Lung Opening and Closing during Ventilation of Acute Respiratory Distress Syndrome

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1 Lung Opening and Closing during Ventilation of Acute Respiratory Distress Syndrome Pietro Caironi 1,2, Massimo Cressoni 1, Davide Chiumello 2, Marco Ranieri 3, Michael Quintel 4, Sebastiano G. Russo 4, Rodrigo Cornejo 5, Guillermo Bugedo 5, Eleonora Carlesso 1, Riccarda Russo 2, Luisa Caspani 2, and Luciano Gattinoni 1,2 1 Dipartimento di Anestesiologia, Terapia Intensiva, e Scienze Dermatologiche, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano, Università degli Studi di Milano, Milan, 2 Dipartimento di Anestesia, Rianimazione e Terapia del Dolore, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano, Milan, and 3 Dipartimento di Anestesia, Azienda Ospedaliera San Giovanni Battista-Molinette, Università degli Studi di Torino, Turin, Italy; 4 Anaesthesiologie II, Operative Intensivmedizin, Universitatsklinikum Göttingen, Göttigen, Germany; and 5 Departementos de Anestesiologia y Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile Rationale: The effects of high positive end-expiratory pressure (PEEP) strictly depend on lung recruitability, which varies widely during acute respiratory distress syndrome (ARDS). Unfortunately, increasing PEEP may lead to opposing effects on two main factors potentially worsening the lung injury, that is, alveolar strain and intratidal opening and closing, being detrimental (increasing the former) or beneficial (decreasing the latter). Objectives: To investigate how lung recruitability influences alveolar strain and intratidal opening and closing after the application of high PEEP. Methods: We analyzed data from a database of 68 patients with acute lung injury or ARDS who underwent whole-lung computed tomography at 5, 15, and 45 cm H 2 O airway pressure. Measurements and Main Results: End-inspiratory nonaerated lung tissue was estimated from computed tomography pressure volume curves. Alveolar strain and opening and closing lung tissue were computed at 5 and 15 cm H 2 O PEEP. In patients with a higher percentage of potentially recruitable lung, the increase in PEEP markedly reduced opening and closing lung tissue (P, 0.001), whereas no differences were observed in patients with a lower percentage of potentially recruitable lung. In contrast, alveolar strain similarly increased in the two groups (P ). Opening and closing lung tissue was distributed mainly in the dependent and hilar lung regions, and it appeared to be an independent risk factor for death (odds ratio, 1.10 for each 10-g increase). Conclusions: In ARDS, especially in patients with higher lung recruitability, the beneficial impact of reducing intratidal alveolar opening and closing by increasing PEEP prevails over the effects of increasing alveolar strain. Keywords: acute respiratory distress syndrome; acute lung injury; ventilator-induced lung injury; mechanical ventilation Since the first investigations on patients affected by acute respiratory distress syndrome (ARDS), lung recruitment has been shown to be critical when approaching the respiratory bundle of its clinical treatment (1, 2), as pulmonary atelectasis is one of the (Received in original form May 26, 2009; accepted in final form November 11, 2009) Supported in part by an Italian grant provided by the Fondazione Fiera di Milano for Translational and Competitive Research (2007, L.G.). Correspondence and requests for reprints should be addressed to Luciano Gattinoni, M.D., Ph.D., Dipartimento di Anestesiologia, Terapia Intensiva, e Scienze Dermatologiche, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico - Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano, Università degli Studi di Milano, Via F. Sforza 35, Milan, Italy. gattinon@policlinico.mi.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 181. pp , 2010 Originally Published in Press as DOI: /rccm OC on November 12, 2009 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The response to high levels of positive end-expiratory pressure (PEEP) depends on lung recruitability, which varies among patients with acute respiratory distress syndrome. Its application appears to be appropriate only in patients with a large amount of potentially recruitable lung. Unfortunately, the increase in PEEP may lead to opposing effects on the two major determinants of the development of ventilator-induced lung injury, that is, alveolar strain and intratidal lung opening and closing. What This Study Adds to the Field In patients with greater lung recruitability, the beneficial impact of reducing the amount of opening and closing lung tissue by increasing PEEP appears to prevail over the potentially harmful effects of increasing alveolar strain. main pathological features of the ARDS lung. Consequently, the ventilatory approach to this syndrome has included, since the beginning, the application of positive pressure at end expiration to avoid lung collapse (1, 3, 4). We have observed that the response to high-level positive end-expiratory pressure (PEEP), that is, the amount of lung collapse prevented by its application, is strictly dependent on the total amount of lung recruitability (as determined at airway pressures close to total lung capacity) and is therefore greatly variable among patients with ARDS (5). Therefore, clinical evaluation of the potentially recruitable lung seems to be essential when approaching how to set the optimal level of PEEP. During ARDS or acute lung injury (ALI), the use of positivepressure ventilation may further increase the lung injury underlying the respiratory insufficiency (6 8). There are two main factors widely recognized as mechanical determinants of ventilator-induced lung injury (VILI): alveolar strain, defined as the ratio between the amount of gas volume delivered during tidal breath and the amount of aerated lung receiving it (9), and intratidal alveolar opening and closing, quantitatively defined as the amount of collapsed lung tissue reopening during inspiration and recollapsing during expiration (10 12). When applying a high level of PEEP to ALI/ARDS lungs, two opposing phenomena theoretically occur: on the one hand, the amount of opening and closing lung tissue will decrease; on the other hand, as a consequence of the enhanced distending pressure, the degree of alveolar strain applied to the open lung will increase. It is

