Inhomogeneity of Lung Parenchyma during the Open Lung Strategy A Computed Tomography Scan Study

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1 Inhomogeneity of Lung Parenchyma during the Open Lung Strategy A Computed Tomography Scan Study Salvatore Grasso 1, Tania Stripoli 1, Marianna Sacchi 1, Paolo Trerotoli 2, Francesco Staffieri 3, Delia Franchini 3, Valentina De Monte 3, Valerio Valentini 3, Paolo Pugliese 4, Antonio Crovace 3, Bernd Driessen 5,6, and Tommaso Fiore 1 1 Dipartimento dell Emergenza e Trapianti d Organo (DETO), Sezione di Anestesiologia e Rianimazione, 2 Dipartimento di Scienze Biomediche ed Oncologia Umana, Cattedra di Statistica Medica, 3 Dipartimento dell Emergenza e Trapianti d Organo (DETO), Sezione di Chirurgia Veterinaria, and 4 Dottorato in Scienze Chirurgiche Sperimentali e Terapie Cellulari, Università degli Studi di Bari, Bari, Italy; 5 Department of Clinical Studies-NBC, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania; and 6 Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California Rationale: The open lung strategy aims at reopening (recruitment) of nonaerated lung areas in patients with acute respiratory distress syndrome, avoiding tidal alveolar hyperinflation in the limited area of normally aerated tissue (baby lung). Objectives: We tested the hypothesis that recruited lung areas do not resume elastic properties of adjacent baby lung. Methods: Twenty-five anesthetized, mechanically ventilated pigs were studied. Four lung-healthy pigs served as controls and the remaining 21 were divided into three groups (n 5 7 each) in which lung injury was produced by surfactant lavage, lipopolysaccharide infusion, or hydrochloride inhalation. Computed tomography scans, respiratory mechanics, and gas exchange parameters were recorded under three conditions: at baseline, during lung recruitment maneuver, and at end-expiration and end-inspiration when ventilating after an open lung protocol. Measurements and Main Results: During recruitment maneuver and open lung protocol, the gas volume entering the insufficiently aerated compartment was 96% (75 117%) and 48% (41 63%) (median [interquartile range]) of the functional residual capacity measured before and at zero end-expiratory pressure, respectively. Nonetheless, the volume of hyperinflated lung increased during both recruitment maneuver (by 1 28% of total lung volume; P, 0.01) and open lung protocol ventilation at end-inspiration (by 1 15% of total lung volume; P, 0.01). Regional elastance of recruited lung tissue was consistently higher than that of the baby lung regardless of the ARDS model (P, 0.01). Conclusions: Alveolar recruitment is not protective against hyperinflation of the baby lung because lung parenchyma is inhomogeneous during ventilation with the open lung strategy. Keywords: acute lung injury; mechanical ventilation; alveolar recruitment; ventilator-induced lung injury In patients with acute respiratory distress syndrome (ARDS), nonaerated, poorly aerated, and normally aerated regions coexist to variable degrees in lung parenchyma (1). Delivering normal VT to the normally aerated regions (the baby lung, following the classical definition by Gattinoni and coworkers) will therefore generate higher than normal transpulmonary pressures (stress), hence leading to abnormal alveolar enlargement (strain) (2, 3). (Received in original form January 30, 2009; accepted in final form June 12, 2009) Correspondence and requests for reprints should be addressed to S. Grasso, M.D., Università degli Studi di Bari Dipartimento dell Emergenza e Trapianti d Organo (DETO), Sezione di Anestesiologia e Rianimazione Ospedale Policlinico Piazza Giulio Cesare 11, Bari, Italy. sgrasso@rianima.uniba.it This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 180. pp , 2009 Originally Published in Press as DOI: /rccm OC on June 19, 2009 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The open lung strategy aims at reopening (recruitment) of nonaerated lung areas in patients with acute respiratory distress syndrome to minimize tidal alveolar hyperinflation in the limited area of normally aerated tissue ( baby lung ). However, this implies that nonaerated areas, once recruited, would resume mechanical properties similar or equal to those of the neighboring baby lung. What This Study Adds to the Field This study shows that alveolar recruitment is not protective against alveolar hyperinflation because recruited lung tissue has mechanical properties that are different from those of the surrounding baby lung. Furthermore, unstable nonaerated areas will undergo collapse at end-expiration and reopening at end-inspiration (atelectrauma) (4). Stress, strain, and atelectrauma are the main determinants of mechanical ventilation-induced lung injury (VILI) (5). Two lung protective ventilatory approaches have been proposed to minimize VILI: (1) maintaining the end-inspiratory plateau pressure below a safe threshold (30 cm H 2 O) by limiting the VT (permissive hypercapnia or low VT strategy) (6), and (2) recruiting (reopening) nonaerated areas via a lung recruitment maneuver (LRM) and subsequently keeping them opened by applying adequate levels of positive end-expiratory pressure (PEEP) ( open lung strategy) (7). Despite 2 decades of research, an optimal protective ventilatory protocol has yet to be defined. Lowering VT significantly reduced mortality in a landmark clinical trial conducted by the ARDS Network (6); however, three subsequent clinical trials failed to unequivocally demonstrate the advantage of combining the open lung and low VT approaches (8 10). The open lung approach is attractive from a physiological standpoint because maximizing alveolar recruitment should minimize both hyperinflation and atelectrauma (7). However, this implies that nonaerated areas, once recruited, would resume mechanical properties similar or equal to those of the neighboring baby lung (i.e., the size of the baby lung should increase after alveolar recruitment and all the opened lung areas should be homogeneous) (11). This assumption is challenged by the fact that poorly aerated and nonaerated areas are sites of hemorrhagic and proteinaceous edema, cellular infiltration, fibrin and hyaline membrane deposition, and surfactant disruption (12). Therefore

