-patient comparisons, such as those performed in our study. Second, the number of patients with SPB data available was limited due to technical problems in the storage of blood samples. However, the changes we observed appear consistent, and the intrapatient analysis significantly increases the statistical power. Third, a further evaluation of DLCO and SPB on the day after anesthesia would have been useful to further understand the dynamics of functional and biological lung damage. However, these additional data were not obtained for organizational reasons, due to the difficulty of patients in performing adequate pulmonary function tests after surgery.

In conclusion, our study found that a brief course of anesthesia, muscle paralysis, and positive-pressure ventilation can lead to an immediate and prolonged deterioration of the gas exchange properties of the lung, mainly due to volume loss, but also to an impairment of aerated lung perfusion and to delayed alveolar damage. The alveolar damage likely worsened during surgery because of the biological effect of anesthesia and mechanical ventilation, and its extent is associated with lung dynamic strain and with the impairment of aerated lung perfusion.

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DISCLOSURES

Name: Fabiano Di Marco, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Fabiano Di Marco has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Daniele Bonacina, MD.

Contribution: This author helped design the study, conduct the study, and analyze the data.

Attestation: Daniele Bonacina has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Emanuele Vassena, MD.

Contribution: This author helped design the study, conduct the study, and analyze the data.

Attestation: Emanuele Vassena has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Erik Arisi, MD.

Contribution: This author helped design the study and conduct the study.

Attestation: Erik Arisi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Anna Apostolo, MD.

Contribution: This author helped design the study and conduct the study.

Attestation: Anna Apostolo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Cristina Banfi, PhD.

Contribution: This author helped conduct the study.

Attestation: Cristina Banfi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Stefano Centanni, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Stefano Centanni has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Piergiuseppe Agostoni, MD, PhD.

Contribution: This author helped design the study and write the manuscript.

Attestation: Piergiuseppe Agostoni has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Roberto Fumagalli, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Roberto Fumagalli has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Avery Tung, MD.

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ACKNOWLEDGMENTS

The authors are indebted to Dr. Guido Bertolini (GiViTI Coordinating Center IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri” Ranica, Bergamo, Italy) for valuable statistical advice.

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