2 Caironi, Cressoni, Chiumello, et al.: Lung Opening and Closing in ARDS 579 b Figure 1. (A) Nonaerated lung tissue at end-inspiration and endexpiration and (B) end-inspiratory alveolar strain for patients with either a lower or a higher percentage of potentially recruitable lung after the application of 5 and 15 cm H 2 Opositiveend-expiratorypressure(PEEP). For clarity, data are expressed as means 6 standard error. To describe the relationship between nonaerated lung tissue and the airway pressure applied, exponential decay functions were used [y 5 y 0 1 a 3 exp( b 3 x)]. Alveolar strain was defined as the ratio between end-inspiratory lung inflation and lung resting volume. For more details, see the online supplement. In patients with a higher percentage of potentially recruitable lung, the increase in PEEP to 15 cm H 2 O markedly reduced the difference between end-expiratory and end-inspiratory nonaerated lung tissue, that is, the amount of opening and closing lung tissue (P, 0.001, dotted lines). In contrast, no effect was observed in patients with a lower percentage of potentially recruitable lung, as the amount of opening and closing lung tissue already equaled a negligible amount at 5 cm H 2 OPEEP (*P, vs. patients with a lower percentage of potentially recruitable lung at the same PEEP, # P, vs. 5 cm H 2 O PEEP within the same group). At 5 cm H 2 O PEEP, the alveolar strain of patients with a higher percentage of potentially recruitable lung was significantly greater than that observed in patients with a lower percentage of potentially recruitable lung. In contrast, the application of 15 cm H 2 O PEEP similarly increased alveolar strain both in patients with either a lower or higher percentage of potentially recruitable lung (P, 0.001). METHODS We analyzed data from a database of a multicenter study investigating lung recruitment during ALI/ARDS (5). The study design is briefly summarized. Study Population Sixty-eight patients were studied at four university hospitals, after approval by the local institutional review boards had been given. Informed consent was obtained according to the national regulations of each institution. Patient enrollment was based on standard criteria for ALI/ARDS (21), excluding those with age less than 16 years, pregnancy, and chronic obstructive pulmonary disease. therefore conceivable that the potential effectiveness of high levels of PEEP will depend on the balance between deleterious and beneficial effects (13). So far, no clinical data are available to support the application of higher levels of PEEP to improve survival in unselected patients with ALI/ARDS (14, 15). After the conclusion of the ALVEOLI (Assessment of Low Tidal Volume and Elevated End-expiratory Volume to Obviate Lung Injury) study (16), two further multicenter randomized clinical trials apparently did not demonstrate any benefit for the application of higher levels of PEEP (as compared with lower levels) during low tidal volume ventilation (17, 18). However, no study has considered the impact of potentially recruitable lung characterizing each patient in relation to the effects of different levels of PEEP on the determinants of VILI (19). We therefore set out to investigate how lung recruitability may influence the development and the effects of alveolar strain as well as alveolar opening and closing after the application of PEEP during ALI/ARDS. Some of the results of these studies have been previously reported in form of an abstract (20). Study Design Under sedation and paralysis, patients underwent whole-lung computed tomography (CT) scanning at three different airway pressures: 45 cm H 2 O end-inspiratory airway pressure, and 5 and 15 cm H 2 O PEEP applied in random order. Baseline mechanical ventilation was set according to the daily clinical treatment. Before each CT scanning, a recruitment maneuver was performed (see additional METHODS in the online supplement) (5). CT Scan Analysis Each cross-sectional image was processed and analyzed with a customdesigned software package (5, 22). Assuming the specific lung weight to be equal to 1, total lung weight and tissue weights of lung regions with different degree of aeration were calculated on the basis of the CT number of each voxel (5). To investigate lung morphology along the sterno vertebral and cephalo caudal axes, CT images of the whole lung were divided into 4 equal segments from sternum to vertebral region, and then arbitrarily grouped into 10 equal intervals, from lung apex to base (23). CT-derived Variables 1. Potentially recruitable lung was defined as the difference between the weight of nonaerated lung tissue at 5 and 45 cm H 2 O airway pressure, expressed as a proportion of the weight of the total lung tissue, and it represents the proportion of the total lung weight accounted for by nonaerated lung tissue in which aeration was restored from 5 to 45 cm H 2 O airway pressure. The study population was divided into two groups, according to its median value (9% of the total lung tissue), as previously reported (5).