2 416 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL it is likely that these areas, once recruited, will have higher elastance than the baby lung (13, 14). Consequently, we hypothesized that nonaerated areas, once recruited, do not resume normal mechanical properties and therefore alveolar recruitment will not protect the baby lung against hyperinflation. To test this hypothesis, we studied the effects of an LRM and mechanical ventilation using the open lung strategy in three porcine ARDS models and obtained spiral thoracic computed tomography (CT) scans at zero endexpiratory pressure (ZEEP), during LRM, and at end-expiration and end-inspiration during open lung strategy ventilation. Data obtained with those models were compared with findings in four control animals free of any lung injury. CT studies provide important physiological information as to the effects of mechanical ventilation on lung parenchyma (1, 15 17). We supposed that, provided the transpulmonary pressure was kept constant during CT imaging, the X-ray attenuation properties of lung tissue would reflect its elastic properties. Briefly, areas characterized by lower elastance (i.e., higher compliance) would be more inflated and showing lower X-ray attenuation, and vice versa. Parts of this study have previously been reported in abstract form (18). METHODS Twenty-five certified healthy mixed breed domestic pigs (weight kg) were studied after approval by the Italian Ministry of Health s Ethical Committee (04/2005 A, Roma, Italy). Animals were anesthetized, muscle paralyzed, and mechanically ventilated. Arterial blood gases, arterial and central venous pressures, and arterial blood oxygen saturation (Sa O2 ) were measured. Flow and airway opening pressure (Pao) were measured proximally to the endotracheal tube; changes in intrathoracic pressure were evaluated by assessment of esophageal pressure (Pes). Transpulmonary pressure (PTP) was measured as Pao minus Pes. Static elastance was measured, partitioned for the respiratory system, chest wall, and lung (Est rs, Est cw, and Est L, respectively) (19). Of the 25 anesthetized and mechanically ventilated pigs, 4 lunghealthy pigs served as controls (control group) while the remaining 21 were divided into three groups (n 5 7 each), in which an ARDS-like lung injury was produced by either surfactant washout or lavage (lavage group) (20), intravenous lipopolysaccharide (LPS) infusion (21) (LPS group), or hydrochloride (HCl) inhalation (22) (HCl group). Frontal tomograms and helical CT scans of the chest were obtained (23). The following lung compartments were identified: hyperinflated (pixels with CT numbers between 21,000 and 2900 Hounsfield units [HU]), normally aerated (between 2900 and 2500 HU), poorly aerated (between 2500 and 2100 HU), nonaerated (between 2100 and 1100 HU) (17, 24 26). The volume of each compartment was measured as: area of the single pixel (0.35 mm 2 ) multiplied by the slice thickness (5 mm) 5 volume of the voxel, multiplied by the number of voxels in each compartment (23). Measurements of alveolar recruitment (27) and regional lung tissue elastance (25) and histograms of volume distributions of CT attenuations (17, 25) were obtained. Protocols Lung-Injured Pigs. After 2 hours of baseline ventilation, an LRM was performed and subsequently an open lung ventilatory protocol (10) was implemented. The LRM was performed by applying continuous positive pressure to the airway opening (Pao) for 40 to 60 seconds (28) starting from ZEEP. The Pao (Pao LRM ) was titrated individually to obtain a transpulmonary pressure (DPTP LRM )of30cmh 2 O. Subsequently, the open lung strategy recently proposed by Mercat and coworkers was applied (10). Thoracic CT scans were obtained at baseline (ZEEP, end-expiration), during the LRM, and after 6 hours of applying the open lung protocol, at end-expiration and at endinspiration. Control (Lung-Healthy) Pigs. Thoracic CT scans were obtained at ZEEP end-expiration and during an LRM with the same DPTP LRM target applied to lung-injured pigs (30 cm H 2 O). Statistical Analysis Continuous data are presented as mean 6 SD if normally distributed or in median (interquartile range) if not normally distributed Comparisons were performed using analysis of variance followed by Tukey procedure for multiple comparisons or nonparametric methods, where appropriate. A linear regression analysis was performed to study the relationship between normally distributed quantitative variables. Differences were considered significant if P was less than 0.05 or if P was less than for nonparametric multiple comparison procedures. Statistical analysis was performed