3 580 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL On the basis of the strict similarity between pressure volume and pressure recruitment curves during ALI/ARDS (24), a sigmoid equation describing the pressure volume curve of the respiratory system (25, 26) was derived from the four values of gas volume and airway pressure available for each patient (5 cm H 2 O PEEP, end-inspiratory plateau pressure from 5 and 15 cm H 2 O PEEP, and end-inspiratory 45 cm H 2 O airway pressure). Gas volume was expressed as a percentage of total lung capacity, defined as the gas volume inflated into the lungs at 45 cm H 2 O airway pressure. From each equation, end-inspiratory nonaerated lung tissue at the corresponding plateau airway pressure was estimated as a percentage of the total amount of potentially recruitable lung of each patient (assuming 0 and 100% lung recruitment, respectively, at 5 and 45 cm H 2 O airway pressure). 3. The amount of opening and closing lung tissue at 5 and 15 cm H 2 O PEEP was calculated as the difference between endexpiratory and end-inspiratory nonaerated lung tissue, that is, the cycling reduction of nonaerated lung tissue caused every breath by VT application. 4. Alveolar strain at 5 and 15 cm H 2 O PEEP was defined as the ratio between end-inspiratory lung inflation, that is, lung volume variation above the estimated volume at 0 cm H 2 O airway pressure (due to both VT and PEEP application), and the lung resting volume, estimated as lung volume at 0 cm H 2 O airway pressure, that is, FRC (27). The calculation was corrected for PEEP-induced and intratidal lung recruitment (see additional methods and Figure E1 in the online supplement). 5. Superimposed pressure was defined as the hydrostatic pressure at the dependent portion of the lung resulting from the weight of the tissue above. Statistical Analysis Statistical significance was defined as a P value less than Unless otherwise indicated, data are expressed as means 6 SD. Additional details on the methods used in this study are provided in the online supplement. RESULTS Intratidal Opening and Closing Lung Tissue and Alveolar Strain of Whole Lung To initially investigate the effect of mechanical ventilation on the determinants of VILI and their relationship with the potentially recruitable lung, opening and closing lung tissue and alveolar strain were analyzed at 5 and 15 cm H 2 O PEEP for the whole lung. At 5 cm H 2 O PEEP, opening and closing lung tissue recorded in patients with a higher percentage of potentially recruitable lung was markedly greater than that observed in patients with a lower percentage of potentially recruitable lung ( vs g, P, 0.001; Figure 1A). In the latter group of patients, its amount was almost negligible, equaling only 2 6 2% of the total lung weight (1, g). When PEEP was increased to 15 cm H 2 O, opening and closing lung tissue significantly decreased only in patients with a higher percentage of potentially recruitable lung (down to g, P, 0.001), resulting unchanged in patients with a lower percentage of potentially recruitable lung ( g, P vs. 5 cm H 2 O PEEP; Figure 1A). After the application of a similar VT at 5 cm H 2 O PEEP, the alveolar strain of patients with a higher percentage of potentially recruitable lung was significantly greater than that observed in patients with a lower percentage of potentially recruitable lung ( vs , P, 0.001; Figure 1B), likely due to a lower estimated FRC recorded in the former group of patients (P ; Table 1). In contrast, after 15 cm H 2 O PEEP was applied, alveolar strain similarly increased in both groups of patients (up to and , respectively, P ; Figure 1B). Regional Distribution of Potentially Recruitable Lung To examine the possibility that inhomogeneity of the ALI/ ARDS lung may affect the distribution of the determinants of VILI within the lung parenchyma, we first investigated the regional distribution of potentially recruitable lung along the cephalo caudal axis. In patients with a lower percentage of potentially recruitable lung, the total amount of nonaerated lung tissue at 5 cm H 2 O PEEP progressively and linearly increased along the entire cephalo caudal axis, from about 10% to about 50% of the total lung tissue weight at each lung level (P, 0.001, one-way analysis of variance [ANOVA]; Figure 2A). In contrast, the amount of nonaerated lung tissue potentially recruitable at 45 cm H 2 O airway pressure, that is, the potentially recruitable lung, appeared to be negligible throughout the entire parenchyma. Of note, the application of 45 cm H 2 O airway pressure determined, at lung base (levels 8 to 10), an alveolar derecruitment, as shown by a negative percentage of potentially recruitable lung (P, 0.05 for levels 9 and 10 vs. other lung levels; Figure 2A). TABLE 1. VENTILATORY SETTINGS AND RESPIRATORY VARIABLES DURING THE STUDY PROTOCOL Patients with Lower Percentage of Potentially Recruitable Lung (n 5 34) Patients with Higher Percentage of Potentially Recruitable Lung (n 5 34) P Value* VT at 5 PEEP, ml VT at 15 PEEP, ml Plateau pressure from 5 PEEP, cm H 2 O ,0.001 Plateau pressure from 15 PEEP, cm H 2 O Respiratory rate at 5 PEEP, breaths/min Respiratory rate at 15 PEEP, breaths/min Minute ventilation at 5 PEEP, L/min Minute ventilation at 15 PEEP, L/min Intrinsic PEEP at 5 PEEP, cm H 2 O Intrinsic PEEP at 15 PEEP, cm H 2 O Total lung tissue weight, g 1, , ,0.001 Estimated FRC, ml 1, Definition of abbreviation: PEEP 5 positive end-expiratory pressure. Patients with a lower percentage of potentially recruitable lung had values at or below 9% of the total lung tissue weight (the median value for the study population), whereas patients with a higher percentage of potentially recruitable lung had values greater than 9%. Plus-minus values represent means 6 SD. * P values were obtained by Student t test or Wilcoxon test, as appropriate. Data regarding these variables, which have been previously reported (5), are presented here for completeness.

4 Caironi, Cressoni, Chiumello, et al.: Lung Opening and Closing in ARDS 581 b Figure 2. Regional distribution of consolidated and potentially recruitable lung for patients with either (A) a lower or (B) a higher percentage of potentially recruitable lung, and regional distribution of superimposed pressure at the most dependent lung regions (C) for both groups of patients at 5 cm H 2 O positive end-expiratory pressure (PEEP). For regional analysis, lung parenchyma was equally divided into 10 intervals along the cephalo caudal axis. Consolidated lung tissue denotes the lung tissue that remained nonaerated even after the application of 45 cm H 2 O airway pressure, whereas the potentially recruitable lung denotes the amount of nonaerated lung tissue at 5 cm H 2 O PEEP that has been recruited at 45 cm H 2 O airway pressure. Therefore, the sum of both the consolidated and the potentially recruitable lung denotes the total amount of nonaerated lung tissue at 5 cm H 2 O PEEP for each lung interval. Both the consolidated and the potentially recruitable lung were expressed as a percentage of the total lung tissue weight of each cephalo caudal lung interval. For clarity, data are expressed as means 6 standard error. For statistical analysis, see the text. In patients with a lower percentage of potentially recruitable lung, the amount of consolidated lung tissue and the total amount of nonaerated lung tissue progressively and linearly increased along the entire cephalo caudal axis, whereas the percentage of potentially recruitable lung appeared to be negligible throughout the entire parenchyma. Conversely, in patients with a higher percentage of potentially recruitable lung, the total amount of potentially recruitable lung was homogeneously distributed along the cephalo caudal axis, and the amount of nonaerated lung tissue at 5 cm H 2 O PEEP equaled about 40 to 50% of the tissue weight of each lung level, with the exception of a slight reduction observed in the first levels. Finally, superimposed pressure at the most dependent lung regions detected in patients with a higher percentage of potentially recruitable lung was markedly greater than that observed in patients with a lower percentage of potentially recruitable lung along the entire lung parenchyma, with the exception of levels at lung base (*P, vs. patients with a lower percentage of potentially recruitable lung). Conversely, in patients with a higher percentage of potentially recruitable lung, the amount of nonaerated lung tissue at 5 cm H 2 O PEEP appeared to equal about 40 50% of the tissue weight of each lung level, with the exception of the first levels at lung apex, in which a slight reduction was observed (P , one-way ANOVA). Similarly, the amount of the potentially recruitable lung was homogeneously distributed along the cephalo caudal axis, equaling about 20 30% of the lung tissue weight of each lung level (P , one-way ANOVA; Figure 2B). As lung collapse may be related to the gravitational forces exerted by the increased tissue weight of the lung parenchyma (28), we analyzed the distribution of superimposed pressure at the most dependent lung regions along the cephalo caudal axis in the two groups. Both in patients with either a lower or a higher percentage of potentially recruitable lung, superimposed pressure was relatively high along the entire cephalo caudal axis (Figure 2C). Moreover, in patients with a higher percentage of potentially recruitable lung, superimposed pressure markedly exceeded that recorded in patients with a lower percentage of potentially recruitable lung within the entire lung parenchyma, with the exception of the last two levels at lung base (P , for both). Regional Distribution of Alveolar Opening and Closing Tissue and Alveolar Strain As shown in Figure 3A, the amount of opening and closing lung tissue in patients with a lower percentage of potentially recruitable lung was quite small along the entire cephalo caudal axis, both at 5 and 15 cm H 2 O PEEP. In contrast, in patients with a higher percentage of potentially recruitable lung, the amount of opening and closing lung tissue at 5 cm H 2 O PEEP was relatively high, particularly at lung apex and hilum (from level 2 to level 7; Figure 3B). The application of 15 cm H 2 O PEEP significantly reduced opening and closing lung tissue (P, 0.05 vs. 5 cm H 2 O PEEP), with the exception of levels 8 to 10 (P ). Alveolar strain at 5 cm H 2 O PEEP significantly decreased toward lung bases in patients with a lower percentage of potentially recruitable lung (P , two-way ANOVA for repeated measurements; Figure E3 in the online supplement). In contrast, in patients with a higher percentage of potentially recruitable lung alveolar strain was homogeneously distributed along the entire cephalo caudal axis (P , two-way ANOVA for repeated measurements). After the application of 15 cm H 2 O PEEP, alveolar strain significantly increased in both groups (P, 0.001, two-way ANOVA for repeated measurements, for both). However, in patients with a higher percentage of potentially recruitable lung the increased strain appeared to be mainly localized only in specific apex and hilar lung regions (see Figure E3). Impact on Survival To assess the impact of potentially recruitable lung on the determinants of VILI in relation to the clinical outcome, we analyzed the amount of opening and closing lung tissue as well as alveolar strain based on the ventilatory parameters set before the