using the software package SAS version 9.1. RESULTS Of the 21 lung-injured pigs (7 per injury model) and 4 lunghealthy (noninjured) animals all animals survived the experimental procedure. Table 1 shows gas exchange and respiratory mechanics data recorded immediately before (baseline) and after 6 hours of ventilation after the open lung strategy protocol. The mean external PEEP applied during the open lung strategy ventilation in lung-injured pigs was 14 (14 16) cm H 2 O without significant differences between groups. Table 2 reports the total volume of hyperinflated, normally aerated, poorly aerated, and nonaerated lung compartments and the percentage of alveolar recruitment under each experimental ventilation condition. Alveolar recruitment was assessed according to Malbouisson and coworkers (27) (i.e., as the gas volume entering the insufficiently aerated compartment, including both poorly aerated and nonaerated compartments, normalized to functional residual capacity at ZEEP [FRC ZEEP ]) (see online supplement for more details). LRM-induced alveolar recruitment was significantly higher in the lavage and LPS group than in the HCl group. During open lung strategy ventilation recruitment decreased significantly in all groups, but remained higher in the lavage and LPS groups than the HCl group. Compared with baseline, the volume of hyperinflated lung tissue significantly increased during the LRM both in lung-healthy (control group) and lung-injured pigs. However, in control group pigs hyperinflated lung tissue represented 35 to 58% of total lung volume (mean %) during the LRM, whereas it accounted for 1 to 28% of total lung volume in pigs with ARDS-type lung injury (mean %). When ventilating the lung-injured pigs with the open lung protocol, hyperinflated lung tissue composed 0.4 to 8.6% of total lung volume at end-expiration (mean 2 6 2%) and 1 to 15% of total lung volume at end inspiration (mean 5 6 4%). The amount of nonaerated lung tissue was not significantly different between end-expiration and end-inspiration during ventilation with the open lung protocol, suggesting the absence of cyclic alveolar collapse. Figure 1 displays representative CT images for all four study groups acquired at a level resulting in the largest transverse lung section between the most cranial point of the diaphragm and the base of the heart under different experimental ventilation conditions. To allow a qualitative estimation of lung tissue attenuation properties, images were read based on the UCLA color coding table (OsiriX image processing software, osirixfoundation.com, Geneva, Switzerland). The LRM induced a rather homogeneous hyperinflation in control group pigs, whereas lung parenchyma was more inhomogeneous in animals with ARDS-type lung injuries. In the latter, the baby lung (color coded in light blue and blue in the CT scan obtained at baseline) became hyperinflated (purple) during the LRM, whereas nonaerated lung tissue (color coded in red at baseline) with recruitment became normally aerated (color coded in light purplish blue and dark blue). During ventilation after the open lung strategy, the baby lung was normally aerated at end-expiration with little degree of hyperinflation, but its hyperinflation in-

3 Grasso, Stripoli, Sacchi, et al.: Elastance of Recruited Lung Tissue 417 TABLE 1. RESPIRATORY MECHANICS AND GAS EXCHANGE DATA RECORDED IN THE DIFFERENT STUDY GROUPS AT BASELINE AND AFTER OPEN LUNG STRATEGY VENTILATION Control Group Lavage Group LPS Group HCl Group Lavage Group LPS Group HCl Group Baseline Baseline Baseline Baseline Open Lung Open Lung Open Lung PEEP ext,cmh 2 O (14 16) 16 (14 17) 14 (12 16) PEEP i,st,cmh 2 O 0.5 (0.2 1) 1.7 ( ) 1.8 (1.2 2) 2 ( ) 0.7 ( ) 0.5 ( ) 0.6 ( ) Est rs,cmh 2 O/L 30 (28 32) 63 (62 64) 65 (64 66) 68 (67 73) 44 (42 52) 48 (41 51)* 55 (54 60) Est L,cmH 2 O/L 22 (19 25) 55 (53 56) 55 (54 56) 61 (57 63) 36 (32 43) 37 (32 41) 44 (42 50) Est cw,cmh 2 O/L 8 (7 9) 8 (7 11) 9 (8 10) 9 (7 10) 9 (9 10) 10 (9 10) 11 (11 11) Est cw /Est rs 0.24 ( ) 0.13 ( ) 0.14 ( ) 0.13 ( ) 0.19 ( ) 0.22 ( ) 0.19 ( ) Pao LRM 45.5 (43 47) 39 (38 41) 39 (38 40) 42 (38 44) DPTP LRM 29.8 (29 31) 30 (29 31) 31 (30 32) 29 (28 31) ph 7.42 ( ) 7.39 ( ) 7.41 ( ) 7.27 ( ) 7.33 ( ) 7.32 ( ) 7.27 ( ) FI O ( ) 0.45 ( ) 0.50 ( ) Pa O2 /FI O2 460 ( ) 124 (88 133) 154 ( ) 85 (64 103) 194 ( ) 212 ( ) 135 ( ) Pa CO2, mm Hg 39 (36 46) 49 (44 53) 39 (35 50)* 69 (61 81) 58 (53 61) 55 (44 62) 83 (64 86) Definition of abbreviations: Est cw 5 static elastance of chest wall; Est L 5 static elastance of lung; Est rs 5 static elastance of respiratory system; FI O2 5 inspired oxygen fraction; HCl 5 inhaled hydrochloride model; lavage 5 surfactant washout model; LPS 5 intravenous lipopolysaccharide model; Pa CO2 5 arterial partial pressure of CO 2 ; Pa O2 5 arterial partial pressure of O 2 ;Pao LRM 5 airway opening pressure during the lung recruitment maneuver; PEEP ext 5 external positive end-expiratory pressure; PEEP i,s 5 static intrinsic positive end-expiratory pressure; DPTP LRM 5 transpulmonary pressure during the lung recruitment maneuver. Data are expressed as median (interquartile range). * P versus HCl group under same condition. P versus control under same condition. P versus lavage group under same condition. creased at end-inspiration. Each image was divided into three equal regions of interest: ventral, medial, and dorsal (Figure 1). The CT histograms of volume distribution of CT attenuations that refer to