5 582 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL potentially recruitable lung ( g, P, 0.001, one-way ANOVA; Figure 4). The progressive increase in opening and closing lung tissue along the increased percentage of potentially recruitable lung was paralleled by a linear increase in mortality at intensive care unit discharge (P by the Hosmer-Lemeshow goodness-of-fit test; c ), as previously reported (5). To further examine a possible association between the determinants of VILI and mortality, a multivariate analysis for independent predictors of mortality was performed. The Simplified Acute Physiology Score (SAPS) II score, as well as opening and closing lung tissue resulting from the ventilatory setting clinically used, appeared to be independently associated with an increased risk of death (P by the Hosmer-Lemeshow goodness-of-fit test; c ); the odds ratios for each one-point increase in SAPS II score and for each 10-g increase in opening and closing lung tissue were, respectively, 1.10 (95% confidence interval, ) and 1.10 (95% confidence interval, ). Of note, alveolar strain did not differ between survivors and nonsurvivors (Table 2). Finally, although the level of PEEP did not appear to be independently associated with an increased risk of death, patients with a very high percentage of potentially recruitable lung who survived were clinically ventilated with a PEEP level significantly higher than that applied in patients who did not survive ( vs , P, 0.05; Figure 5). Figure 3. Regional distribution of opening and closing lung tissue for patients with either (A) a lower or (B) a higher percentage of potentially recruitable lung at 5 and 15 cm H 2 O positive end-expiratory pressure (PEEP). For regional analysis, lung parenchyma was equally divided into 10 intervals along the cephalo caudal axis. Opening and closing lung tissue was computed for each PEEP level as the difference between endexpiratory and end-inspiratory nonaerated lung tissue. In patients with a lower percentage of potentially recruitable lung, the amount of opening and closing lung tissue was similar and almost negligible both at 5 and 15 cm H 2 O PEEP along the entire parenchyma. In contrast, in patients with a higher percentage of potentially recruitable lung, the amount of opening and closing lung tissue was particularly high at lung apex and hilum and was significantly reduced, although not to a negligible amount, by the application of 15 cm H 2 O PEEP (*P, 0.05 vs. 5cmH 2 O PEEP). beginning of the study. For this purpose, the study population was divided into quartiles according to the percentage of potentially recruitable lung (5). As previously reported (5), VT and PEEP appeared to be identical between the four groups of patients (see Table E1 in the online supplement), equaling, respectively, about 9 ml/kg predicted body weight and 11 cm H 2 O. Alveolar strain appeared to be constant in the first three quartiles of potentially recruitable lung, whereas it significantly increased only in patients with a very high percentage of potentially recruitable lung (Figure 4 and Table E1, P , one-way ANOVA). In contrast, the amount of opening and closing lung tissue linearly increased from patients with a very low percentage ( g) to patients with a very high percentage of DISCUSSION During ALI/ARDS, when PEEP is increased, two different phenomena may simultaneously occur: on the one hand, the increase in pressure applied at end-expiration will determine a greater inflation of the aerated portion of the lung, leading to hyperinflation and an increase in alveolar strain; on the other hand, the increase in PEEP will prevent a greater portion of the lung from collapsing, thereby reducing the amount of lung tissue undergoing intratidal and cycling opening and closing (27, 29). We found that in patients with a lower percentage of potentially recruitable lung the application of higher levels of PEEP did not significantly affect the amount of opening and closing lung tissue, as it already equaled, at lower PEEP, a negligible fraction of lung tissue weight. In contrast, in patients with a higher percentage of potentially recruitable lung, opening and closing lung tissue was almost halved by the increase in PEEP from 5 to 15 cm H 2 O. Surprisingly, the increment of PEEP led to an identical increase in alveolar strain in the two groups of patients, despite the lower estimated FRC detected in patients with a higher percentage of potentially recruitable lung. These findings suggest a great impact of the amount of intratidal lung recruitment on the effective endinspiratory alveolar strain resulting from the ventilatory setting applied (30). In fact, in patients with a higher percentage of potentially recruitable lung, the open lung area potentially receiving VT at the beginning of inspiration (i.e., FRC) is relatively smaller. In contrast, at end-inspiration, such an area will consist of the sum of the aerated regions at the beginning of inspiration and the nonaerated lung regions that have been recruited during the tidal breath (31) (i.e., the amount of opening and closing lung tissue), which will increase the size of the initial baby lung receiving the delivered gas volume. Therefore, it is conceivable that the greater the potentially recruitable lung, the lower the actual increment of end-inspiratory alveolar strain derived from the application of specific VT and PEEP (see the online supplement for details of modeling), thereby protecting the lung parenchyma from PEEP-induced overdistention. It has been previously observed that the amount of lung tissue that remained nonaerated after the application of 45 cm H 2 O airway pressure is quite constant in the ALI/ARDS population (5) (z25% of the total lung tissue). We have therefore

6 Caironi, Cressoni, Chiumello, et al.: Lung Opening and Closing in ARDS 583 Figure 4. Alveolar strain and opening and closing lung tissue as derived from the ventilatory parameters clinically set before the beginning of the study, as well as mortality at intensive care unit (ICU) discharge in relation to the potentially recruitable lung. The study population was divided into quartiles of 17 patients each according to the percentage of the potentially recruitable lung. Alveolar strain was defined as the ratio between endinspiratory lung inflation and lung resting volume, whereas opening and closing lung tissue was computed as the difference between end-expiratory and end-inspiratory nonaerated lung tissue. For more details, see the online supplement. Alveolar strain resulting from the ventilatory setting clinically set did not differ between the four groups of patients, with the exception of a significant increase in patients with a very high percentage of potentially recruitable lung. In contrast, opening and closing lung tissue progressively and linearly increased with the increase in the percentage of the potentially recruitable lung, and was paralleled by a linear increase in mortality at ICU discharge (*P, 0.05 vs. other quartiles of potentially recruitable lung). hypothesized that the potentially recruitable lung may reflect the extent of the inflammatory reaction surrounding the initial core disease, that is, the unrecruitable or consolidated lung tissue. The regional analysis here presented may provide an important confirmation of this hypothesis. In fact, whereas in patients with a higher percentage of potentially recruitable lung the consolidated lung tissue was homogeneously distributed along the entire parenchyma, in patients with a lower percentage of potentially recruitable lung it appeared to be located mainly in the lung basal section, suggesting a lobar pattern of its distribution (32, 33). Moreover, the derecruitment observed in the latter group at the highest airway pressure applied (levels 8 10; Figure 2A), as compared with the moderate lung recruitment in patients with a higher percentage of potentially recruitable lung at similar values of superimposed pressure, may indicate different causes for the development of atelectasis in those lung regions (23, 34, 35). In fact, we may speculate that the lobar nature of the collapsed lung regions in patients with a lower percentage of potentially recruitable lung determines high values of threshold opening pressure in those lung regions, thereby leading to local alveolar compression when insufficient opening pressures are applied (even 45 cm H 2 O), as previously observed (24, 36). Taken together, these findings support the hypothesis that patients with a lower amount of potentially recruitable lung are those in whom the initial pathologic lesion remains anatomically and functionally compartmentalized. In contrast, patients with a higher percentage of potentially recruitable lung are likely those in whom a more diffuse insult affects the lung parenchyma, leading to the loss of compartmentalization, a generalized inflammation with edema formation, a greater increment of lung weight, and a greater and widespread alveolar collapse (24, 36). Moreover, these results could further suggest how the possible findings detectable both by CT scanning and chest X-ray may help to elucidate lung functional morphology of patients with ALI/ARDS. In fact, on the basis of the more frequent recurrence of a lobar pattern of lung atelectasis in patients with a lower percentage of potentially recruitable lung (as previously observed by Puybasset and colleagues [32]), it is conceivable that the visual inspection of lung imaging morphology may initially single out patients less responsive to high levels of PEEP and at a greater risk of lung hyperinflation (37). When we regionally investigated alveolar strain at the two different levels of PEEP, a similar distribution was observed between patients with either a lower or higher percentage of potentially recruitable lung. In contrast, patients with a higher percentage of potentially recruitable lung showed a greater prevalence of opening and closing lung tissue at the dependent regions of lung apex and hilum, as compared with that observed at the lung base (see Figure E5 in the online supplement). These data suggest that, as a consequence of intratidal lung opening and closing, the dependent areas of the hilar regions may represent pulmonary areas more susceptible to the injury induced by mechanical ventilation. In support of this hypothesis, CT scan analysis of lung morphology demonstrated a higher prevalence of bullae per lung in patients with late ARDS after long-term mechanical ventilation, with predominance in the dependent