the CT slices shown in Figure 1 are depicted in Figures 2 and 3. Figure 4 reports the value of regional elastance of recruited lung tissue and baby lung. In lung-injured animals regional elastance of recruited lung tissue was significantly higher than the elastance of baby lung, regardless of the ARDS model used. On the contrary, in lung-healthy pigs (control group) recruited TABLE 2. VOLUME OF NORMALLY AERATED, POORLY AERATED, NONAERATED, AND HYPERINFLATED LUNG COMPARTMENTS UNDER EACH EXPERIMENTAL VENTILATION CONDITION Baseline ZEEP End-Exp LRM Open Lung End-Exp Open Lung End-Insp Control group (n 5 4) Hyperinflated, ml , * Normally aerated, ml * Poorly aerated, ml * Nonaerated, ml * Total volume, ml , * Recruitment, % of FRC ZEEP 81 (70 90) Lavage group (n 5 7) Hyperinflated, ml * x Normally aerated, ml , * , x Poorly aerated, ml * x Nonaerated, ml * Total volume, ml , * 1, , x Recruitment, % of FRC ZEEP 135 ( ) 78 (40 90) k, LPS group (n 5 7) Hyperinflated, ml * x Normally aerated, ml , * x Poorly aerated, ml * Nonaerated, ml * Total volume, ml 1, , * 1, , x Recruitment, % of FRC ZEEP 111 (90 120) 48 (40 60) k HCl group (n 5 7) Hyperinflated, ml * x Normally aerated, ml , * x Poorly aerated, ml Nonaerated, ml * Total volume, ml 1, , * 1, , x Recruitment, % of FRC ZEEP 60 (30 60) 35 (30 40) k Data are expressed as mean 6 SD if normally distributed or as mean (interquartile range) if not normally distributed. Definition of abbreviations: end-exp 5 end-expiratory; end-insp 5 end-inspiratory; FRC ZEEP 5 functional residual capacity at ZEEP; HCl 5 inhaled hydrochloride model; lavage 5 surfactant washout model; LPS 5 intravenous lipopolysaccharide model; LRM 5 lung recruiting maneuver; ZEEP 5 zero end-expiratory pressure. Parametric tests: * P, 0.05 ZEEP end-exp versus LRM in the same animal group; x P, 0.05 open lung end-exp versus open lung end-insp in the same animal group; P, 0.05 ZEEP versus open lung end-exp in the same animal group. Non-parametric tests: P, versus HCl under the same experimental condition; k P, LRM versus open lung end-exp in the same animal group.

4 418 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Representative computed tomography (CT) images for all four study groups acquired at a level resulting in the largest transverse lung section between the most cranial point of the diaphragm and the base of the heart under different experimental ventilation conditions. To allow a qualitative estimation of lung tissue attenuation properties, images were read based on the UCLA color coding table (OsiriX image processing software, com, Geneva, Switzerland). Each image is divided into three equal regions of interest: ventral (V), medial (M), and dorsal (D). Control group 5 lunghealthy control pigs (n 5 4); lavage group 5 pig group (n 5 7) undergoing surfactant washout with intratracheal saline administration; LPS group 5 pig group (n 5 7) undergoing intravenous lipopolysaccharide solution administration; HCl group 5 pig group (n 5 7) undergoing inhalation of hydrochloride solution. The LRM induced a rather homogeneous hyperinflation in control group pigs, whereas lung parenchyma was more inhomogeneous in animals with ARDS-type lung injuries (lavage, LPS, and HCl groups). In the latter, the baby lung (color coded in light blue and blue in the CT scan obtained at baseline) became hyperinflated (purple) during the LRM, whereas nonaerated lung tissue (color coded in red at baseline) with recruitment became normally aerated (color coded in light purplish blue and dark blue). During ventilation with the open lung strategy, the baby lung was normally aerated at end-expiration with little degree of hyperinflation, but its hyperinflation increased at end-inspiration. HU 5 Hounsfield units; LRM 5 lung recruitment maneuver; ZEEP 5 zero end-expiratory pressure. lung tissue regained elastic properties similar to those of normally aerated lung. The regional elastance of the baby lung was significantly higher in all three types of lung injury when compared with the regional elastance of normally aerated lung tissue in the control group. Figure 5 shows the histograms of volume distribution of CT attenuations in the normally aerated compartment at ZEEP in control group as compared with lung-injured groups. The baby lung was characterized by a higher CT attenuation peak. The mean CT numbers, referring to the entire normally aerated compartment, were , , and for the lavage, LPS, and HCl groups, respectively (P. 0.05, not significant) and for the control group (P, 0.01 compared with each of the lung-injured groups). In all three lung-injured animal groups, linear regression analysis revealed a significant correlation between total baby lung volume at baseline and total hyperinflated lung volume during the LRM (both referring to the whole lung, i.e., obtained by analyzing all the lung CT scans for each animal), with F , regression coefficient , and R (P, 0.001; Figure 6A). Linear regression analysis also revealed a significant but less strong correlation between total baby lung volume at baseline and total hyperinflated lung volume at end-inspiration during the open lung strategy ventilation, with F , regression coefficient , and R (P ; Figure 6B). Interestingly, we obtained even stronger correlations when considering the relationship between the total volume of baby lung characterized by CT attenuation ranging from 2800 to 2900 at ZEEP (i.e., the portion of the baby lung that was already fully