portion of lung hilum and base (38). Moreover, the histological analysis at autopsy of a series of patients with ARDS revealed a higher incidence of bronchopneumonia (defined as a general inflammation) in the lung segments of posterior lobes (39). Therefore, we may speculate that the intratidal lung opening and closing may create alveolar shear stresses located predominantly in the dependent portion of the lung, which may lead to pathological lesions (such as bullae and pseudocysts) that are not simply related to the development of alveolar overdistention, located predominantly in the nondependent lung regions (40). Because we have previously observed a linear increase in mortality rate at intensive care unit discharge associated with the increment of potentially recruitable lung (5), we analyzed in the study population the determinants of VILI derived from the ventilatory settings clinically used before the beginning of the study. Despite similar values of VT and PEEP, the amount of opening and closing lung tissue linearly increased with the progressive increment of potentially recruitable lung, as previously suggested by Grasso and colleagues (41). No major differences

7 584 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. BASELINE CLINICAL AND RESPIRATORY VARIABLES, VENTILATORY SETTINGS, AND LUNG MORPHOLOGICAL CHARACTERISTICS OF SURVIVORS AND NONSURVIVORS Survivors (n 5 49) Nonsurvivors (n 5 19) P Value* Age, yr SAPS II VT, ml/kg predicted body weight PEEP, cm H 2 O Plateau airway pressure, cm H 2 O x Respiratory rate, breaths/min Minute ventilation, L/min Pa O2 /FI k O Pa CO2,mmHg k Respiratory system compliance, ml/cm H 2 O k{ Dead space, % VT k ** ,0.001 Shunt, % cardiac output k Total lung tissue weight, g k 1, , Nonaerated lung tissue, % total lung weight k Potentially recruitable lung, % total lung weight Opening and closing lung tissue, g x Alveolar strain x Survival was calculated at intensive care unit discharge. Plus-minus values represent means 6 SD. * P values were obtained by Student t test or Wilcoxon test, as appropriate. Data regarding these variables, which have been previously reported (5), are presented here for completeness. The Simplified Acute Physiology Score (SAPS II) (48) was used to assess the severity of systemic illness at study entry. Scores can range from 0 to 163, with higher values indicating more severe illness. x Values of plateau airway pressure resulting from the VT clinically applied, and consequently values of opening and closing lung tissue and alveolar strain are available for 61 patients (43 survivors and 18 nonsurvivors). k Values of Pa O2 /FI O2,Pa CO2, respiratory system compliance, dead space, shunt, total lung tissue weight, and nonaerated lung tissue were obtained at 5 cm H 2 O PEEP. { Respiratory system compliance was calculated as the ratio of VT to the difference between inspiratory plateau pressure and PEEP. ** Dead space was calculated by a standard formula, as previously reported (5), and was available for 48 patients (33 survivors and 15 nonsurvivors). The intrapulmonary right-to-left shunt was calculated by a standard formula, as previously reported (5), and was available for 60 patients (42 survivors and 18 nonsurvivors). were observed regarding alveolar strain, with the exception of patients with a very high percentage of potentially recruitable lung. Moreover, opening and closing lung tissue appeared to be an independent risk factor for death. On the basis of these findings, although a greater severity of lung disease cannot be separated from lung recruitability, we may speculate that the higher mortality rate observed in patients with a higher potentially recruitable lung may be due not only to the greater severity of the underlying lung injury (as previously observed [5]), but also to the higher amount of opening and closing lung tissue caused by the ventilatory setting clinically used. Moreover, these findings support the hypothesis that these patients may really benefit from a level of PEEP greater than 10 cm H 2 O. In fact, if we estimate the balance between the increase in alveolar strain and the associated decrease in opening and closing lung tissue for each cm H 2 O increase in PEEP, two considerations become evident: first, in patients with a lower percentage of potentially recruitable lung the balance is entirely in disfavor of an increase in PEEP, as it will cause an excessive increase in alveolar strain and a negligible reduction of opening and closing lung tissue (Figure E7 in the Figure 5. Values of positive end-expiratory pressure (PEEP) clinically applied before the beginning of the study, for both survivors and nonsurvivors, as a function of different percentages of potentially recruitable lung. The study population was divided into quartiles of 17 patients each according to the percentage of potentially recruitable lung. Mortality was computed as the number of deaths at intensive care unit discharge. As shown, in the first three quartiles of potentially recruitable lung, no difference was observed between values of PEEP clinically used for either survivors or nonsurvivors. In contrast, in patients with a very high percentage of potentially recruitable lung, the PEEP clinically applied in survivors appears to be significantly greater than that applied in nonsurvivors (P, 0.05).

8 Caironi, Cressoni, Chiumello, et al.: Lung Opening and Closing in ARDS 585 online supplement); second, in patients with a higher percentage of potentially recruitable lung, the increase in PEEP will determine an extensive reduction of opening and closing lung tissue, associated with a moderate enhancement of alveolar strain. At this point, we may ask ourselves: is there any clinical evidence to confirm the critical role of opening and closing lung tissue in determining VILI and thereby affecting survival during ALI/ARDS? Although not straightforward, the answer may be considered affirmative. Villar and colleagues (42) showed in patients with ALI/ARDS ventilated with low VT and high PEEP a lower mortality rate as compared with those ventilated with a lower PEEP and a relatively higher VT. As the plateau airway pressure on Day 1 (which may be considered an indirect signal for alveolar strain) did not differ between the two groups, these results may indirectly suggest an impact of opening and closing lung tissue on the difference in survival observed. Similarly, Hager and colleagues (43), in a secondary analysis of the ARDS Network database, highlighted the critical role of VT reduction for the improvement of survival regardless of the values of plateau airway pressure derived, further suggesting a greater importance of opening and closing lung tissue in mortality as compared with the overall alveolar strain. More recently, the two concluded and published clinical trials, the ExPress (Comparison of Two Strategies for Setting Positive End-expiratory Pressure in Acute Lung Injury/Acute Respiratory Distress Syndrome) study (18) and the LOVS (Lung Open Ventilation to Decrease Mortality in the Acute Respiratory Distress Syndrome) study (17), investigating the effects of low versus high levels of PEEP, did actually demonstrate a lower progression of pulmonary damage after the application of higher PEEP (19). Finally, Talmor and colleagues (44) have observed a trend toward a lower mortality rate after the application of PEEP adjusted according to measurements of esophageal pressure, as compared with a ventilatory strategy according to the ARDS Network recommendations. In these patients, although the end-inspiratory transpulmonary pressure was similar between the two strategies, the end-expiratory transpulmonary pressure was significantly higher in those ventilated according to esophageal pressure, as compared with the control group, thereby further suggesting a possible impact of opening and closing lung tissue on survival (45, 46). Of note, in our study population, survivors with a very high percentage of potentially recruitable lung were clinically ventilated with PEEP levels significantly greater than those of patients who did not survive. In conclusion, based on the uncertainty of how much PEEP would be necessary during ALI/ARDS, the current study suggests evidence in favor of the application of high levels of PEEP, especially in patients with great lung recruitability. In fact, although in patients with a lower percentage of potentially recruitable lung the use of 15 cm H 2 O inevitably leads to an increase in alveolar strain, such a parameter (at least at the moderate levels observed in this study) does not appear to be associated with an increased risk of death. In contrast, similar levels of PEEP may cause a robust reduction of opening and closing lung tissue in patients with a higher percentage of potentially recruitable lung, possibly protecting the lung from the harmful effects of mechanical ventilation. If we consider a plateau airway pressure of about cm H 2 O as safer (43, 47), in this category of patients a PEEP value between 15 and 20 cm H 2 O is likely to reduce the amount of opening and closing lung tissue to an acceptable and markedly less harmful level. Conflict of Interest Statement: P.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.R. received $10,001 $50,000 from Eli Lilly in consultancy fees for PI Prowess Shock and $10,001 $50,000 from Maquet and $10,001 $50,000 from Hemodec for serving on an advisory board. M.Q. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.G.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The authors are indebted to Pietro Biondetti, M.D., Marco Lazzarini, M.D., Benedetta Finamore, M.D., and Cristian Bonelli, of the Dipartimento di Radiologia, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano, Milan, Italy, for technical assistance with CT scan image analyses and to Milena Racagni, M.D., Laura Landi, M.D., Alice D Adda, M.D., Serena Azzari, M.D., Sonia Terragni, M.D., Federico Polli, M.D., Paola Cozzi, M.D., Giuliana Motta, M.D., Federica Tallarini, M.D., Cristian Carsenzola, M.D., and Monica Chierichetti, M.D., of the Dipartimento di Anestesiologia, Terapia Intensiva, e Scienze Dermatologiche, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano, Università degli Studi di Milano, Milan, Italy, for help in data analysis. 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