distended, but not hyperinflated, at ZEEP) and the volume of hyperinflated lung tissue during the LRM (F ; regression coefficient and R ; P, ; Figure 6C) and at end-inspiration during the open lung strategy ventilation (F ; regression coefficient 5 1.8; R ; P, ; Figure 6D). DISCUSSION The main finding of our study is that lung parenchyma is not homogeneous during ventilation after the open lung strategy. Recruited lung tissue assumed the X-ray attenuation characteristics of normally aerated tissue, whereas lung tissue that was normally aerated at ZEEP (i.e., the baby lung) was prone to develop hyperinflation during the LRM and at end-inspiration. Confirming our study hypothesis, we document that the regional elastance of recruited lung tissue was consistently higher than the regional elastance of the baby lung in all studied ARDS models. Although our study reveals some of the physiological effects of open lung strategy ventilation in ARDS, one needs to exercise extreme caution when extrapolating these findings to the clinical situation in human patients. In particular, we cannot exclude an uneven distribution of lung damage in our ARDS models, which would help explain, at least in part, our results (as one may argue that the baby lung per se may have not been affected at all by the experimental lung injury in our pig models). Nonetheless, we studied the effects of LRM and open lung strategy ventilation in three porcine ARDS models that are quite different in terms of the kind and extent of lung damage induced and hence de-

5 Grasso, Stripoli, Sacchi, et al.: Elastance of Recruited Lung Tissue 419 Figure 2. Density histograms of computed tomography (CT) scans taken at baseline zero end-expiratory pressure (ZEEP) and during the lung recruitment maneuver (LRM) (corresponding to CT images shown in Figure 1). For each study group histograms were obtained in three regions of interest: ventral, medial, and dorsal (see Figure 1). Closed diamond curves represent density histograms from the CT scan obtained at baseline, ZEEP endexpiration during a prolonged end-expiratory pause. Open diamond curves represent density histograms from the CT scan obtained during the LRM. rangement in respiratory mechanics produced (5, 20 22), yet we obtained similar results independent of the model. Furthermore, confirming previous results in the CT scan ARDS study group (25), CT scan attenuation properties and regional elastance of normally aerated lung tissue (i.e., the baby lung) were different in lung-injured animals versus the control group (Figures 4 and 5). Another possible limitation of our study is that during CT image analysis we were not able to return each time to exactly the same region of interest within the scanned lung parenchyma that was studied under different experimental conditions. However, in Figures 1 3, we made sure, in accordance with previous studies (24, 29), to study CT scans acquired at different lung inflation points that always captured the same cross-sectional plane of the chest (i.e., one between the most cranial point of the diaphragm and the base of the heart where the transverse lung section is the largest). Moreover, we analyzed all the CT slices to measure the total volume of each lung compartment and alveolar recruitment (Table 2), regional elastance (Figure 4), volume distribution of CT attenuations in the normally aerated compartment at ZEEP (Figure 5), and the correlations between the volume of baby lung and hyperinflation (Figure 6). The controversy regarding the open lung theory is still ongoing (30). Similarly to human ARDS, applying a well-studied LRM (31) and a ventilatory strategy applying low VT and a safe plateau pressure of 30 cm H 2 O (10) yielded a variable degree of alveolar recruitment in the different lung-injury groups (32, 33). Moreover, we document that the open lung approach may lead to hyperinflation of the baby lung, regardless of the degree of alveolar recruitment. This confirms that hyperinflation and recruitment occur in general simultaneously, as has been previously demonstrated both in animal models (34) and in patients (16, 17, 35, 36). Thanks to a CT scan based method, previously validated by Puybasset and coworkers (17) (see online supplement), we show that the regional elastance of recruited lung tissue was significantly higher than regional elastance of baby lung in all the lung-injured groups (Figure 4). This finding clearly confirms our

6 420 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 3. Density histograms of computed tomography (CT) scans obtained during ventilation with the open lung protocol (corresponding to CT images shown in Figure 1). For each study group histograms were obtained for three regions of interest: ventral, medial, and dorsal (see Figure 1). Closed diamond curves represent density histograms from the CT scan obtained during the open lung strategy ventilation period when a prolonged end-expiratory pause was applied. Open diamond curves represent density histograms from the CT scan obtained during a prolonged endinspiratory pause performed during the open lung strategy ventilation. study hypothesis, that the insufficiently aerated compartment, once recruited, does not resume the elastic characteristics of the surrounding baby lung, and that therefore alveolar recruitment per se is not able to protect the baby lung from hyperinflation, in contrast to the theoretical assumption of the open lung strategy (7, 37). In particular, we speculate that during the open lung ventilation strategy the opened-up lung is so elastic that it inflates minimally as compared with baby lung. We also speculate that the mechanical inhomogeneity of the recruited lung could lead to mechanical stress at the interface between recruited lung areas and the baby lung. The relative stiffness of recruited lung areas could explain the observation that patients with focal or lobar ARDS (a morphologic pattern characterized by a significant surface area of baby lung) are more prone to develop alveolar hyperinflation than patients with diffuse ARDS (35, 38). Indeed, we found that the degree of alveolar hyperinflation during the open lung ventilation strategy was proportional to the surface area of the baby lung (i.e., the larger the baby lung the higher the risk of hyperinflation). Furthermore, we found an even stronger correlation between the volume of baby lung characterized by CT attenuations ranging between 2900 and 2800 HU at ZEEP and the volume of hyperinflated lung regions during the open lung strategy (Figure 6). Both these results confirm previous findings of the CT scan ARDS study group, indicating that normally aerated lung regions at ZEEP and even more those regions that are already fully distended at ZEEP are prone to develop alveolar hyperinflation with PEEP. In light of these results, we point out that hyperinflation is proportional to both the applied transpulmonary pressure and the surface of baby lung and is hardly influenced by alveolar recruitment, although more studies are needed to establish the respective impact of these parameters. Chiumello and coworkers recently showed that mechanical properties of baby lung are remarkably similar to those of healthy lung tissue in human ARDS (3), contradicting the results of previous studies accounting for an excess of lung tissue in the baby lung, likely due to an interstitial accumulation of inflammatory cells (17, 25). At ZEEP, we found that regional elastance, mean HU numbers, and peak in volume distribution of CT attenuations of normally aerated lung tissue were higher in lung-injured groups than in the control group (Figures 5 and 6). This implies that normally aerated lung tissue at ZEEP in the lung-injured models (i.e., the baby lung) had more tissue

7 Grasso, Stripoli, Sacchi, et al.: Elastance of Recruited Lung Tissue 421 Figure 4. Regional static elastance (E streg ) of the baby lung (left panel) and of recruited lung tissue (right panel) in all the study groups. *P, 0.05 recruited lung tissue versus baby lung tissue; x P, 0.05 versus control group; D P, 0.05 versus HCl group. and consequently less gas volume as compared with normally aerated lung tissue at ZEEP in the control group. Overall, our data support the assumption that the baby lung cannot be considered healthy lung tissue. Recently Carvalho and coworkers, confirming the results of a previous pioneer study by Suter and coworkers (39), elegantly showed that the best PEEP capable to minimize static lung elastance represents a compromise because it generates both alveolar hyperinflation and lung recruitment. Carvalho s and our data emphasize the notion that the recruited lung is inhomogeneous and that measurement of static elastance is not a valid surrogate suitable to define the exact amount of alveolar recruitment and hyperinflation at any given transpulmonary pressure (34). Ventilatory protocols using LRM are based on the application of a pressure of 40 to 60 cm H 2 O to the airway opening, based on various algorithms (31). In a previous study, we showed that the transpulmonary pressure (i.e., the lung distending pressure) reached during an LRM may vary widely among ARDS patients because of variable derangements of lung and chest wall mechanics (28). In a typical patient with early primitive or pulmonary ARDS (i.e., with severely compromised lung parenchyma but relatively unaffected chest wall), the Est cw /Est rs ratio has been found to be approximately 0.2 (40). However, if concomitantly a severe chest wall impairment exists, the Est cw /Est rs ratio may reach higher values (i.e., up to 0.8) (41). Applying a 40 cm H 2 O LRM, as suggested by several protocols (31) in patient with an Est cw /Est rs ratio of 0.2, will generate a pleural pressure (Ppl) of 8 cm H 2 O, according to the formula: Ppl 5 Pao Est cw =Est rs ; Figure 5. Histograms of volume distributions of computed tomography (CT) attenuations in the normally aerated tissue at zero-end expiratory pressure (ZEEP). In all the lung-injured groups, the normally aerated tissue at ZEEP (i.e., the baby lung) was characterized by a higher CT attenuation peak as compared with the normally aerated tissue at ZEEP in the control group. with a transpulmonary pressure (Pao-Ppl) of 32 cm H 2 O. In our study, we aimed at a transpulmonary pressure compatible with the clinical situation in human patients (30 cm H 2 O) in all three porcine models, regardless of the differences in the changes of lung and chest-wall mechanics, and we showed significant hyperinflation of the baby lung at this transpulmonary pressure. Recently, Borges and coworkers proposed a maximum recruitment strategy based on an LRM applying pressures of up to 60 cm H 2 O to the airways (42) that leads to a transpulmonary pressure of 48 cm H 2 O in patient with an Est cw /Est rs ratio of 0.2. Our data suggest that more studies are required to fully understand the physiological impact of such an aggressive strategy on the baby lung. However, we must point out that the LRM applied in Borges study (progressive increase in PEEP while ventilating with a constant level of pressure control ventilation) was different from the one applied in the present study (continuous positive airway pressure for s, starting from ZEEP). It would be important to investigate the impact of different kinds of recruiting maneuvers on alveolar hyperinflation. Indeed, limiting the delta lung distending pressure by applying PEEP (as in the Borges study) or performing the LRM while limiting the expansion of the baby lung by stiffening the ventral part of the chest wall could

8 422 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 6. (A) Graph depicting the significant linear relationship (r ; P, 0.01) between the volume of normally aerated tissue determined at baseline zero-end expiratory pressure (ZEEP), end-expiration (the baby lung) and that of hyperinflated tissue during the lung recruitment maneuver (LRM; see Table 2). Each point represents data from one of the 21 studied lung-injured pigs. (B) Graph depicting the significant linear relationship (r ; P, 0.022) between the volume of normally aerated tissue at baseline ZEEP, end-expiration and that of hyperinflated tissue at end inspiration during the use of the open lung ventilatory protocol (see Table 2). (C ) Graph depicting the significant linear relationship (r ; P, ) between the volume of normally aerated tissue characterized by attenuation numbers of 2900 to 2800 HU at baseline ZEEP, end-expiration and that of hyperinflated tissue during the LRM. (D) Graph depicting the significant linear relationship (r ; P, ) between the volume of normally aerated tissue characterized by attenuation numbers of 2900 to 2800 HU at baseline ZEEP, end-expiration and that of hyperinflated tissue at end inspiration during the use of the open lung ventilatory protocol. potentially reduce LRM-induced alveolar hyperinflation, but these issues deserve further investigation. Lung recruitment maneuvers are largely used to reverse anesthesia-induced atelectasis (43). In our control group (i.e., lung-healthy anesthetized pigs) we found a significant degree of hyperinflation during the LRM. Of note, the airway opening pressure applied during the LRM (median 45.5 cm H 2 O, interquartile range, 41 47) was within the range suggested for the clinical patient population (44). However, we must consider that our pig model was characterized by an Est cw /Est rs ratio of 0.24, whereas the normal Est cw /Est rs ratio in humans is 0.5 (41). In the latter case transpulmonary pressure would have been 22 cm H 2 O and not 29.8 cm H 2 O as in the present study (see formulas above). We have no data to predict how healthy porcine lung tissue responds to a transpulmonary pressure lower than 29.8 cm H 2 O, but we believe that this aspect deserves further investigation. In conclusion, largely confirming previous human data, this study adds an additional piece of information to the body of evidence outlining the risks of uncontrolled increase in intrathoracic pressures in ARDS. Despite expert opinion suggesting that LRM and PEEP need to be tailored to the individual lung pathology to avoid unnecessary alveolar hyperinflation (33), three recent inconclusive randomized clinical trials applied LRM and PEEP based on standardized criteria in all the patients (9, 10, 45). Tailoring a lung-recruiting strategy with the goal of minimizing concomitant baby lung hyperinflation could prove crucial when designing a trial with a reasonable chance of success in assessing the impact of LRM and PEEP optimization on mortality rate and duration of mechanical ventilation (33). Our findings will further help design such a physiology-based lung protective ventilatory protocol. Conflict of Interest Statement: S.G. has participated as a speaker in scientific courses organized by Covidien and Maquet. T.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References 1. Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 2001;164: Gattinoni L, Pesenti A. The concept of Baby lung. Intensive Care Med 2005;31: Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F, Polli F, Tallarini F, Cozzi P, Cressoni M, Colombo A, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 2008;178: Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149: Slutsky AS. Ventilator-induced lung injury: from barotrauma to biotrauma. Respir Care 2005;50: Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute

9 Grasso, Stripoli, Sacchi, et al.: Elastance of Recruited Lung Tissue 423 lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342: Barbas CS, de Matos GF, Pincelli MP, da Rosa Borges E, Antunes T, de Barros JM, Okamoto V, Borges JB, Amato MB, de Carvalho CR. Mechanical ventilation in acute respiratory failure: recruitment and high positive end-expiratory pressure are necessary. Curr Opin Crit Care 2005;11: Gattinoni L, Caironi P. Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA 2008;299: Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive endexpiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299: Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, et al. Positive endexpiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299: Haitsma JJ, Lachmann RA, Lachmann B. Open lung in ARDS. Acta Pharmacol Sin 2003;24: Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl JMed2000;342: Hubmayr RD. Perspective on lung injury and recruitment: a skeptical look at the opening and collapse story. Am J Respir Crit Care Med 2002;165: DiRocco JD, Pavone LA, Carney DE, Lutz CJ, Gatto LA, Landas SK, Nieman GF. Dynamic alveolar mechanics in four models of lung injury. Intensive Care Med 2006;32: Dambrosio M, Roupie E, Mollet JJ, Anglade MC, Vasile N, Lemaire F, Brochard L. Effects of positive end-expiratory pressure and different tidal volumes on alveolar recruitment and hyperinflation. Anesthesiology 1997;87: Nieszkowska A, Lu Q, Vieira S, Elman M, Fetita C, Rouby JJ. Incidence and regional distribution of lung overinflation during mechanical ventilation with positive end-expiratory pressure. Crit Care Med 2004; 32: Puybasset L, Gusman P, Muller JC, Cluzel P, Coriat P, Rouby JJ. Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end-expiratory pressure. CT scan ARDS study group. Adult respiratory distress syndrome. Intensive Care Med 2000;26: Grasso S, Stripoli T, Staffieri F, Franchini D, Sacchi M, Pugliese P, De Monte V, Valentini V, Crovace A, Fiore T. Elastic properties of recruited lung tissue in experimental ARDS: A CT scan study [abstract]. Intensive Care Med 2008;34:S Grasso S, Fanelli V, Cafarelli A, Anaclerio R, Amabile M, Ancona G, Fiore T. Effects of high versus low positive end-expiratory pressures in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005;171: Lachmann B, Robertson B, Vogel J. In vivo lung lavage as an experimental model of the respiratory distress syndrome. Acta Anaesthesiol Scand 1980;24: Lutz C, Carney D, Finck C, Picone A, Gatto LA, Paskanik A, Langenback E, Nieman G. Aerosolized surfactant improves pulmonary function in endotoxin-induced lung injury. Am J Respir Crit Care Med 1998;158: Rosenthal C, Caronia C, Quinn C, Lugo N, Sagy M. A comparison among animal models of acute lung injury. Crit Care Med 1998;26: Grasso S, Terragni P, Mascia L, Fanelli V, Quintel M, Herrmann P, Hedenstierna G, Slutsky AS, Ranieri VM. Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury. Crit Care Med 2004;32: Neumann P, Berglund JE, Fernandez Mondejar E, Magnusson A, Hedenstierna G. Dynamics of lung collapse and recruitment during prolonged breathing in porcine lung injury. J Appl Physiol 1998;85: Puybasset L, Cluzel P, Gusman P, Grenier P, Preteux F, Rouby JJ. Regional distribution of gas and tissue in acute respiratory distress syndrome. I. Consequences for lung morphology. CT scan ARDS study group. Intensive Care Med 2000;26: Rouby JJ, Puybasset L, Cluzel P, Richecoeur J, Lu Q, Grenier P. Regional distribution of gas and tissue in acute respiratory distress syndrome. II. Physiological correlations and definition of an ARDS severity score. CT scan ARDS study group. Intensive Care Med 2000; 26: Malbouisson LM, Muller JC, Constantin JM, Lu Q, Puybasset L, Rouby JJ. Computed tomography assessment of positive end-expiratory pressure-induced alveolar recruitment in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163: Grasso S, Mascia L, Del Turco M, Malacarne P, Giunta F, Brochard L, Slutsky AS, Marco Ranieri V. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002;96: Neumann P, Berglund JE, Mondejar EF, Magnusson A, Hedenstierna G. Effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury. Am J Respir Crit Care Med 1998;158: Rouby JJ, Ferrari F, Bouhemad B, Lu Q. Positive end-expiratory pressure in acute respiratory distress syndrome: Should the open lung strategy be replaced by a protective lung strategy? Crit Care 2007;11: Fan E, Wilcox ME, Brower RG, Stewart TE, Mehta S, Lapinsky SE, Meade MO, Ferguson ND. Recruitment maneuvers for acute lung injury: A systematic review. Am J Respir Crit Care Med 2008;178: Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354: Rouby JJ, Lu Q, Goldstein I. Selecting the right level of positive endexpiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165: Carvalho AR, Jandre FC, Pino AV, Bozza FA, Salluh J, Rodrigues R, Ascoli FO, Giannella-Neto A. Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury. Crit Care 2007;11:R Grasso S, Stripoli T, De Michele M, Bruno F, Moschetta M, Angelelli G, Munno I, Ruggiero V, Anaclerio R, Cafarelli A, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive endexpiratory pressure. Am J Respir Crit Care Med 2007;176: Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175: Haitsma JJ, Lachmann B. Lung protective ventilation in ARDS: the open lung maneuver. Minerva Anestesiol 2006;72: Vieira SR, Puybasset L, Lu Q, Richecoeur J, Cluzel P, Coriat P, Rouby JJ. A scanographic assessment of pulmonary morphology in acute lung injury. Significance of the lower inflection point detected on the lung pressure-volume curve. Am J Respir Crit Care Med 1999;159: Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975; 292: Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 1998; 158: Gattinoni L, Chiumello D, Carlesso E, Valenza F. Bench-to-bedside review: chest wall elastance in acute lung injury/acute respiratory distress syndrome patients. Crit Care 2004;8: Borges JB, Okamoto VN, Matos GF, Caramez MP, Arantes PR, Barros F, Souza CE, Victorino JA, Kacmarek RM, Barbas CS, et al. Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;174: Hedenstierna G, Rothen HU. Atelectasis formation during anesthesia: causes and measures to prevent it. J Clin Monit Comput 2000;16: Magnusson L, Tenling A, Lemoine R, Hogman M, Tyden H, Hedenstierna G. The safety of one, or repeated, vital capacity maneuvers during general anesthesia. Anesth Analg 2000;91: Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351: